An endocrinologist in Naples, Fla., faces multiple federal charges after police found homemade explosives and bomb-making supplies, as well as numerous illegal drugs, in his home.

Police were executing a search warrant at the home of Christy Daniel Cugini, MD, 63, on March 30 when they found the items, according to Collier County Sheriff’s Office (CCSO).

“An investigation continues and more charges could be brought,” the sheriff’s office said in a statement. As of April 1, Dr. Cugini was out on bond. His next court appearance is on April 26.

A search of his bedroom turned up marijuana, tramadol, oxycodone, and hydrocodone, the sheriff’s office said. According to nbcmiami.com, police also found 560 grams of marijuana and $20,000 in cash and jewelry in a safe.

“Some of the narcotics were in pill bottles with other people’s names on them. Many of the substances were of trafficking quantities. The search also turned up numerous items of narcotic paraphernalia, including heat seal bags, a vacuum sealer, and a scale,” the CCSO report said.

Charges against Dr. Cugini include narcotics trafficking; possession of marijuana with intent to sell/manufacture/deliver; possession of more than 20 grams of marijuana; possession of a controlled substance; and possession of narcotic paraphernalia, according to the report.

He was also charged with nine counts of making/possessing a destructive device.

The CCSO bomb squad was brought in to investigate the homemade explosive devices and supplies, including potassium nitrate and ammonium nitrate – which can be used as oxidizers – PVC pipe, and flash powders used in fireworks in Dr. Cugini’s house and garage.

Newsweek reported that the bomb squad found six red cylindrical devices about 4 inches long, according to information reported in an affidavit from Collier County Officer Jeffrey Tayar. They may have been intended to be a hand-tossed improvised explosive device, Mr. Tayar wrote.

An officer also found three other devices made up of PVC pipe attached to a small wood square. A rifle round was inserted into the PVC pipe, Mr. Tayar’s report said.

“The device could be placed on the ground in such a manner as to leave the rifle round facing up,” Mr. Tayar reportedly wrote. “If downward pressure were applied on the tip of the round ... the rifle round [would] discharge, launching the projectile portion of the round upward, presumably into the foot of the subject stepping on it.”

NBC News reported that deputies said Dr. Cugini appeared to live only with his young daughter.

He initially agreed to speak with deputies but then invoked his Miranda rights and stopped answering questions, NBC said.

Dr. Cugini’s profile has been removed from the Millennium Physician Group website.

His employer offered this statement via spokesperson Liza Fernandez: “We are shocked at the allegations regarding Dr. Christy Cugini. He has been placed on administrative leave until further notice. Millennium is committed to cooperating with law enforcement and is conducting an internal investigation.”

According to U.S. News & World Report, Dr. Cugini is affiliated with NCH Baker Hospital. He received his medical degree from Ross University School of Medicine, now located in Barbados, and has been practicing for more than 20 years.

Attempts to contact Dr. Cugini were unsuccessful.

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

An endocrinologist in Naples, Fla., faces multiple federal charges after police found homemade explosives and bomb-making supplies, as well as numerous illegal drugs, in his home.

Police were executing a search warrant at the home of Christy Daniel Cugini, MD, 63, on March 30 when they found the items, according to Collier County Sheriff’s Office (CCSO).

“An investigation continues and more charges could be brought,” the sheriff’s office said in a statement. As of April 1, Dr. Cugini was out on bond. His next court appearance is on April 26.

A search of his bedroom turned up marijuana, tramadol, oxycodone, and hydrocodone, the sheriff’s office said. According to nbcmiami.com, police also found 560 grams of marijuana and $20,000 in cash and jewelry in a safe.

“Some of the narcotics were in pill bottles with other people’s names on them. Many of the substances were of trafficking quantities. The search also turned up numerous items of narcotic paraphernalia, including heat seal bags, a vacuum sealer, and a scale,” the CCSO report said.

Charges against Dr. Cugini include narcotics trafficking; possession of marijuana with intent to sell/manufacture/deliver; possession of more than 20 grams of marijuana; possession of a controlled substance; and possession of narcotic paraphernalia, according to the report.

He was also charged with nine counts of making/possessing a destructive device.

The CCSO bomb squad was brought in to investigate the homemade explosive devices and supplies, including potassium nitrate and ammonium nitrate – which can be used as oxidizers – PVC pipe, and flash powders used in fireworks in Dr. Cugini’s house and garage.

Newsweek reported that the bomb squad found six red cylindrical devices about 4 inches long, according to information reported in an affidavit from Collier County Officer Jeffrey Tayar. They may have been intended to be a hand-tossed improvised explosive device, Mr. Tayar wrote.

An officer also found three other devices made up of PVC pipe attached to a small wood square. A rifle round was inserted into the PVC pipe, Mr. Tayar’s report said.

“The device could be placed on the ground in such a manner as to leave the rifle round facing up,” Mr. Tayar reportedly wrote. “If downward pressure were applied on the tip of the round ... the rifle round [would] discharge, launching the projectile portion of the round upward, presumably into the foot of the subject stepping on it.”

NBC News reported that deputies said Dr. Cugini appeared to live only with his young daughter.

He initially agreed to speak with deputies but then invoked his Miranda rights and stopped answering questions, NBC said.

Dr. Cugini’s profile has been removed from the Millennium Physician Group website.

His employer offered this statement via spokesperson Liza Fernandez: “We are shocked at the allegations regarding Dr. Christy Cugini. He has been placed on administrative leave until further notice. Millennium is committed to cooperating with law enforcement and is conducting an internal investigation.”

According to U.S. News & World Report, Dr. Cugini is affiliated with NCH Baker Hospital. He received his medical degree from Ross University School of Medicine, now located in Barbados, and has been practicing for more than 20 years.

Attempts to contact Dr. Cugini were unsuccessful.

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

An endocrinologist in Naples, Fla., faces multiple federal charges after police found homemade explosives and bomb-making supplies, as well as numerous illegal drugs, in his home.

Police were executing a search warrant at the home of Christy Daniel Cugini, MD, 63, on March 30 when they found the items, according to Collier County Sheriff’s Office (CCSO).

“An investigation continues and more charges could be brought,” the sheriff’s office said in a statement. As of April 1, Dr. Cugini was out on bond. His next court appearance is on April 26.

A search of his bedroom turned up marijuana, tramadol, oxycodone, and hydrocodone, the sheriff’s office said. According to nbcmiami.com, police also found 560 grams of marijuana and $20,000 in cash and jewelry in a safe.

“Some of the narcotics were in pill bottles with other people’s names on them. Many of the substances were of trafficking quantities. The search also turned up numerous items of narcotic paraphernalia, including heat seal bags, a vacuum sealer, and a scale,” the CCSO report said.

Charges against Dr. Cugini include narcotics trafficking; possession of marijuana with intent to sell/manufacture/deliver; possession of more than 20 grams of marijuana; possession of a controlled substance; and possession of narcotic paraphernalia, according to the report.

He was also charged with nine counts of making/possessing a destructive device.

The CCSO bomb squad was brought in to investigate the homemade explosive devices and supplies, including potassium nitrate and ammonium nitrate – which can be used as oxidizers – PVC pipe, and flash powders used in fireworks in Dr. Cugini’s house and garage.

Newsweek reported that the bomb squad found six red cylindrical devices about 4 inches long, according to information reported in an affidavit from Collier County Officer Jeffrey Tayar. They may have been intended to be a hand-tossed improvised explosive device, Mr. Tayar wrote.

An officer also found three other devices made up of PVC pipe attached to a small wood square. A rifle round was inserted into the PVC pipe, Mr. Tayar’s report said.

“The device could be placed on the ground in such a manner as to leave the rifle round facing up,” Mr. Tayar reportedly wrote. “If downward pressure were applied on the tip of the round ... the rifle round [would] discharge, launching the projectile portion of the round upward, presumably into the foot of the subject stepping on it.”

NBC News reported that deputies said Dr. Cugini appeared to live only with his young daughter.

He initially agreed to speak with deputies but then invoked his Miranda rights and stopped answering questions, NBC said.

Dr. Cugini’s profile has been removed from the Millennium Physician Group website.

His employer offered this statement via spokesperson Liza Fernandez: “We are shocked at the allegations regarding Dr. Christy Cugini. He has been placed on administrative leave until further notice. Millennium is committed to cooperating with law enforcement and is conducting an internal investigation.”

According to U.S. News & World Report, Dr. Cugini is affiliated with NCH Baker Hospital. He received his medical degree from Ross University School of Medicine, now located in Barbados, and has been practicing for more than 20 years.

Attempts to contact Dr. Cugini were unsuccessful.

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

Patients with migraine experienced about a 60% reduction in pain intensity and number of headache days per month after exposure to green light therapy, according to results of a small study from the University of Arizona, Tucson.

“This is the first clinical study to evaluate green light exposure as a potential preventive therapy for patients with migraine, “ senior author Mohab M. Ibrahim, MD, PhD, said in a press release. “Now I have another tool in my toolbox to treat one of the most difficult neurologic conditions – migraine.”

“Given the safety, affordability, and efficacy of green light exposure, there is merit to conduct a larger study,” he and coauthors from the university wrote in their paper.

The study included 29 adult patients (average age 52.2 years), 22 with chronic migraine and the rest with episodic migraine who were recruited from the University of Arizona/Banner Medical Center chronic pain clinic. To be included, patients had to meet the International Headache Society diagnostic criteria for chronic or episodic migraine, have an average headache pain intensity of 5 out of 10 or greater on the numeric pain scale (NPS) over the 10 weeks prior to enrolling in the study, and be dissatisfied with their current migraine therapy.

The patients were free to start, continue, or discontinue any other migraine treatments as recommended by their physicians as long as this was reported to the study team.
 

White versus green

The one-way crossover design involved exposure to 10 weeks of white light emitting diodes, for 1-2 hours per day, followed by a 2-week washout period and then 10 weeks’ exposure to green light emitting diodes (GLED) for the same daily duration. The protocol involved use of a light strip emitting an intensity of between 4 and 100 lux measured at approximately 2 m and 1 m from a lux meter.

Patients were instructed to use the light in a dark room, without falling asleep, and to participate in activities that did not require external light sources, such as listening to music, reading books, doing exercises, or engaging in similar activities. The daily minimum exposure of 1 hour, up to a maximum of 2 hours, was to be completed in one sitting.

The primary outcome measure was the number of headache days per month, defined as days with moderate to severe headache pain for at least 4 hours. Secondary outcomes included perceived reduction in duration and intensity of the headache phase of the migraine episodes assessed every 2 weeks with the NPS, improved ability to fall and stay asleep, improved ability to perform work and daily activity, improved quality of life, and reduction of pain medications.

The researchers found that when the patients with chronic migraine and episodic migraine were examined as separate groups, white light exposure did not significantly reduce the number of headache days per month, but when the chronic migraine and episodic migraine groups were combined there was a significant reduction from 18.2 to 16.5 headache days per month.

On the other hand, green light did result in significantly reduced headache days both in the separate (from 7.9 to 2.4 days in the episodic migraine group and 22.3 to 9.4 days in the chronic migraine group) and combined groups (from 18.4 to 7.4 days).

“While some improvement in secondary outcomes was observed with white light emitting diodes, more secondary outcomes with significantly greater magnitude including assessments of quality of life, Short-Form McGill Pain Questionnaire, Headache Impact Test-6, and Five-level version of the EuroQol five-dimensional survey without reported side effects were observed with green light emitting diodes,” the authors reported.

“The use of a nonpharmacological therapy such as green light can be of tremendous help to a variety of patients that either do not want to be on medications or do not respond to them,” coauthor Amol M. Patwardhan, MD, PhD, said in the press release. “The beauty of this approach is the lack of associated side effects. If at all, it appears to improve sleep and other quality of life measures,” said Dr. Patwardhan, associate professor and vice chair of research in the University of Arizona’s department of anesthesiology.
 

Better than white light

Asked to comment on the findings, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said research has shown for some time that exposure to green light has beneficial effects in migraine patients. This study, although small, does indicate that green light is more beneficial than is white light and reduces headache days and intensity. “I believe patients would be willing to spend 1-2 hours a day in green light to reduce and improve their migraine with few side effects. A larger randomized trial should be done,” he said.

The study was funded by support from the National Center for Complementary and Integrative Health (to Dr. Ibrahim), the Comprehensive Chronic Pain and Addiction Center–University of Arizona, and the University of Arizona CHiLLI initiative. Dr. Ibrahim and one coauthor have a patent pending through the University of Arizona for use of green light therapy for the management of chronic pain. Dr. Rapoport is a former president of the International Headache Society. He is an editor of Headache and CNS Drugs, and Editor-in-Chief of Neurology Reviews. He reviews for many peer-reviewed journals such as Cephalalgia, Neurology, New England Journal of Medicine, and Headache.

Patients with migraine experienced about a 60% reduction in pain intensity and number of headache days per month after exposure to green light therapy, according to results of a small study from the University of Arizona, Tucson.

“This is the first clinical study to evaluate green light exposure as a potential preventive therapy for patients with migraine, “ senior author Mohab M. Ibrahim, MD, PhD, said in a press release. “Now I have another tool in my toolbox to treat one of the most difficult neurologic conditions – migraine.”

“Given the safety, affordability, and efficacy of green light exposure, there is merit to conduct a larger study,” he and coauthors from the university wrote in their paper.

The study included 29 adult patients (average age 52.2 years), 22 with chronic migraine and the rest with episodic migraine who were recruited from the University of Arizona/Banner Medical Center chronic pain clinic. To be included, patients had to meet the International Headache Society diagnostic criteria for chronic or episodic migraine, have an average headache pain intensity of 5 out of 10 or greater on the numeric pain scale (NPS) over the 10 weeks prior to enrolling in the study, and be dissatisfied with their current migraine therapy.

The patients were free to start, continue, or discontinue any other migraine treatments as recommended by their physicians as long as this was reported to the study team.
 

White versus green

The one-way crossover design involved exposure to 10 weeks of white light emitting diodes, for 1-2 hours per day, followed by a 2-week washout period and then 10 weeks’ exposure to green light emitting diodes (GLED) for the same daily duration. The protocol involved use of a light strip emitting an intensity of between 4 and 100 lux measured at approximately 2 m and 1 m from a lux meter.

Patients were instructed to use the light in a dark room, without falling asleep, and to participate in activities that did not require external light sources, such as listening to music, reading books, doing exercises, or engaging in similar activities. The daily minimum exposure of 1 hour, up to a maximum of 2 hours, was to be completed in one sitting.

The primary outcome measure was the number of headache days per month, defined as days with moderate to severe headache pain for at least 4 hours. Secondary outcomes included perceived reduction in duration and intensity of the headache phase of the migraine episodes assessed every 2 weeks with the NPS, improved ability to fall and stay asleep, improved ability to perform work and daily activity, improved quality of life, and reduction of pain medications.

The researchers found that when the patients with chronic migraine and episodic migraine were examined as separate groups, white light exposure did not significantly reduce the number of headache days per month, but when the chronic migraine and episodic migraine groups were combined there was a significant reduction from 18.2 to 16.5 headache days per month.

On the other hand, green light did result in significantly reduced headache days both in the separate (from 7.9 to 2.4 days in the episodic migraine group and 22.3 to 9.4 days in the chronic migraine group) and combined groups (from 18.4 to 7.4 days).

“While some improvement in secondary outcomes was observed with white light emitting diodes, more secondary outcomes with significantly greater magnitude including assessments of quality of life, Short-Form McGill Pain Questionnaire, Headache Impact Test-6, and Five-level version of the EuroQol five-dimensional survey without reported side effects were observed with green light emitting diodes,” the authors reported.

“The use of a nonpharmacological therapy such as green light can be of tremendous help to a variety of patients that either do not want to be on medications or do not respond to them,” coauthor Amol M. Patwardhan, MD, PhD, said in the press release. “The beauty of this approach is the lack of associated side effects. If at all, it appears to improve sleep and other quality of life measures,” said Dr. Patwardhan, associate professor and vice chair of research in the University of Arizona’s department of anesthesiology.
 

Better than white light

Asked to comment on the findings, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said research has shown for some time that exposure to green light has beneficial effects in migraine patients. This study, although small, does indicate that green light is more beneficial than is white light and reduces headache days and intensity. “I believe patients would be willing to spend 1-2 hours a day in green light to reduce and improve their migraine with few side effects. A larger randomized trial should be done,” he said.

The study was funded by support from the National Center for Complementary and Integrative Health (to Dr. Ibrahim), the Comprehensive Chronic Pain and Addiction Center–University of Arizona, and the University of Arizona CHiLLI initiative. Dr. Ibrahim and one coauthor have a patent pending through the University of Arizona for use of green light therapy for the management of chronic pain. Dr. Rapoport is a former president of the International Headache Society. He is an editor of Headache and CNS Drugs, and Editor-in-Chief of Neurology Reviews. He reviews for many peer-reviewed journals such as Cephalalgia, Neurology, New England Journal of Medicine, and Headache.

Patients with migraine experienced about a 60% reduction in pain intensity and number of headache days per month after exposure to green light therapy, according to results of a small study from the University of Arizona, Tucson.

“This is the first clinical study to evaluate green light exposure as a potential preventive therapy for patients with migraine, “ senior author Mohab M. Ibrahim, MD, PhD, said in a press release. “Now I have another tool in my toolbox to treat one of the most difficult neurologic conditions – migraine.”

“Given the safety, affordability, and efficacy of green light exposure, there is merit to conduct a larger study,” he and coauthors from the university wrote in their paper.

The study included 29 adult patients (average age 52.2 years), 22 with chronic migraine and the rest with episodic migraine who were recruited from the University of Arizona/Banner Medical Center chronic pain clinic. To be included, patients had to meet the International Headache Society diagnostic criteria for chronic or episodic migraine, have an average headache pain intensity of 5 out of 10 or greater on the numeric pain scale (NPS) over the 10 weeks prior to enrolling in the study, and be dissatisfied with their current migraine therapy.

The patients were free to start, continue, or discontinue any other migraine treatments as recommended by their physicians as long as this was reported to the study team.
 

White versus green

The one-way crossover design involved exposure to 10 weeks of white light emitting diodes, for 1-2 hours per day, followed by a 2-week washout period and then 10 weeks’ exposure to green light emitting diodes (GLED) for the same daily duration. The protocol involved use of a light strip emitting an intensity of between 4 and 100 lux measured at approximately 2 m and 1 m from a lux meter.

Patients were instructed to use the light in a dark room, without falling asleep, and to participate in activities that did not require external light sources, such as listening to music, reading books, doing exercises, or engaging in similar activities. The daily minimum exposure of 1 hour, up to a maximum of 2 hours, was to be completed in one sitting.

The primary outcome measure was the number of headache days per month, defined as days with moderate to severe headache pain for at least 4 hours. Secondary outcomes included perceived reduction in duration and intensity of the headache phase of the migraine episodes assessed every 2 weeks with the NPS, improved ability to fall and stay asleep, improved ability to perform work and daily activity, improved quality of life, and reduction of pain medications.

The researchers found that when the patients with chronic migraine and episodic migraine were examined as separate groups, white light exposure did not significantly reduce the number of headache days per month, but when the chronic migraine and episodic migraine groups were combined there was a significant reduction from 18.2 to 16.5 headache days per month.

On the other hand, green light did result in significantly reduced headache days both in the separate (from 7.9 to 2.4 days in the episodic migraine group and 22.3 to 9.4 days in the chronic migraine group) and combined groups (from 18.4 to 7.4 days).

“While some improvement in secondary outcomes was observed with white light emitting diodes, more secondary outcomes with significantly greater magnitude including assessments of quality of life, Short-Form McGill Pain Questionnaire, Headache Impact Test-6, and Five-level version of the EuroQol five-dimensional survey without reported side effects were observed with green light emitting diodes,” the authors reported.

“The use of a nonpharmacological therapy such as green light can be of tremendous help to a variety of patients that either do not want to be on medications or do not respond to them,” coauthor Amol M. Patwardhan, MD, PhD, said in the press release. “The beauty of this approach is the lack of associated side effects. If at all, it appears to improve sleep and other quality of life measures,” said Dr. Patwardhan, associate professor and vice chair of research in the University of Arizona’s department of anesthesiology.
 

Better than white light

Asked to comment on the findings, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said research has shown for some time that exposure to green light has beneficial effects in migraine patients. This study, although small, does indicate that green light is more beneficial than is white light and reduces headache days and intensity. “I believe patients would be willing to spend 1-2 hours a day in green light to reduce and improve their migraine with few side effects. A larger randomized trial should be done,” he said.

The study was funded by support from the National Center for Complementary and Integrative Health (to Dr. Ibrahim), the Comprehensive Chronic Pain and Addiction Center–University of Arizona, and the University of Arizona CHiLLI initiative. Dr. Ibrahim and one coauthor have a patent pending through the University of Arizona for use of green light therapy for the management of chronic pain. Dr. Rapoport is a former president of the International Headache Society. He is an editor of Headache and CNS Drugs, and Editor-in-Chief of Neurology Reviews. He reviews for many peer-reviewed journals such as Cephalalgia, Neurology, New England Journal of Medicine, and Headache.

Has anyone else noticed how slow it has been on your pediatric floors? Well, you are not alone.

The COVID pandemic has had a significant impact on health care volumes, with pediatric volumes decreasing across the nation. A Children’s Hospital Association CEO survey, currently unpublished, noted a 10%-20% decline in inpatient admissions and a 30%-50% decline in pediatric ED visits this past year. Even our usual respiratory surge has been disrupted. The rate of influenza tracked by the CDC is around 1%, compared with the usual seasonal flu baseline national rate of 2.6%. These COVID-related declines have occurred amidst the backdrop of already-decreasing inpatient admissions because of the great work of the pediatric hospital medicine (PHM) community in reducing unnecessary admissions and lengths of stay.

For many hospitals, several factors related to the pandemic have raised significant financial concerns. According to Becker Hospital Review, as of August 2020 over 500 hospitals had furloughed workers. While 26 of those hospitals had brought back workers by December 2020, many did not. Similar financial concerns were noted in a Kaufmann Hall report from January 2021, which showed a median drop of 55% in operating margins. The CARES Act helped reduce some of the detrimental impact on operating margins, but it did not diminish the added burden of personal protective equipment expenses, longer length of stay for COVID patients, and a reimbursement shift to more government payors and uninsured caused by pandemic-forced job losses.

COVID’s impact specific to pediatric hospital medicine has been substantial. A recent unpublished survey by the PHM Economics Research Collaborative (PERC) demonstrated how COVID has affected pediatric hospital medicine programs. Forty-five unique PHM programs from over 21 states responded, with 98% reporting a decrease in pediatric inpatient admissions as well as ED visits. About 11% reported temporary unit closures, while 51% of all programs reported staffing restrictions ranging from hiring freezes to downsizing the number of hospitalists in the group. Salaries decreased in 26% of reporting programs, and 20%-56% described reduced benefits, ranging from less CME/vacation time and stipends to retirement benefits. The three most frequent benefit losses included annual salary increases, educational stipends, and bonuses.

Community hospitals felt the palpable, financial strain of decreasing pediatric admissions well before the pandemic. Hospitals like MedStar Franklin Square Hospital in Baltimore and Harrington Hospital in Southbridge, Mass., had decided to close their pediatrics units before COVID hit. In a 2014 unpublished survey of 349 community PHM (CPHM) programs, 57% of respondents felt that finances and justification for a pediatric program were primary concerns.

Responding to financial stressors is not a novel challenge for CPHM programs. To keep these vital pediatric programs in place despite lower inpatient volumes, those of us in CPHM have learned many lessons over the years on how to adapt. Such adaptations have included diversification in procedures and multifloor coverage in the hospital. Voiding cystourethrogram catheterizations and circumcisions are now more commonly performed by CPHM providers, who may also cover multiple areas of the hospital, including the ED, NICU, and well-newborn nursery. Comanagement of subspecialty or surgical patients is yet another example of such diversification.

Furthermore, the PERC survey showed that some PHM programs temporarily covered pediatric ICUs and step-down units and began doing ED and urgent care coverage as primary providers Most programs reported no change in newborn visits while 16% reported an increase in newborn volume and 14% reported a decrease in newborn volume. My own health system was one of the groups that had an increase in newborn volume. This was caused by community pediatricians who had stopped coming in to see their own newborns. This coverage adjustment has yet to return to baseline and will likely become permanent.

There was a 11% increase from prepandemic baselines (from 9% to 20%) in programs doing telemedicine. Most respondents stated that they will continue to offer telemedicine with an additional 25% of programs considering starting. There was also a slight increase during the pandemic of coverage of mental health units (from 11% to 13%), which may have led 11% of respondents to consider the addition of this service. The survey also noted that about 28% of PHM programs performed circumcisions, frenectomies, and sedation prepandemic, and 14%-18% are considering adding these services.

Overall, the financial stressors are improving, but our need to adapt in PHM is more pressing than ever. The pandemic has given us the push for evolution and some opportunities that did not exist before. One is the use of telemedicine to expand our subspecialty support to community hospitals, as well as to children’s hospitals in areas where subspecialists are in short supply. These telemedicine consults are being reimbursed for the first time, which allows more access to these services.

With the pandemic, many hospitals are moving to single room occupancy models. Construction to add more beds is costly, and unnecessary if we can utilize community hospitals to keep appropriate patients in their home communities. The opportunity to partner with community hospital programs to provide telemedicine support should not be overlooked. This is also an opportunity for academic referral centers to have more open beds for critical care and highly specialized patients.

Another opportunity is to expand scope by changing age limits, as 18% of respondents to the PERC survey reported that they had started to care for adults since the pandemic. The Pediatric Overflow Planning Contingency Response Network (POPCoRN) has been a valuable resource for education on caring for adults, guidance on which patient populations are appropriate, and the resources needed to do this. While caring for older adults, even in their 90s, was a pandemic-related phenomenon, there is an opportunity to see if the age limit we care for should be raised to 21, or even 25, as some CPHM programs had been doing prepandemic.

Along with the expansion of age limits, there are many other areas of opportunity highlighted within the PERC survey. These include expanding coverage within pediatric ICUs, EDs, and urgent care areas, along with coverage of well newborns that were previously covered by community pediatricians. Also, the increase of mental health admissions is another area where PHM programs might expand their services.

While I hope the financial stressors improve, hope is not a plan and therefore we need to think and prepare for what the post-COVID future may look like. Some have predicted a rebound pediatric respiratory surge next year as the masks come off and children return to in-person learning and daycare. This may be true, but we would be foolish not to use lessons from the pandemic as well as the past to consider options in our toolkit to become more financially stable. POPCoRN, as well as the American Academy of Pediatrics’ listserv and subcommittees, have been a source of collaboration and shared knowledge during a time when we have needed to quickly respond to ever-changing information. These networks and information sharing should be leveraged once the dust settles for us to prepare for future challenges.

New innovations may arise as we look at how we address the growing need for mental health services and incorporate new procedures, like point of care ultrasound. As Charles Darwin said: “It is not the strongest of the species that survives nor the most intelligent that survives. It is the one that is most adaptable to change.” It is time for us to evolve.
 

Dr. Dias is a clinical associate professor of pediatrics at Yale University, New Haven, Conn., in the division of pediatric hospital medicine. She has practiced community pediatric hospital medicine for over 21 years in New Jersey, Pennsylvania, and Connecticut. She is the chair of the Education Working Group for the AAP’s section on hospital medicine’s subcommittee on community hospitalists as well as the cochair of the Community Hospital Operations Group of the POPCoRN network.

Has anyone else noticed how slow it has been on your pediatric floors? Well, you are not alone.

The COVID pandemic has had a significant impact on health care volumes, with pediatric volumes decreasing across the nation. A Children’s Hospital Association CEO survey, currently unpublished, noted a 10%-20% decline in inpatient admissions and a 30%-50% decline in pediatric ED visits this past year. Even our usual respiratory surge has been disrupted. The rate of influenza tracked by the CDC is around 1%, compared with the usual seasonal flu baseline national rate of 2.6%. These COVID-related declines have occurred amidst the backdrop of already-decreasing inpatient admissions because of the great work of the pediatric hospital medicine (PHM) community in reducing unnecessary admissions and lengths of stay.

For many hospitals, several factors related to the pandemic have raised significant financial concerns. According to Becker Hospital Review, as of August 2020 over 500 hospitals had furloughed workers. While 26 of those hospitals had brought back workers by December 2020, many did not. Similar financial concerns were noted in a Kaufmann Hall report from January 2021, which showed a median drop of 55% in operating margins. The CARES Act helped reduce some of the detrimental impact on operating margins, but it did not diminish the added burden of personal protective equipment expenses, longer length of stay for COVID patients, and a reimbursement shift to more government payors and uninsured caused by pandemic-forced job losses.

COVID’s impact specific to pediatric hospital medicine has been substantial. A recent unpublished survey by the PHM Economics Research Collaborative (PERC) demonstrated how COVID has affected pediatric hospital medicine programs. Forty-five unique PHM programs from over 21 states responded, with 98% reporting a decrease in pediatric inpatient admissions as well as ED visits. About 11% reported temporary unit closures, while 51% of all programs reported staffing restrictions ranging from hiring freezes to downsizing the number of hospitalists in the group. Salaries decreased in 26% of reporting programs, and 20%-56% described reduced benefits, ranging from less CME/vacation time and stipends to retirement benefits. The three most frequent benefit losses included annual salary increases, educational stipends, and bonuses.

Community hospitals felt the palpable, financial strain of decreasing pediatric admissions well before the pandemic. Hospitals like MedStar Franklin Square Hospital in Baltimore and Harrington Hospital in Southbridge, Mass., had decided to close their pediatrics units before COVID hit. In a 2014 unpublished survey of 349 community PHM (CPHM) programs, 57% of respondents felt that finances and justification for a pediatric program were primary concerns.

Responding to financial stressors is not a novel challenge for CPHM programs. To keep these vital pediatric programs in place despite lower inpatient volumes, those of us in CPHM have learned many lessons over the years on how to adapt. Such adaptations have included diversification in procedures and multifloor coverage in the hospital. Voiding cystourethrogram catheterizations and circumcisions are now more commonly performed by CPHM providers, who may also cover multiple areas of the hospital, including the ED, NICU, and well-newborn nursery. Comanagement of subspecialty or surgical patients is yet another example of such diversification.

Furthermore, the PERC survey showed that some PHM programs temporarily covered pediatric ICUs and step-down units and began doing ED and urgent care coverage as primary providers Most programs reported no change in newborn visits while 16% reported an increase in newborn volume and 14% reported a decrease in newborn volume. My own health system was one of the groups that had an increase in newborn volume. This was caused by community pediatricians who had stopped coming in to see their own newborns. This coverage adjustment has yet to return to baseline and will likely become permanent.

There was a 11% increase from prepandemic baselines (from 9% to 20%) in programs doing telemedicine. Most respondents stated that they will continue to offer telemedicine with an additional 25% of programs considering starting. There was also a slight increase during the pandemic of coverage of mental health units (from 11% to 13%), which may have led 11% of respondents to consider the addition of this service. The survey also noted that about 28% of PHM programs performed circumcisions, frenectomies, and sedation prepandemic, and 14%-18% are considering adding these services.

Overall, the financial stressors are improving, but our need to adapt in PHM is more pressing than ever. The pandemic has given us the push for evolution and some opportunities that did not exist before. One is the use of telemedicine to expand our subspecialty support to community hospitals, as well as to children’s hospitals in areas where subspecialists are in short supply. These telemedicine consults are being reimbursed for the first time, which allows more access to these services.

With the pandemic, many hospitals are moving to single room occupancy models. Construction to add more beds is costly, and unnecessary if we can utilize community hospitals to keep appropriate patients in their home communities. The opportunity to partner with community hospital programs to provide telemedicine support should not be overlooked. This is also an opportunity for academic referral centers to have more open beds for critical care and highly specialized patients.

Another opportunity is to expand scope by changing age limits, as 18% of respondents to the PERC survey reported that they had started to care for adults since the pandemic. The Pediatric Overflow Planning Contingency Response Network (POPCoRN) has been a valuable resource for education on caring for adults, guidance on which patient populations are appropriate, and the resources needed to do this. While caring for older adults, even in their 90s, was a pandemic-related phenomenon, there is an opportunity to see if the age limit we care for should be raised to 21, or even 25, as some CPHM programs had been doing prepandemic.

Along with the expansion of age limits, there are many other areas of opportunity highlighted within the PERC survey. These include expanding coverage within pediatric ICUs, EDs, and urgent care areas, along with coverage of well newborns that were previously covered by community pediatricians. Also, the increase of mental health admissions is another area where PHM programs might expand their services.

While I hope the financial stressors improve, hope is not a plan and therefore we need to think and prepare for what the post-COVID future may look like. Some have predicted a rebound pediatric respiratory surge next year as the masks come off and children return to in-person learning and daycare. This may be true, but we would be foolish not to use lessons from the pandemic as well as the past to consider options in our toolkit to become more financially stable. POPCoRN, as well as the American Academy of Pediatrics’ listserv and subcommittees, have been a source of collaboration and shared knowledge during a time when we have needed to quickly respond to ever-changing information. These networks and information sharing should be leveraged once the dust settles for us to prepare for future challenges.

New innovations may arise as we look at how we address the growing need for mental health services and incorporate new procedures, like point of care ultrasound. As Charles Darwin said: “It is not the strongest of the species that survives nor the most intelligent that survives. It is the one that is most adaptable to change.” It is time for us to evolve.
 

Dr. Dias is a clinical associate professor of pediatrics at Yale University, New Haven, Conn., in the division of pediatric hospital medicine. She has practiced community pediatric hospital medicine for over 21 years in New Jersey, Pennsylvania, and Connecticut. She is the chair of the Education Working Group for the AAP’s section on hospital medicine’s subcommittee on community hospitalists as well as the cochair of the Community Hospital Operations Group of the POPCoRN network.

Has anyone else noticed how slow it has been on your pediatric floors? Well, you are not alone.

The COVID pandemic has had a significant impact on health care volumes, with pediatric volumes decreasing across the nation. A Children’s Hospital Association CEO survey, currently unpublished, noted a 10%-20% decline in inpatient admissions and a 30%-50% decline in pediatric ED visits this past year. Even our usual respiratory surge has been disrupted. The rate of influenza tracked by the CDC is around 1%, compared with the usual seasonal flu baseline national rate of 2.6%. These COVID-related declines have occurred amidst the backdrop of already-decreasing inpatient admissions because of the great work of the pediatric hospital medicine (PHM) community in reducing unnecessary admissions and lengths of stay.

For many hospitals, several factors related to the pandemic have raised significant financial concerns. According to Becker Hospital Review, as of August 2020 over 500 hospitals had furloughed workers. While 26 of those hospitals had brought back workers by December 2020, many did not. Similar financial concerns were noted in a Kaufmann Hall report from January 2021, which showed a median drop of 55% in operating margins. The CARES Act helped reduce some of the detrimental impact on operating margins, but it did not diminish the added burden of personal protective equipment expenses, longer length of stay for COVID patients, and a reimbursement shift to more government payors and uninsured caused by pandemic-forced job losses.

COVID’s impact specific to pediatric hospital medicine has been substantial. A recent unpublished survey by the PHM Economics Research Collaborative (PERC) demonstrated how COVID has affected pediatric hospital medicine programs. Forty-five unique PHM programs from over 21 states responded, with 98% reporting a decrease in pediatric inpatient admissions as well as ED visits. About 11% reported temporary unit closures, while 51% of all programs reported staffing restrictions ranging from hiring freezes to downsizing the number of hospitalists in the group. Salaries decreased in 26% of reporting programs, and 20%-56% described reduced benefits, ranging from less CME/vacation time and stipends to retirement benefits. The three most frequent benefit losses included annual salary increases, educational stipends, and bonuses.

Community hospitals felt the palpable, financial strain of decreasing pediatric admissions well before the pandemic. Hospitals like MedStar Franklin Square Hospital in Baltimore and Harrington Hospital in Southbridge, Mass., had decided to close their pediatrics units before COVID hit. In a 2014 unpublished survey of 349 community PHM (CPHM) programs, 57% of respondents felt that finances and justification for a pediatric program were primary concerns.

Responding to financial stressors is not a novel challenge for CPHM programs. To keep these vital pediatric programs in place despite lower inpatient volumes, those of us in CPHM have learned many lessons over the years on how to adapt. Such adaptations have included diversification in procedures and multifloor coverage in the hospital. Voiding cystourethrogram catheterizations and circumcisions are now more commonly performed by CPHM providers, who may also cover multiple areas of the hospital, including the ED, NICU, and well-newborn nursery. Comanagement of subspecialty or surgical patients is yet another example of such diversification.

Furthermore, the PERC survey showed that some PHM programs temporarily covered pediatric ICUs and step-down units and began doing ED and urgent care coverage as primary providers Most programs reported no change in newborn visits while 16% reported an increase in newborn volume and 14% reported a decrease in newborn volume. My own health system was one of the groups that had an increase in newborn volume. This was caused by community pediatricians who had stopped coming in to see their own newborns. This coverage adjustment has yet to return to baseline and will likely become permanent.

There was a 11% increase from prepandemic baselines (from 9% to 20%) in programs doing telemedicine. Most respondents stated that they will continue to offer telemedicine with an additional 25% of programs considering starting. There was also a slight increase during the pandemic of coverage of mental health units (from 11% to 13%), which may have led 11% of respondents to consider the addition of this service. The survey also noted that about 28% of PHM programs performed circumcisions, frenectomies, and sedation prepandemic, and 14%-18% are considering adding these services.

Overall, the financial stressors are improving, but our need to adapt in PHM is more pressing than ever. The pandemic has given us the push for evolution and some opportunities that did not exist before. One is the use of telemedicine to expand our subspecialty support to community hospitals, as well as to children’s hospitals in areas where subspecialists are in short supply. These telemedicine consults are being reimbursed for the first time, which allows more access to these services.

With the pandemic, many hospitals are moving to single room occupancy models. Construction to add more beds is costly, and unnecessary if we can utilize community hospitals to keep appropriate patients in their home communities. The opportunity to partner with community hospital programs to provide telemedicine support should not be overlooked. This is also an opportunity for academic referral centers to have more open beds for critical care and highly specialized patients.

Another opportunity is to expand scope by changing age limits, as 18% of respondents to the PERC survey reported that they had started to care for adults since the pandemic. The Pediatric Overflow Planning Contingency Response Network (POPCoRN) has been a valuable resource for education on caring for adults, guidance on which patient populations are appropriate, and the resources needed to do this. While caring for older adults, even in their 90s, was a pandemic-related phenomenon, there is an opportunity to see if the age limit we care for should be raised to 21, or even 25, as some CPHM programs had been doing prepandemic.

Along with the expansion of age limits, there are many other areas of opportunity highlighted within the PERC survey. These include expanding coverage within pediatric ICUs, EDs, and urgent care areas, along with coverage of well newborns that were previously covered by community pediatricians. Also, the increase of mental health admissions is another area where PHM programs might expand their services.

While I hope the financial stressors improve, hope is not a plan and therefore we need to think and prepare for what the post-COVID future may look like. Some have predicted a rebound pediatric respiratory surge next year as the masks come off and children return to in-person learning and daycare. This may be true, but we would be foolish not to use lessons from the pandemic as well as the past to consider options in our toolkit to become more financially stable. POPCoRN, as well as the American Academy of Pediatrics’ listserv and subcommittees, have been a source of collaboration and shared knowledge during a time when we have needed to quickly respond to ever-changing information. These networks and information sharing should be leveraged once the dust settles for us to prepare for future challenges.

New innovations may arise as we look at how we address the growing need for mental health services and incorporate new procedures, like point of care ultrasound. As Charles Darwin said: “It is not the strongest of the species that survives nor the most intelligent that survives. It is the one that is most adaptable to change.” It is time for us to evolve.
 

Dr. Dias is a clinical associate professor of pediatrics at Yale University, New Haven, Conn., in the division of pediatric hospital medicine. She has practiced community pediatric hospital medicine for over 21 years in New Jersey, Pennsylvania, and Connecticut. She is the chair of the Education Working Group for the AAP’s section on hospital medicine’s subcommittee on community hospitalists as well as the cochair of the Community Hospital Operations Group of the POPCoRN network.

COVID-19 increases the risk of developing erectile dysfunction (ED) by nearly sixfold, according to data from the first study to investigate the association between ED and COVID-19 in young men in a real-life setting.

The preliminary data also indicated that ED is a marker of increased susceptibility to SARS-CoV-2 infection. Men with ED are more than five times more likely to have COVID-19 (odds ratio, 5.27).

For men with a history of COVID-19, the odds ratio of developing ED was 5.66. The strength of the association remained after adjusting for factors considered to affect ED.

The study, which was led by Emmanuele A. Jannini, MD, professor of endocrinology and medical sexology, University of Rome Tor Vergata, was published on March 20 in Andrology.
 

‘Mask up to keep it up’

ED can be both a short-term and a long-term complication of COVID-19, Dr. Jannini suggests.

“When offered, men should have the COVID vaccination. It also gives a whole new meaning to wearing the mask – mask up to keep it up,” he said. “It could possibly have the added benefit of preventing sexual dysfunction.”

He points out that older age, diabetes, high body mass index, and smoking increase the risk of contracting COVID-19.

“These are the same as risk factors for ED. Results of our study agree with the pathophysiological mechanisms linking ED, endothelial dysfunction, and COVID-19. Basically, endothelial dysfunction is common in both conditions [COVID-10 and ED].

“We would like to find some sort of biomarker of endothelial dysfunction post COVID, because it seems that there are many sequelae that coexist for a long time after infection,” added Dr. Jannini. “Asking a patient if they have ED after COVID might provide a measure of systemic wellness.”

Allan Pacey, MD, professor of andrology at the University of Sheffield (England), welcomed the research, noting, “This seems to be a well-conducted study. However, at the moment, the relationship is just a correlation, and it might be that some of the comorbidities that increased the men’s chances of getting a significant COVID-19 infection may have also independently increased their chances of erectile dysfunction.

“But the authors offer a plausible mechanism by which COVID-19 may impact directly on erectile function,” agrees Dr. Pacey. However, “There’s more work to be done,” he said. “I’d also argue it’s a good reason for men to wear a mask, practice social distancing, and take the vaccine when it’s offered to them.”

Urologist John Mulhall, MD, from Memorial Sloan Kettering Cancer Center, New York, remarked, “It was a highly preliminary study, but the data are suggestive of a potential link between COVID-19 infection and ED.

“However, it raises enough questions such that further large, more long-term analyses are required to define causation. Future studies assessing testosterone levels and erectile hemodynamics will be needed to provide definite evidence of a causative link,» he stressed.
 

Erectile problems a ‘hallmark’ of systemic endothelial dysfunction

Prior research has suggested that asymptomatic COVID-19 could be associated with subclinical microvascular involvement with long-term cardiovascular effects.

“Indeed, COVID-19 is by all means an endothelial disease, in which systemic manifestations ... can potentially be due to alterations in the endothelial thrombotic/fibrinolytic balance,” emphasized Dr. Jannini. “In addition, endothelial cells express many of the cofactors used by SARS-CoV-2 to invade host cells.

“Erectile dysfunction has often been considered a hallmark of endothelial dysfunction, and as such, a potential association between ED and COVID-19 has also been postulated and underpinned the investigation in this study,” he explained.

The study was predicated on the fact that ED is often considered a clinical marker of impaired overall health status, which often features cardiovascular events at an early age. It aimed to investigate the bidirectional relationship between COVID-19 and ED. It asked whether ED could be a risk factor for contracting COVID-19 and whether having COVID-19 predisposes to developing ED.

“This would possibly suggest that men with ED, due to the underlying conditions which impair erectile response, could also be more susceptible to contracting COVID-19,” said Dr. Jannini.

Data were drawn from the Sex@COVID online survey, which was conducted from April 7 to May 4, 2020, in Italy. The survey included 6,821 participants aged 18 years or older (4,177 women; 2,644 men; mean age, 32.83 ± 11.24 years). Participants were stratified on the basis of marital status and sexual activity during lockdown. From these participants, 985 sexually active men were identified, among whom 25 (2.54%) reported having tested positive for COVID-19. These persons were matched with 75 COVID-19–negative men using propensity score matching in a 1:3 ratio.

The researchers used standardized psychometric tools to measure the effects of lockdown and social distancing on the intrapsychic, relational, and sexual health of the participants.

Erectile function was measured with the International Index of Erectile Function or the Sexual Health Inventory for Men, which are often used in clinical settings. In light of the two-way interaction between sexual activity and psychological well-being, results were adjusted for any influence of anxiety and depression, which were measured with recognized scales for use in patients with a history of COVID-19.

Results showed that the prevalence of ED was significantly higher among men who self-reported a history of COVID-19, compared with a matching COVID-negative population (28% vs. 9.33%; P = .027).

After adjusting for variables that are considered to have a bearing on the development of ED, such as psychological status, age, and BMI, the odds ratio for developing ED after having had COVID-19 was 5.66 (95% confidence interval, 1.50-24.01).

Similarly, after adjusting for age and BMI, men with ED were more likely to have COVID‐19 (OR, 5.27; 95% CI, 1.49-20.09).

The authors note that persons who experience “a sudden onset or worsening of ED might also consider precautionary quarantine or nasopharyngeal swab, as COVID‐19 might act as a potential initiating trigger for the onset of erectile impairment, or an aggravating factor for its progression to more severe forms.”

Similarly, patients who have ED “should consider their erectile impairment as a sign of possible underlying conditions that could increase the likelihood of suffering from COVID‐19,” they write.

Dr. Mulhall highlighted several limitations of the study, including its retrospective nature, recall bias associated with the use of online questionnaires, and the inclusion of COVID‐19 diagnoses that were based on the response to the survey rather than on testing with nasopharyngeal swabs. In addition, comorbidity data were incomplete, and there was no indication of duration after COVID-19 infection, the severity of COVID-19, or the severity of ED.

The authors have disclosed no relevant financial relationships. Dr. Pacey is chairman of the advisory committee of the U.K. National External Quality Assurance Schemes in Andrology, editor-in-chief of Human Fertility, trustee of the Progress Educational Trust, and trustee of the British Fertility Society (all unpaid). Dr. Mulhall has disclosed no relevant financial relationships.

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

COVID-19 increases the risk of developing erectile dysfunction (ED) by nearly sixfold, according to data from the first study to investigate the association between ED and COVID-19 in young men in a real-life setting.

The preliminary data also indicated that ED is a marker of increased susceptibility to SARS-CoV-2 infection. Men with ED are more than five times more likely to have COVID-19 (odds ratio, 5.27).

For men with a history of COVID-19, the odds ratio of developing ED was 5.66. The strength of the association remained after adjusting for factors considered to affect ED.

The study, which was led by Emmanuele A. Jannini, MD, professor of endocrinology and medical sexology, University of Rome Tor Vergata, was published on March 20 in Andrology.
 

‘Mask up to keep it up’

ED can be both a short-term and a long-term complication of COVID-19, Dr. Jannini suggests.

“When offered, men should have the COVID vaccination. It also gives a whole new meaning to wearing the mask – mask up to keep it up,” he said. “It could possibly have the added benefit of preventing sexual dysfunction.”

He points out that older age, diabetes, high body mass index, and smoking increase the risk of contracting COVID-19.

“These are the same as risk factors for ED. Results of our study agree with the pathophysiological mechanisms linking ED, endothelial dysfunction, and COVID-19. Basically, endothelial dysfunction is common in both conditions [COVID-10 and ED].

“We would like to find some sort of biomarker of endothelial dysfunction post COVID, because it seems that there are many sequelae that coexist for a long time after infection,” added Dr. Jannini. “Asking a patient if they have ED after COVID might provide a measure of systemic wellness.”

Allan Pacey, MD, professor of andrology at the University of Sheffield (England), welcomed the research, noting, “This seems to be a well-conducted study. However, at the moment, the relationship is just a correlation, and it might be that some of the comorbidities that increased the men’s chances of getting a significant COVID-19 infection may have also independently increased their chances of erectile dysfunction.

“But the authors offer a plausible mechanism by which COVID-19 may impact directly on erectile function,” agrees Dr. Pacey. However, “There’s more work to be done,” he said. “I’d also argue it’s a good reason for men to wear a mask, practice social distancing, and take the vaccine when it’s offered to them.”

Urologist John Mulhall, MD, from Memorial Sloan Kettering Cancer Center, New York, remarked, “It was a highly preliminary study, but the data are suggestive of a potential link between COVID-19 infection and ED.

“However, it raises enough questions such that further large, more long-term analyses are required to define causation. Future studies assessing testosterone levels and erectile hemodynamics will be needed to provide definite evidence of a causative link,» he stressed.
 

Erectile problems a ‘hallmark’ of systemic endothelial dysfunction

Prior research has suggested that asymptomatic COVID-19 could be associated with subclinical microvascular involvement with long-term cardiovascular effects.

“Indeed, COVID-19 is by all means an endothelial disease, in which systemic manifestations ... can potentially be due to alterations in the endothelial thrombotic/fibrinolytic balance,” emphasized Dr. Jannini. “In addition, endothelial cells express many of the cofactors used by SARS-CoV-2 to invade host cells.

“Erectile dysfunction has often been considered a hallmark of endothelial dysfunction, and as such, a potential association between ED and COVID-19 has also been postulated and underpinned the investigation in this study,” he explained.

The study was predicated on the fact that ED is often considered a clinical marker of impaired overall health status, which often features cardiovascular events at an early age. It aimed to investigate the bidirectional relationship between COVID-19 and ED. It asked whether ED could be a risk factor for contracting COVID-19 and whether having COVID-19 predisposes to developing ED.

“This would possibly suggest that men with ED, due to the underlying conditions which impair erectile response, could also be more susceptible to contracting COVID-19,” said Dr. Jannini.

Data were drawn from the Sex@COVID online survey, which was conducted from April 7 to May 4, 2020, in Italy. The survey included 6,821 participants aged 18 years or older (4,177 women; 2,644 men; mean age, 32.83 ± 11.24 years). Participants were stratified on the basis of marital status and sexual activity during lockdown. From these participants, 985 sexually active men were identified, among whom 25 (2.54%) reported having tested positive for COVID-19. These persons were matched with 75 COVID-19–negative men using propensity score matching in a 1:3 ratio.

The researchers used standardized psychometric tools to measure the effects of lockdown and social distancing on the intrapsychic, relational, and sexual health of the participants.

Erectile function was measured with the International Index of Erectile Function or the Sexual Health Inventory for Men, which are often used in clinical settings. In light of the two-way interaction between sexual activity and psychological well-being, results were adjusted for any influence of anxiety and depression, which were measured with recognized scales for use in patients with a history of COVID-19.

Results showed that the prevalence of ED was significantly higher among men who self-reported a history of COVID-19, compared with a matching COVID-negative population (28% vs. 9.33%; P = .027).

After adjusting for variables that are considered to have a bearing on the development of ED, such as psychological status, age, and BMI, the odds ratio for developing ED after having had COVID-19 was 5.66 (95% confidence interval, 1.50-24.01).

Similarly, after adjusting for age and BMI, men with ED were more likely to have COVID‐19 (OR, 5.27; 95% CI, 1.49-20.09).

The authors note that persons who experience “a sudden onset or worsening of ED might also consider precautionary quarantine or nasopharyngeal swab, as COVID‐19 might act as a potential initiating trigger for the onset of erectile impairment, or an aggravating factor for its progression to more severe forms.”

Similarly, patients who have ED “should consider their erectile impairment as a sign of possible underlying conditions that could increase the likelihood of suffering from COVID‐19,” they write.

Dr. Mulhall highlighted several limitations of the study, including its retrospective nature, recall bias associated with the use of online questionnaires, and the inclusion of COVID‐19 diagnoses that were based on the response to the survey rather than on testing with nasopharyngeal swabs. In addition, comorbidity data were incomplete, and there was no indication of duration after COVID-19 infection, the severity of COVID-19, or the severity of ED.

The authors have disclosed no relevant financial relationships. Dr. Pacey is chairman of the advisory committee of the U.K. National External Quality Assurance Schemes in Andrology, editor-in-chief of Human Fertility, trustee of the Progress Educational Trust, and trustee of the British Fertility Society (all unpaid). Dr. Mulhall has disclosed no relevant financial relationships.

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

COVID-19 increases the risk of developing erectile dysfunction (ED) by nearly sixfold, according to data from the first study to investigate the association between ED and COVID-19 in young men in a real-life setting.

The preliminary data also indicated that ED is a marker of increased susceptibility to SARS-CoV-2 infection. Men with ED are more than five times more likely to have COVID-19 (odds ratio, 5.27).

For men with a history of COVID-19, the odds ratio of developing ED was 5.66. The strength of the association remained after adjusting for factors considered to affect ED.

The study, which was led by Emmanuele A. Jannini, MD, professor of endocrinology and medical sexology, University of Rome Tor Vergata, was published on March 20 in Andrology.
 

‘Mask up to keep it up’

ED can be both a short-term and a long-term complication of COVID-19, Dr. Jannini suggests.

“When offered, men should have the COVID vaccination. It also gives a whole new meaning to wearing the mask – mask up to keep it up,” he said. “It could possibly have the added benefit of preventing sexual dysfunction.”

He points out that older age, diabetes, high body mass index, and smoking increase the risk of contracting COVID-19.

“These are the same as risk factors for ED. Results of our study agree with the pathophysiological mechanisms linking ED, endothelial dysfunction, and COVID-19. Basically, endothelial dysfunction is common in both conditions [COVID-10 and ED].

“We would like to find some sort of biomarker of endothelial dysfunction post COVID, because it seems that there are many sequelae that coexist for a long time after infection,” added Dr. Jannini. “Asking a patient if they have ED after COVID might provide a measure of systemic wellness.”

Allan Pacey, MD, professor of andrology at the University of Sheffield (England), welcomed the research, noting, “This seems to be a well-conducted study. However, at the moment, the relationship is just a correlation, and it might be that some of the comorbidities that increased the men’s chances of getting a significant COVID-19 infection may have also independently increased their chances of erectile dysfunction.

“But the authors offer a plausible mechanism by which COVID-19 may impact directly on erectile function,” agrees Dr. Pacey. However, “There’s more work to be done,” he said. “I’d also argue it’s a good reason for men to wear a mask, practice social distancing, and take the vaccine when it’s offered to them.”

Urologist John Mulhall, MD, from Memorial Sloan Kettering Cancer Center, New York, remarked, “It was a highly preliminary study, but the data are suggestive of a potential link between COVID-19 infection and ED.

“However, it raises enough questions such that further large, more long-term analyses are required to define causation. Future studies assessing testosterone levels and erectile hemodynamics will be needed to provide definite evidence of a causative link,» he stressed.
 

Erectile problems a ‘hallmark’ of systemic endothelial dysfunction

Prior research has suggested that asymptomatic COVID-19 could be associated with subclinical microvascular involvement with long-term cardiovascular effects.

“Indeed, COVID-19 is by all means an endothelial disease, in which systemic manifestations ... can potentially be due to alterations in the endothelial thrombotic/fibrinolytic balance,” emphasized Dr. Jannini. “In addition, endothelial cells express many of the cofactors used by SARS-CoV-2 to invade host cells.

“Erectile dysfunction has often been considered a hallmark of endothelial dysfunction, and as such, a potential association between ED and COVID-19 has also been postulated and underpinned the investigation in this study,” he explained.

The study was predicated on the fact that ED is often considered a clinical marker of impaired overall health status, which often features cardiovascular events at an early age. It aimed to investigate the bidirectional relationship between COVID-19 and ED. It asked whether ED could be a risk factor for contracting COVID-19 and whether having COVID-19 predisposes to developing ED.

“This would possibly suggest that men with ED, due to the underlying conditions which impair erectile response, could also be more susceptible to contracting COVID-19,” said Dr. Jannini.

Data were drawn from the Sex@COVID online survey, which was conducted from April 7 to May 4, 2020, in Italy. The survey included 6,821 participants aged 18 years or older (4,177 women; 2,644 men; mean age, 32.83 ± 11.24 years). Participants were stratified on the basis of marital status and sexual activity during lockdown. From these participants, 985 sexually active men were identified, among whom 25 (2.54%) reported having tested positive for COVID-19. These persons were matched with 75 COVID-19–negative men using propensity score matching in a 1:3 ratio.

The researchers used standardized psychometric tools to measure the effects of lockdown and social distancing on the intrapsychic, relational, and sexual health of the participants.

Erectile function was measured with the International Index of Erectile Function or the Sexual Health Inventory for Men, which are often used in clinical settings. In light of the two-way interaction between sexual activity and psychological well-being, results were adjusted for any influence of anxiety and depression, which were measured with recognized scales for use in patients with a history of COVID-19.

Results showed that the prevalence of ED was significantly higher among men who self-reported a history of COVID-19, compared with a matching COVID-negative population (28% vs. 9.33%; P = .027).

After adjusting for variables that are considered to have a bearing on the development of ED, such as psychological status, age, and BMI, the odds ratio for developing ED after having had COVID-19 was 5.66 (95% confidence interval, 1.50-24.01).

Similarly, after adjusting for age and BMI, men with ED were more likely to have COVID‐19 (OR, 5.27; 95% CI, 1.49-20.09).

The authors note that persons who experience “a sudden onset or worsening of ED might also consider precautionary quarantine or nasopharyngeal swab, as COVID‐19 might act as a potential initiating trigger for the onset of erectile impairment, or an aggravating factor for its progression to more severe forms.”

Similarly, patients who have ED “should consider their erectile impairment as a sign of possible underlying conditions that could increase the likelihood of suffering from COVID‐19,” they write.

Dr. Mulhall highlighted several limitations of the study, including its retrospective nature, recall bias associated with the use of online questionnaires, and the inclusion of COVID‐19 diagnoses that were based on the response to the survey rather than on testing with nasopharyngeal swabs. In addition, comorbidity data were incomplete, and there was no indication of duration after COVID-19 infection, the severity of COVID-19, or the severity of ED.

The authors have disclosed no relevant financial relationships. Dr. Pacey is chairman of the advisory committee of the U.K. National External Quality Assurance Schemes in Andrology, editor-in-chief of Human Fertility, trustee of the Progress Educational Trust, and trustee of the British Fertility Society (all unpaid). Dr. Mulhall has disclosed no relevant financial relationships.

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

Cardiovascular and metabolic risk factors are increased among transgender youths, compared with youths who are not transgender. Elevations in lipid levels and body mass index (BMI) also occur in adult transgender patients, new research shows.

“This is the first study of its size in the United States of which we are aware that looks at the odds of youth with a diagnosis of gender dysphoria having medical diagnoses that relate to overall metabolic and cardiovascular health,” first author Anna Valentine, MD, of Children’s Hospital Colorado, Aurora, said in a press statement.

Although previous studies have shown that among transgender adults, BMI is higher and there is an increased risk for cardiovascular events, such as stroke or heart attack, compared with nontransgender people, research on adolescent transgender patients has been lacking.

With a recent survey showing that nearly 2% of adolescents identify as transgender, interest in health outcomes among younger patients is high.

To investigate, Dr. Valentine, and colleagues evaluated data from the PEDSnet pediatric database on 4,177 youths who had received a diagnosis of gender dysphoria. The participants had been enrolled at six sites from 2009 to 2019. The researchers compared these patients in a ratio of 1:4 with 16,664 control persons who had not been diagnosed with gender dysphoria. They reported their findings as a poster at the annual meeting of the Endocrine Society.

For the propensity-score analysis, participants were matched according to year of birth, age at last visit, site, race, ethnicity, insurance status, and duration in the database.

In both the transgender and control groups, about 66% were female at birth, 73% were White, and 9% Hispanic. For both groups, the average age was 16.2 years at the last visit. The average duration in the database was 7 years.
 

Study didn’t distinguish between those receiving and those not receiving gender-affirming hormones

In the retrospective study, among those who identified as transgender, the rates of diagnoses of dyslipidemia (odds ratio, 1.6; P < .0001) and metabolic syndrome (OR, 1.9; P = .0086) were significantly higher, compared with those without gender dysphoria.

Among the transgender male patients (born female) but not transgender female patients (born male), rates of diagnoses of overweight/obesity (OR, 1.7; P < .0001) and polycystic ovary syndrome were higher (OR, 1.9, P = .0006), compared with controls.

Gender-affirming hormone therapy, such as with testosterone or estradiol, is among the suspected culprits for the cardiovascular effects. However, importantly, this study did not differentiate between patients who had received estradiol or testosterone for gender affirmation and those who had not, Dr. Valentine said.

“We don’t know [whether gender-affirming hormone therapy is a cause], as we have not looked at this yet,” she said in an interview. “We are looking at that in our next analyses and will be including that in our future publication.

“We’ll also be looking at the relationship between having overweight/obesity and the other diagnoses that influence cardiovascular health (high blood pressure, liver dysfunction, and abnormal cholesterol), as that could certainly be playing a role as well,” she said.

For many transgender patients, gender-affirming hormone therapy is lifelong. One question that needs to be evaluated concerns whether the dose of such therapy has a role on cardiovascular effects and if so, whether adjustments could be made without compromising the therapeutic effect, Dr. Valentine noted.

“This is an important question, and future research is needed to evaluate whether doses [of gender-affirming hormones] are related to cardiometabolic outcomes,” she said.

Potential confounders in the study include the fact that rates of overweight and obesity are higher among youths with gender dysphoria. This can in itself can increase the risk for other disorders, Dr. Valentine noted.

Furthermore, rates of mental health comorbidities are higher among youths with gender dysphoria. One consequence of this may be that they engage in less physical activity, she said.
 

Hormone therapy, health care disparities, or both could explain risk

In commenting on the study, Joshua D. Safer, MD, executive director of the Center for Transgender Medicine and Surgery, the Mount Sinai Health System, New York, said that although similar cardiovascular effects are known to occur in transgender adults as well, they may or may not be hormone related. Other factors can increase the risk.

“With transgender adults, any differences in lipids or cardiac risk factors relative to cisgender people might be attributable either to hormone therapy or to health care disparities,” he said in an interview.

“The data are mixed. It may be that most differences relate to lack of access to care and to mistreatment by society,” he said. “Even studies that focus on hormones see a worsened situation for trans women versus trans men.”

Other recent research that shows potential cardiovascular effects among adult transgender men includes a study of more than 1,000 transgender men (born female) who received testosterone. That study, which was also presented at the ENDO meeting and was reported by this news organization, found an increased risk for high hematocrit levels, which could lead to a thrombotic event.

However, a study published in Pediatrics, which was also reported by this news organization, that included 611 transgender youths who had taken gender-affirming hormone therapy for more than a year found no increased risk for thrombosis, even in the presence of thrombosis risk factors, including obesity, tobacco use, and family history of thrombosis. However, the senior author of that study pointed out that the duration of follow-up in that study was relatively short, which may have been why they did not find an increased risk for thrombosis.

Dr. Safer noted that transgender youths and adults alike face a host of cultural factors that could play a role in increased cardiovascular risks.

“For adults, the major candidate explanations for worse BMI and cardiac risk factors are societal mistreatment, and for trans women specifically, progestins. For youth, the major candidate explanations are societal mistreatment and lack of access to athletics,” he said.

The authors and Dr. Safer disclosed no relevant financial relationships.

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

Cardiovascular and metabolic risk factors are increased among transgender youths, compared with youths who are not transgender. Elevations in lipid levels and body mass index (BMI) also occur in adult transgender patients, new research shows.

“This is the first study of its size in the United States of which we are aware that looks at the odds of youth with a diagnosis of gender dysphoria having medical diagnoses that relate to overall metabolic and cardiovascular health,” first author Anna Valentine, MD, of Children’s Hospital Colorado, Aurora, said in a press statement.

Although previous studies have shown that among transgender adults, BMI is higher and there is an increased risk for cardiovascular events, such as stroke or heart attack, compared with nontransgender people, research on adolescent transgender patients has been lacking.

With a recent survey showing that nearly 2% of adolescents identify as transgender, interest in health outcomes among younger patients is high.

To investigate, Dr. Valentine, and colleagues evaluated data from the PEDSnet pediatric database on 4,177 youths who had received a diagnosis of gender dysphoria. The participants had been enrolled at six sites from 2009 to 2019. The researchers compared these patients in a ratio of 1:4 with 16,664 control persons who had not been diagnosed with gender dysphoria. They reported their findings as a poster at the annual meeting of the Endocrine Society.

For the propensity-score analysis, participants were matched according to year of birth, age at last visit, site, race, ethnicity, insurance status, and duration in the database.

In both the transgender and control groups, about 66% were female at birth, 73% were White, and 9% Hispanic. For both groups, the average age was 16.2 years at the last visit. The average duration in the database was 7 years.
 

Study didn’t distinguish between those receiving and those not receiving gender-affirming hormones

In the retrospective study, among those who identified as transgender, the rates of diagnoses of dyslipidemia (odds ratio, 1.6; P < .0001) and metabolic syndrome (OR, 1.9; P = .0086) were significantly higher, compared with those without gender dysphoria.

Among the transgender male patients (born female) but not transgender female patients (born male), rates of diagnoses of overweight/obesity (OR, 1.7; P < .0001) and polycystic ovary syndrome were higher (OR, 1.9, P = .0006), compared with controls.

Gender-affirming hormone therapy, such as with testosterone or estradiol, is among the suspected culprits for the cardiovascular effects. However, importantly, this study did not differentiate between patients who had received estradiol or testosterone for gender affirmation and those who had not, Dr. Valentine said.

“We don’t know [whether gender-affirming hormone therapy is a cause], as we have not looked at this yet,” she said in an interview. “We are looking at that in our next analyses and will be including that in our future publication.

“We’ll also be looking at the relationship between having overweight/obesity and the other diagnoses that influence cardiovascular health (high blood pressure, liver dysfunction, and abnormal cholesterol), as that could certainly be playing a role as well,” she said.

For many transgender patients, gender-affirming hormone therapy is lifelong. One question that needs to be evaluated concerns whether the dose of such therapy has a role on cardiovascular effects and if so, whether adjustments could be made without compromising the therapeutic effect, Dr. Valentine noted.

“This is an important question, and future research is needed to evaluate whether doses [of gender-affirming hormones] are related to cardiometabolic outcomes,” she said.

Potential confounders in the study include the fact that rates of overweight and obesity are higher among youths with gender dysphoria. This can in itself can increase the risk for other disorders, Dr. Valentine noted.

Furthermore, rates of mental health comorbidities are higher among youths with gender dysphoria. One consequence of this may be that they engage in less physical activity, she said.
 

Hormone therapy, health care disparities, or both could explain risk

In commenting on the study, Joshua D. Safer, MD, executive director of the Center for Transgender Medicine and Surgery, the Mount Sinai Health System, New York, said that although similar cardiovascular effects are known to occur in transgender adults as well, they may or may not be hormone related. Other factors can increase the risk.

“With transgender adults, any differences in lipids or cardiac risk factors relative to cisgender people might be attributable either to hormone therapy or to health care disparities,” he said in an interview.

“The data are mixed. It may be that most differences relate to lack of access to care and to mistreatment by society,” he said. “Even studies that focus on hormones see a worsened situation for trans women versus trans men.”

Other recent research that shows potential cardiovascular effects among adult transgender men includes a study of more than 1,000 transgender men (born female) who received testosterone. That study, which was also presented at the ENDO meeting and was reported by this news organization, found an increased risk for high hematocrit levels, which could lead to a thrombotic event.

However, a study published in Pediatrics, which was also reported by this news organization, that included 611 transgender youths who had taken gender-affirming hormone therapy for more than a year found no increased risk for thrombosis, even in the presence of thrombosis risk factors, including obesity, tobacco use, and family history of thrombosis. However, the senior author of that study pointed out that the duration of follow-up in that study was relatively short, which may have been why they did not find an increased risk for thrombosis.

Dr. Safer noted that transgender youths and adults alike face a host of cultural factors that could play a role in increased cardiovascular risks.

“For adults, the major candidate explanations for worse BMI and cardiac risk factors are societal mistreatment, and for trans women specifically, progestins. For youth, the major candidate explanations are societal mistreatment and lack of access to athletics,” he said.

The authors and Dr. Safer disclosed no relevant financial relationships.

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

Cardiovascular and metabolic risk factors are increased among transgender youths, compared with youths who are not transgender. Elevations in lipid levels and body mass index (BMI) also occur in adult transgender patients, new research shows.

“This is the first study of its size in the United States of which we are aware that looks at the odds of youth with a diagnosis of gender dysphoria having medical diagnoses that relate to overall metabolic and cardiovascular health,” first author Anna Valentine, MD, of Children’s Hospital Colorado, Aurora, said in a press statement.

Although previous studies have shown that among transgender adults, BMI is higher and there is an increased risk for cardiovascular events, such as stroke or heart attack, compared with nontransgender people, research on adolescent transgender patients has been lacking.

With a recent survey showing that nearly 2% of adolescents identify as transgender, interest in health outcomes among younger patients is high.

To investigate, Dr. Valentine, and colleagues evaluated data from the PEDSnet pediatric database on 4,177 youths who had received a diagnosis of gender dysphoria. The participants had been enrolled at six sites from 2009 to 2019. The researchers compared these patients in a ratio of 1:4 with 16,664 control persons who had not been diagnosed with gender dysphoria. They reported their findings as a poster at the annual meeting of the Endocrine Society.

For the propensity-score analysis, participants were matched according to year of birth, age at last visit, site, race, ethnicity, insurance status, and duration in the database.

In both the transgender and control groups, about 66% were female at birth, 73% were White, and 9% Hispanic. For both groups, the average age was 16.2 years at the last visit. The average duration in the database was 7 years.
 

Study didn’t distinguish between those receiving and those not receiving gender-affirming hormones

In the retrospective study, among those who identified as transgender, the rates of diagnoses of dyslipidemia (odds ratio, 1.6; P < .0001) and metabolic syndrome (OR, 1.9; P = .0086) were significantly higher, compared with those without gender dysphoria.

Among the transgender male patients (born female) but not transgender female patients (born male), rates of diagnoses of overweight/obesity (OR, 1.7; P < .0001) and polycystic ovary syndrome were higher (OR, 1.9, P = .0006), compared with controls.

Gender-affirming hormone therapy, such as with testosterone or estradiol, is among the suspected culprits for the cardiovascular effects. However, importantly, this study did not differentiate between patients who had received estradiol or testosterone for gender affirmation and those who had not, Dr. Valentine said.

“We don’t know [whether gender-affirming hormone therapy is a cause], as we have not looked at this yet,” she said in an interview. “We are looking at that in our next analyses and will be including that in our future publication.

“We’ll also be looking at the relationship between having overweight/obesity and the other diagnoses that influence cardiovascular health (high blood pressure, liver dysfunction, and abnormal cholesterol), as that could certainly be playing a role as well,” she said.

For many transgender patients, gender-affirming hormone therapy is lifelong. One question that needs to be evaluated concerns whether the dose of such therapy has a role on cardiovascular effects and if so, whether adjustments could be made without compromising the therapeutic effect, Dr. Valentine noted.

“This is an important question, and future research is needed to evaluate whether doses [of gender-affirming hormones] are related to cardiometabolic outcomes,” she said.

Potential confounders in the study include the fact that rates of overweight and obesity are higher among youths with gender dysphoria. This can in itself can increase the risk for other disorders, Dr. Valentine noted.

Furthermore, rates of mental health comorbidities are higher among youths with gender dysphoria. One consequence of this may be that they engage in less physical activity, she said.
 

Hormone therapy, health care disparities, or both could explain risk

In commenting on the study, Joshua D. Safer, MD, executive director of the Center for Transgender Medicine and Surgery, the Mount Sinai Health System, New York, said that although similar cardiovascular effects are known to occur in transgender adults as well, they may or may not be hormone related. Other factors can increase the risk.

“With transgender adults, any differences in lipids or cardiac risk factors relative to cisgender people might be attributable either to hormone therapy or to health care disparities,” he said in an interview.

“The data are mixed. It may be that most differences relate to lack of access to care and to mistreatment by society,” he said. “Even studies that focus on hormones see a worsened situation for trans women versus trans men.”

Other recent research that shows potential cardiovascular effects among adult transgender men includes a study of more than 1,000 transgender men (born female) who received testosterone. That study, which was also presented at the ENDO meeting and was reported by this news organization, found an increased risk for high hematocrit levels, which could lead to a thrombotic event.

However, a study published in Pediatrics, which was also reported by this news organization, that included 611 transgender youths who had taken gender-affirming hormone therapy for more than a year found no increased risk for thrombosis, even in the presence of thrombosis risk factors, including obesity, tobacco use, and family history of thrombosis. However, the senior author of that study pointed out that the duration of follow-up in that study was relatively short, which may have been why they did not find an increased risk for thrombosis.

Dr. Safer noted that transgender youths and adults alike face a host of cultural factors that could play a role in increased cardiovascular risks.

“For adults, the major candidate explanations for worse BMI and cardiac risk factors are societal mistreatment, and for trans women specifically, progestins. For youth, the major candidate explanations are societal mistreatment and lack of access to athletics,” he said.

The authors and Dr. Safer disclosed no relevant financial relationships.

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

An antibiotic course of 5 days is usually just as effective as longer courses but with fewer side effects and decreased overall antibiotic exposure for a number of common bacterial conditions, according to new clinical guidelines published by the American College of Physicians.

The guidelines focus on treatment of uncomplicated cases involving pneumonia, urinary tract infections (UTIs), cellulitis, chronic obstructive pulmonary disease (COPD) exacerbations, and acute bronchitis. The goal of the guidelines is to continue improving antibiotic stewardship given the increasing threat of antibiotic resistance and the adverse effects of antibiotics.

“Any use of antibiotics (including necessary use) has downstream effects outside of treating infection,” Dawn Nolt, MD, MPH, a professor of pediatric infection disease at Oregon Health & Science University, Portland, said in an interview. Dr. Nolt was not involved in developing these guidelines. “Undesirable outcomes include allergic reactions, diarrhea, and antibiotic-resistant bacteria. When we reduce unnecessary antibiotic, we reduce undesirable outcomes,” she said.

According to background information in the paper, 1 in 10 patients receives an antibiotic prescription during visits, yet nearly a third of these (30%) are unnecessary and last too long, especially for sinusitis and bronchitis. Meanwhile, overuse of antibiotics, particularly broad-spectrum ones, leads to resistance and adverse effects in up to 20% of patients.

“Prescribing practices can vary based on the type of provider, the setting where the antibiotic is being prescribed, what geographic area you are looking at, the medical reason for which the antibiotic is being prescribed, the actual germ being targeted, and the type of patient,” Dr. Nolt said. “But this variability can be reduced when prescribing providers are aware and follow best practice standards as through this article.”

The new ACP guidelines are a distillation of recommendations from preexisting infectious disease organizations, Dr. Nolt said, but aimed specifically at those practicing internal medicine.

“We define appropriate antibiotic use as prescribing the right antibiotic at the right dose for the right duration for a specific condition,” Rachael A. Lee, MD, MSPH, of the University of Alabama at Birmingham, and colleagues wrote in the article detailing the new guidelines. “Despite evidence and guidelines supporting shorter durations of antibiotic use, many physicians do not prescribe short-course therapy, frequently defaulting to 10-day courses regardless of the condition.”

The reasons for this default response vary. Though some clinicians prescribe longer courses specifically to prevent antibiotic resistance, no evidence shows that continuing to take antibiotics after symptoms have resolved actually reduces likelihood of resistance, the authors noted.

“In fact, resistance is a documented side effect of prolonged antibiotic use due to natural selection pressure,” they wrote.

Another common reason is habit.

“This was the ‘conventional wisdom’ for so long, just trying to make sure all bacteria causing the infection were completely eradicated, with no stragglers that had been exposed to the antibiotic but were not gone and now could evolve into resistant organisms,” Jacqueline W. Fincher, MD, a primary care physician and president of the ACP, said in an interview. “While antibiotic stewardship has been very important for over a decade, we now have more recent head-to-head studies/data showing that, in these four conditions, shorter courses of treatment are just as efficacious with less side effects and adverse events.”

The researchers reviewed all existing clinical guidelines related to bronchitis with COPD exacerbations, community-acquired pneumonia, UTIs, and cellulitis, as well as any other relevant studies in the literature. Although they did not conduct a formal systematic review, they compiled the guidelines specifically for all internists, family physicians and other clinicians caring for patients with these conditions.

“Although most patients with these infections will be seen in the outpatient setting, these best-practice advice statements also apply to patients who present in the inpatient setting,” the authors wrote. They also note the importance of ensuring the patient has the correct diagnosis and appropriate corresponding antibiotic prescription. “If a patient is not improving with appropriate antibiotics, it is important for the clinician to reassess for other causes of symptoms rather than defaulting to a longer duration of antibiotic therapy,” they wrote, calling a longer course “the exception and not the rule.”
 

Acute bronchitis with COPD exacerbations

Antibiotic treatment for COPD exacerbations and acute uncomplicated bronchitis with signs of a bacterial infection should last no longer than 5 days. The authors define this condition as an acute respiratory infection with a normal chest x-ray, most often caused by a virus. Although patients with bronchitis do not automatically need antibiotics if there’s no evidence of pneumonia, the authors did advise antibiotics in cases involving COPD and a high likelihood of bacterial infection. Clinicians should base their choice of antibiotics on the most common bacterial etiology: Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. Ideal candidates for therapy may include aminopenicillin with clavulanic acid, a macrolide, or a tetracycline.

Community-acquired pneumonia

The initial course of antibiotics should be at least 5 days for pneumonia and only extended after considering validated evidence of the patient’s clinical stability, such as resuming normal vital signs, mental activity, and the ability to eat. Multiple randomized, controlled trials have shown no improved benefit from longer courses, though longer courses are linked to increased adverse events and mortality.

Again, antibiotics used should “cover common pathogens, such as S. pneumoniae, H. influenzae, Mycoplasma pneumoniae, and Staphylococcus aureus, and atypical pathogens, such as Legionella species,” the authors wrote. Options include “amoxicillin, doxycycline, or a macrolide for healthy adults or a beta-lactam with a macrolide or a respiratory fluoroquinolone in patients with comorbidities.”
 

UTIs: Uncomplicated cystitis and pyelonephritis

For women’s bacterial cystitis – 75% of which is caused by Escherichia coli – the guidelines recommend nitrofurantoin for 5 days, trimethoprim-sulfamethoxazole for 3 days, or fosfomycin as a single dose. For uncomplicated pyelonephritis in both men and women, clinicians can consider fluoroquinolones for 5-7 days or trimethoprim-sulfamethoxazole for 14 days, depending on antibiotic susceptibility.

This recommendation does not include UTIs in women who are pregnant or UTIs with other functional abnormalities present, such as obstruction. The authors also intentionally left out acute bacterial prostatitis because of its complexity and how long it can take to treat.
 

Cellulitis

MRSA, which has been increasing in prevalence, is a leading cause of skin and soft-tissue infections, such as necrotizing infections, cellulitis, and erysipelas. Unless the patient has penetrating trauma, evidence of MRSA infection elsewhere, injection drug use, nasal colonization of MRSA, or systemic inflammatory response syndrome, the guidelines recommend a 5- to 6-day course of cephalosporin, penicillin, or clindamycin, extended only if the infection has not improved in 5 days. Further research can narrow down the most appropriate treatment course.

This guidance does not apply to purulent cellulitis, such as conditions with abscesses, furuncles, or carbuncles that typically require incision and drainage.
 

Continuing to get the message out

Dr. Fincher emphasized the importance of continuing to disseminate messaging for clinicians about reducing unnecessary antibiotic use.

“In medicine we are constantly bombarded with new information. It is those patients and disease states that we see and treat every day that are especially important for us as physicians and other clinicians to keep our skills and knowledge base up to date when it comes to use of antibiotics,” Dr. Fincher said in an interview. “We just need to continue to educate and push out the data, guidelines, and recommendations.”

Dr. Nolt added that it’s important to emphasize how to translate these national recommendations into local practices since local guidance can also raise awareness and encourage local compliance.

Other strategies for reducing overuse of antibiotics “include restriction on antibiotics available at health care systems (formulary restriction), not allowing use of antibiotics unless there is discussion about the patient’s case (preauthorization), and reviewing cases of patients on antibiotics and advising on next steps (prospective audit and feedback),” she said.

The research was funded by the ACP. Dr. Lee has received personal fees from this news organization and Prime Education. Dr. Fincher owns stock in Johnson & Johnson and Procter and Gamble. Dr. Nolt and the article’s coauthors disclosed no relevant financial relationships.

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

An antibiotic course of 5 days is usually just as effective as longer courses but with fewer side effects and decreased overall antibiotic exposure for a number of common bacterial conditions, according to new clinical guidelines published by the American College of Physicians.

The guidelines focus on treatment of uncomplicated cases involving pneumonia, urinary tract infections (UTIs), cellulitis, chronic obstructive pulmonary disease (COPD) exacerbations, and acute bronchitis. The goal of the guidelines is to continue improving antibiotic stewardship given the increasing threat of antibiotic resistance and the adverse effects of antibiotics.

“Any use of antibiotics (including necessary use) has downstream effects outside of treating infection,” Dawn Nolt, MD, MPH, a professor of pediatric infection disease at Oregon Health & Science University, Portland, said in an interview. Dr. Nolt was not involved in developing these guidelines. “Undesirable outcomes include allergic reactions, diarrhea, and antibiotic-resistant bacteria. When we reduce unnecessary antibiotic, we reduce undesirable outcomes,” she said.

According to background information in the paper, 1 in 10 patients receives an antibiotic prescription during visits, yet nearly a third of these (30%) are unnecessary and last too long, especially for sinusitis and bronchitis. Meanwhile, overuse of antibiotics, particularly broad-spectrum ones, leads to resistance and adverse effects in up to 20% of patients.

“Prescribing practices can vary based on the type of provider, the setting where the antibiotic is being prescribed, what geographic area you are looking at, the medical reason for which the antibiotic is being prescribed, the actual germ being targeted, and the type of patient,” Dr. Nolt said. “But this variability can be reduced when prescribing providers are aware and follow best practice standards as through this article.”

The new ACP guidelines are a distillation of recommendations from preexisting infectious disease organizations, Dr. Nolt said, but aimed specifically at those practicing internal medicine.

“We define appropriate antibiotic use as prescribing the right antibiotic at the right dose for the right duration for a specific condition,” Rachael A. Lee, MD, MSPH, of the University of Alabama at Birmingham, and colleagues wrote in the article detailing the new guidelines. “Despite evidence and guidelines supporting shorter durations of antibiotic use, many physicians do not prescribe short-course therapy, frequently defaulting to 10-day courses regardless of the condition.”

The reasons for this default response vary. Though some clinicians prescribe longer courses specifically to prevent antibiotic resistance, no evidence shows that continuing to take antibiotics after symptoms have resolved actually reduces likelihood of resistance, the authors noted.

“In fact, resistance is a documented side effect of prolonged antibiotic use due to natural selection pressure,” they wrote.

Another common reason is habit.

“This was the ‘conventional wisdom’ for so long, just trying to make sure all bacteria causing the infection were completely eradicated, with no stragglers that had been exposed to the antibiotic but were not gone and now could evolve into resistant organisms,” Jacqueline W. Fincher, MD, a primary care physician and president of the ACP, said in an interview. “While antibiotic stewardship has been very important for over a decade, we now have more recent head-to-head studies/data showing that, in these four conditions, shorter courses of treatment are just as efficacious with less side effects and adverse events.”

The researchers reviewed all existing clinical guidelines related to bronchitis with COPD exacerbations, community-acquired pneumonia, UTIs, and cellulitis, as well as any other relevant studies in the literature. Although they did not conduct a formal systematic review, they compiled the guidelines specifically for all internists, family physicians and other clinicians caring for patients with these conditions.

“Although most patients with these infections will be seen in the outpatient setting, these best-practice advice statements also apply to patients who present in the inpatient setting,” the authors wrote. They also note the importance of ensuring the patient has the correct diagnosis and appropriate corresponding antibiotic prescription. “If a patient is not improving with appropriate antibiotics, it is important for the clinician to reassess for other causes of symptoms rather than defaulting to a longer duration of antibiotic therapy,” they wrote, calling a longer course “the exception and not the rule.”
 

Acute bronchitis with COPD exacerbations

Antibiotic treatment for COPD exacerbations and acute uncomplicated bronchitis with signs of a bacterial infection should last no longer than 5 days. The authors define this condition as an acute respiratory infection with a normal chest x-ray, most often caused by a virus. Although patients with bronchitis do not automatically need antibiotics if there’s no evidence of pneumonia, the authors did advise antibiotics in cases involving COPD and a high likelihood of bacterial infection. Clinicians should base their choice of antibiotics on the most common bacterial etiology: Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. Ideal candidates for therapy may include aminopenicillin with clavulanic acid, a macrolide, or a tetracycline.

Community-acquired pneumonia

The initial course of antibiotics should be at least 5 days for pneumonia and only extended after considering validated evidence of the patient’s clinical stability, such as resuming normal vital signs, mental activity, and the ability to eat. Multiple randomized, controlled trials have shown no improved benefit from longer courses, though longer courses are linked to increased adverse events and mortality.

Again, antibiotics used should “cover common pathogens, such as S. pneumoniae, H. influenzae, Mycoplasma pneumoniae, and Staphylococcus aureus, and atypical pathogens, such as Legionella species,” the authors wrote. Options include “amoxicillin, doxycycline, or a macrolide for healthy adults or a beta-lactam with a macrolide or a respiratory fluoroquinolone in patients with comorbidities.”
 

UTIs: Uncomplicated cystitis and pyelonephritis

For women’s bacterial cystitis – 75% of which is caused by Escherichia coli – the guidelines recommend nitrofurantoin for 5 days, trimethoprim-sulfamethoxazole for 3 days, or fosfomycin as a single dose. For uncomplicated pyelonephritis in both men and women, clinicians can consider fluoroquinolones for 5-7 days or trimethoprim-sulfamethoxazole for 14 days, depending on antibiotic susceptibility.

This recommendation does not include UTIs in women who are pregnant or UTIs with other functional abnormalities present, such as obstruction. The authors also intentionally left out acute bacterial prostatitis because of its complexity and how long it can take to treat.
 

Cellulitis

MRSA, which has been increasing in prevalence, is a leading cause of skin and soft-tissue infections, such as necrotizing infections, cellulitis, and erysipelas. Unless the patient has penetrating trauma, evidence of MRSA infection elsewhere, injection drug use, nasal colonization of MRSA, or systemic inflammatory response syndrome, the guidelines recommend a 5- to 6-day course of cephalosporin, penicillin, or clindamycin, extended only if the infection has not improved in 5 days. Further research can narrow down the most appropriate treatment course.

This guidance does not apply to purulent cellulitis, such as conditions with abscesses, furuncles, or carbuncles that typically require incision and drainage.
 

Continuing to get the message out

Dr. Fincher emphasized the importance of continuing to disseminate messaging for clinicians about reducing unnecessary antibiotic use.

“In medicine we are constantly bombarded with new information. It is those patients and disease states that we see and treat every day that are especially important for us as physicians and other clinicians to keep our skills and knowledge base up to date when it comes to use of antibiotics,” Dr. Fincher said in an interview. “We just need to continue to educate and push out the data, guidelines, and recommendations.”

Dr. Nolt added that it’s important to emphasize how to translate these national recommendations into local practices since local guidance can also raise awareness and encourage local compliance.

Other strategies for reducing overuse of antibiotics “include restriction on antibiotics available at health care systems (formulary restriction), not allowing use of antibiotics unless there is discussion about the patient’s case (preauthorization), and reviewing cases of patients on antibiotics and advising on next steps (prospective audit and feedback),” she said.

The research was funded by the ACP. Dr. Lee has received personal fees from this news organization and Prime Education. Dr. Fincher owns stock in Johnson & Johnson and Procter and Gamble. Dr. Nolt and the article’s coauthors disclosed no relevant financial relationships.

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

An antibiotic course of 5 days is usually just as effective as longer courses but with fewer side effects and decreased overall antibiotic exposure for a number of common bacterial conditions, according to new clinical guidelines published by the American College of Physicians.

The guidelines focus on treatment of uncomplicated cases involving pneumonia, urinary tract infections (UTIs), cellulitis, chronic obstructive pulmonary disease (COPD) exacerbations, and acute bronchitis. The goal of the guidelines is to continue improving antibiotic stewardship given the increasing threat of antibiotic resistance and the adverse effects of antibiotics.

“Any use of antibiotics (including necessary use) has downstream effects outside of treating infection,” Dawn Nolt, MD, MPH, a professor of pediatric infection disease at Oregon Health & Science University, Portland, said in an interview. Dr. Nolt was not involved in developing these guidelines. “Undesirable outcomes include allergic reactions, diarrhea, and antibiotic-resistant bacteria. When we reduce unnecessary antibiotic, we reduce undesirable outcomes,” she said.

According to background information in the paper, 1 in 10 patients receives an antibiotic prescription during visits, yet nearly a third of these (30%) are unnecessary and last too long, especially for sinusitis and bronchitis. Meanwhile, overuse of antibiotics, particularly broad-spectrum ones, leads to resistance and adverse effects in up to 20% of patients.

“Prescribing practices can vary based on the type of provider, the setting where the antibiotic is being prescribed, what geographic area you are looking at, the medical reason for which the antibiotic is being prescribed, the actual germ being targeted, and the type of patient,” Dr. Nolt said. “But this variability can be reduced when prescribing providers are aware and follow best practice standards as through this article.”

The new ACP guidelines are a distillation of recommendations from preexisting infectious disease organizations, Dr. Nolt said, but aimed specifically at those practicing internal medicine.

“We define appropriate antibiotic use as prescribing the right antibiotic at the right dose for the right duration for a specific condition,” Rachael A. Lee, MD, MSPH, of the University of Alabama at Birmingham, and colleagues wrote in the article detailing the new guidelines. “Despite evidence and guidelines supporting shorter durations of antibiotic use, many physicians do not prescribe short-course therapy, frequently defaulting to 10-day courses regardless of the condition.”

The reasons for this default response vary. Though some clinicians prescribe longer courses specifically to prevent antibiotic resistance, no evidence shows that continuing to take antibiotics after symptoms have resolved actually reduces likelihood of resistance, the authors noted.

“In fact, resistance is a documented side effect of prolonged antibiotic use due to natural selection pressure,” they wrote.

Another common reason is habit.

“This was the ‘conventional wisdom’ for so long, just trying to make sure all bacteria causing the infection were completely eradicated, with no stragglers that had been exposed to the antibiotic but were not gone and now could evolve into resistant organisms,” Jacqueline W. Fincher, MD, a primary care physician and president of the ACP, said in an interview. “While antibiotic stewardship has been very important for over a decade, we now have more recent head-to-head studies/data showing that, in these four conditions, shorter courses of treatment are just as efficacious with less side effects and adverse events.”

The researchers reviewed all existing clinical guidelines related to bronchitis with COPD exacerbations, community-acquired pneumonia, UTIs, and cellulitis, as well as any other relevant studies in the literature. Although they did not conduct a formal systematic review, they compiled the guidelines specifically for all internists, family physicians and other clinicians caring for patients with these conditions.

“Although most patients with these infections will be seen in the outpatient setting, these best-practice advice statements also apply to patients who present in the inpatient setting,” the authors wrote. They also note the importance of ensuring the patient has the correct diagnosis and appropriate corresponding antibiotic prescription. “If a patient is not improving with appropriate antibiotics, it is important for the clinician to reassess for other causes of symptoms rather than defaulting to a longer duration of antibiotic therapy,” they wrote, calling a longer course “the exception and not the rule.”
 

Acute bronchitis with COPD exacerbations

Antibiotic treatment for COPD exacerbations and acute uncomplicated bronchitis with signs of a bacterial infection should last no longer than 5 days. The authors define this condition as an acute respiratory infection with a normal chest x-ray, most often caused by a virus. Although patients with bronchitis do not automatically need antibiotics if there’s no evidence of pneumonia, the authors did advise antibiotics in cases involving COPD and a high likelihood of bacterial infection. Clinicians should base their choice of antibiotics on the most common bacterial etiology: Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. Ideal candidates for therapy may include aminopenicillin with clavulanic acid, a macrolide, or a tetracycline.

Community-acquired pneumonia

The initial course of antibiotics should be at least 5 days for pneumonia and only extended after considering validated evidence of the patient’s clinical stability, such as resuming normal vital signs, mental activity, and the ability to eat. Multiple randomized, controlled trials have shown no improved benefit from longer courses, though longer courses are linked to increased adverse events and mortality.

Again, antibiotics used should “cover common pathogens, such as S. pneumoniae, H. influenzae, Mycoplasma pneumoniae, and Staphylococcus aureus, and atypical pathogens, such as Legionella species,” the authors wrote. Options include “amoxicillin, doxycycline, or a macrolide for healthy adults or a beta-lactam with a macrolide or a respiratory fluoroquinolone in patients with comorbidities.”
 

UTIs: Uncomplicated cystitis and pyelonephritis

For women’s bacterial cystitis – 75% of which is caused by Escherichia coli – the guidelines recommend nitrofurantoin for 5 days, trimethoprim-sulfamethoxazole for 3 days, or fosfomycin as a single dose. For uncomplicated pyelonephritis in both men and women, clinicians can consider fluoroquinolones for 5-7 days or trimethoprim-sulfamethoxazole for 14 days, depending on antibiotic susceptibility.

This recommendation does not include UTIs in women who are pregnant or UTIs with other functional abnormalities present, such as obstruction. The authors also intentionally left out acute bacterial prostatitis because of its complexity and how long it can take to treat.
 

Cellulitis

MRSA, which has been increasing in prevalence, is a leading cause of skin and soft-tissue infections, such as necrotizing infections, cellulitis, and erysipelas. Unless the patient has penetrating trauma, evidence of MRSA infection elsewhere, injection drug use, nasal colonization of MRSA, or systemic inflammatory response syndrome, the guidelines recommend a 5- to 6-day course of cephalosporin, penicillin, or clindamycin, extended only if the infection has not improved in 5 days. Further research can narrow down the most appropriate treatment course.

This guidance does not apply to purulent cellulitis, such as conditions with abscesses, furuncles, or carbuncles that typically require incision and drainage.
 

Continuing to get the message out

Dr. Fincher emphasized the importance of continuing to disseminate messaging for clinicians about reducing unnecessary antibiotic use.

“In medicine we are constantly bombarded with new information. It is those patients and disease states that we see and treat every day that are especially important for us as physicians and other clinicians to keep our skills and knowledge base up to date when it comes to use of antibiotics,” Dr. Fincher said in an interview. “We just need to continue to educate and push out the data, guidelines, and recommendations.”

Dr. Nolt added that it’s important to emphasize how to translate these national recommendations into local practices since local guidance can also raise awareness and encourage local compliance.

Other strategies for reducing overuse of antibiotics “include restriction on antibiotics available at health care systems (formulary restriction), not allowing use of antibiotics unless there is discussion about the patient’s case (preauthorization), and reviewing cases of patients on antibiotics and advising on next steps (prospective audit and feedback),” she said.

The research was funded by the ACP. Dr. Lee has received personal fees from this news organization and Prime Education. Dr. Fincher owns stock in Johnson & Johnson and Procter and Gamble. Dr. Nolt and the article’s coauthors disclosed no relevant financial relationships.

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

The Food and Drug Administration has approved the nonstimulant medication viloxazine extended-release capsules (Qelbree, Supernus Pharmaceuticals) for the treatment of attention deficit hyperactivity disorder (ADHD) in children aged 6-17 years, the company has announced.

Viloxazine (formerly SPN-812) is a selective norepinephrine reuptake inhibitor. Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce, as needed.

The approval of viloxazine is supported by data from four phase 3 clinical trials involving more than 1,000 pediatric patients aged 6-17 years, the company said.

In one randomized, placebo-controlled phase 3 study that included more than 400 children, viloxazine reduced symptoms of ADHD as soon as 1 week after dosing and was well tolerated.

As reported by this news organization, the study was published last July in Clinical Therapeutics.

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical associate professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interview.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The prescribing label for viloxazine includes a boxed warning regarding the potential for suicidal thoughts and behaviors in some children with ADHD treated with the drug, especially within the first few months of treatment or when the dose is changed. 

In clinical trials, higher rates of suicidal thoughts and behavior were reported in pediatric patients treated with viloxazine than in patients treated with placebo. Patients taking viloxazine should be closely monitored for any new or sudden changes in mood, behavior, thoughts, and feelings.

Viloxazine has shown promise in a phase 3 trial involving adults with ADHD.

The company plans to submit a supplemental new drug application to the FDA for viloxazine in adults later this year.

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

The Food and Drug Administration has approved the nonstimulant medication viloxazine extended-release capsules (Qelbree, Supernus Pharmaceuticals) for the treatment of attention deficit hyperactivity disorder (ADHD) in children aged 6-17 years, the company has announced.

Viloxazine (formerly SPN-812) is a selective norepinephrine reuptake inhibitor. Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce, as needed.

The approval of viloxazine is supported by data from four phase 3 clinical trials involving more than 1,000 pediatric patients aged 6-17 years, the company said.

In one randomized, placebo-controlled phase 3 study that included more than 400 children, viloxazine reduced symptoms of ADHD as soon as 1 week after dosing and was well tolerated.

As reported by this news organization, the study was published last July in Clinical Therapeutics.

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical associate professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interview.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The prescribing label for viloxazine includes a boxed warning regarding the potential for suicidal thoughts and behaviors in some children with ADHD treated with the drug, especially within the first few months of treatment or when the dose is changed. 

In clinical trials, higher rates of suicidal thoughts and behavior were reported in pediatric patients treated with viloxazine than in patients treated with placebo. Patients taking viloxazine should be closely monitored for any new or sudden changes in mood, behavior, thoughts, and feelings.

Viloxazine has shown promise in a phase 3 trial involving adults with ADHD.

The company plans to submit a supplemental new drug application to the FDA for viloxazine in adults later this year.

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

The Food and Drug Administration has approved the nonstimulant medication viloxazine extended-release capsules (Qelbree, Supernus Pharmaceuticals) for the treatment of attention deficit hyperactivity disorder (ADHD) in children aged 6-17 years, the company has announced.

Viloxazine (formerly SPN-812) is a selective norepinephrine reuptake inhibitor. Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce, as needed.

The approval of viloxazine is supported by data from four phase 3 clinical trials involving more than 1,000 pediatric patients aged 6-17 years, the company said.

In one randomized, placebo-controlled phase 3 study that included more than 400 children, viloxazine reduced symptoms of ADHD as soon as 1 week after dosing and was well tolerated.

As reported by this news organization, the study was published last July in Clinical Therapeutics.

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical associate professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interview.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The prescribing label for viloxazine includes a boxed warning regarding the potential for suicidal thoughts and behaviors in some children with ADHD treated with the drug, especially within the first few months of treatment or when the dose is changed. 

In clinical trials, higher rates of suicidal thoughts and behavior were reported in pediatric patients treated with viloxazine than in patients treated with placebo. Patients taking viloxazine should be closely monitored for any new or sudden changes in mood, behavior, thoughts, and feelings.

Viloxazine has shown promise in a phase 3 trial involving adults with ADHD.

The company plans to submit a supplemental new drug application to the FDA for viloxazine in adults later this year.

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

Following a recent article in the Guardian, the Internet has erupted with tales of periods gone awry. The stress and loss of normalcy over the last year appears to have altered cycles and amplified the premenstrual syndrome (PMS) symptoms many women experience. And after the piece published, many responded on social media with the same sentiment: “So, it’s not just me?”

Women have experienced the loss of their period, excessive and prolonged bleeding, severe mood swings, and irritability, according to the Guardian article. London-based gynecologist Anita Mitra, MBChB, PhD, took an informal survey and found that 65% of 5,677 respondents had noticed a change in their menstrual cycle, the Guardian reported. Another survey, which was posted on medRxiv but hasn’t been peer reviewed yet, found 53% of the 749 respondents had noticed a change in their menstrual cycle, including increased cycle length.

“The pandemic in itself has made more stress for women,” said Karen Carlson, MD, obstetrician and gynecologist at Nebraska Medicine. There’s preliminary evidence that the cycling progesterone and estrogen experienced by reproductive age women actually offers a protective effect against COVID-19, which is good news. But Dr. Carlson said that because they are less likely than men and the elderly to become seriously ill, many women have taken on a lot of the additional responsibilities brought on by the pandemic. They often juggle homeschooling and elder care in addition to the ubiquitous stressors of isolation and concerns around personal health.

“Abnormal bleeding is the most common reason people present to the gynecologist,” Dr. Carlson said in an interview. But in recent months, Dr. Carlson said she’s seen a slight uptick in these issues, and there might have been even more women presenting to their physicians if the pandemic hadn’t also suppressed access to care.

Stress, or rather the cortisol it causes the body to produce, is the culprit for disrupted cycles. It can suppress pituitary hormones that stimulate ovulation. “Some women don’t feel right because they are stuck in the one phase of the cycle,” Dr. Carlson said. They may go months without a period and when they do eventually shed their uterine lining the bleeding goes on for a while.

Some irregularity in a person’s cycle is a normal response to stress and even likely, given the last year. However, bleeding for more than 2 weeks or irregularity for more than 3 months could point to something more serious like an infection or cancer, Dr. Carlson said. Getting a clear history so you know when you need to do blood and hormone workups is critical.
 

Anxiety and depression amplified

For some women it’s not bleeding that’s a problem, rather their PMS has become crippling. And some of their significant others have noticed drastic changes in their mood. In the Guardian article, one woman said she’d gone from feeling withdrawn during her period to being totally unreachable and experiencing intense anxiety.

Maureen Whelihan, MD, a gynecologist in Palm Beach, Fla., said that, for the majority of her patients under 39 years of age, these feelings aren’t a hormone issue, but a stress and neuroreceptor issue. She says she’s seen approximately a 30% increase in mood disorders since the start of the pandemic. Even though many of her patients are cycling relatively normally, their anxiety and depression have been amplified.

Caroline Gurvich, PhD, a neuroscientist at Monash University in Melbourne, attributes this to the loss of typical coping mechanisms. “Having changes to the support system and routine and things that would keep them mentally healthy can exacerbate PMS,” she said in an interview. Dr. Gurvich’s advice is to build routines into the pandemic lifestyle. Normal wake and sleep times, healthy eating, and practices that bring happiness can be “crucial to keeping those PMS systems as controlled as possible.”

Telehealth has made it much easier to access some patients struggling with PMS and offer them the medication or counseling they need, Dr. Carlson said. But that approach doesn’t work for everyone. “I feel like there are a lot of silent sufferers,” she said.

This is where screening practices like the Patient Health Questionnaire-9 are so critical, according to Dr. Whelihan, who screens every patient as part of their routine iPad check-in process. Even in a normal year, “I think one-third of gynecology is psychiatry,” she said in an interview. She finds many of the patients struggling with excessive PMS symptoms, both during the pandemic and before, benefit from a child-sized dose of antidepressant. This may allow them to get to a place where they can make impactful routine decisions about exercise or sleep, and then taper off the antidepressant.

It may also be important for clinicians to help patients make the initial connection between their worsening mood or cognitive function and their period. Knowing their feelings of stress, irritability, fogginess, or being withdrawn are linked to their hormone cycle and possibly worsened by the stress of the pandemic can be helpful, Dr. Gurvich said. “If they become conscious of how they are feeling it can be helpful for management of these stressful symptoms,” she said.

Following a recent article in the Guardian, the Internet has erupted with tales of periods gone awry. The stress and loss of normalcy over the last year appears to have altered cycles and amplified the premenstrual syndrome (PMS) symptoms many women experience. And after the piece published, many responded on social media with the same sentiment: “So, it’s not just me?”

Women have experienced the loss of their period, excessive and prolonged bleeding, severe mood swings, and irritability, according to the Guardian article. London-based gynecologist Anita Mitra, MBChB, PhD, took an informal survey and found that 65% of 5,677 respondents had noticed a change in their menstrual cycle, the Guardian reported. Another survey, which was posted on medRxiv but hasn’t been peer reviewed yet, found 53% of the 749 respondents had noticed a change in their menstrual cycle, including increased cycle length.

“The pandemic in itself has made more stress for women,” said Karen Carlson, MD, obstetrician and gynecologist at Nebraska Medicine. There’s preliminary evidence that the cycling progesterone and estrogen experienced by reproductive age women actually offers a protective effect against COVID-19, which is good news. But Dr. Carlson said that because they are less likely than men and the elderly to become seriously ill, many women have taken on a lot of the additional responsibilities brought on by the pandemic. They often juggle homeschooling and elder care in addition to the ubiquitous stressors of isolation and concerns around personal health.

“Abnormal bleeding is the most common reason people present to the gynecologist,” Dr. Carlson said in an interview. But in recent months, Dr. Carlson said she’s seen a slight uptick in these issues, and there might have been even more women presenting to their physicians if the pandemic hadn’t also suppressed access to care.

Stress, or rather the cortisol it causes the body to produce, is the culprit for disrupted cycles. It can suppress pituitary hormones that stimulate ovulation. “Some women don’t feel right because they are stuck in the one phase of the cycle,” Dr. Carlson said. They may go months without a period and when they do eventually shed their uterine lining the bleeding goes on for a while.

Some irregularity in a person’s cycle is a normal response to stress and even likely, given the last year. However, bleeding for more than 2 weeks or irregularity for more than 3 months could point to something more serious like an infection or cancer, Dr. Carlson said. Getting a clear history so you know when you need to do blood and hormone workups is critical.
 

Anxiety and depression amplified

For some women it’s not bleeding that’s a problem, rather their PMS has become crippling. And some of their significant others have noticed drastic changes in their mood. In the Guardian article, one woman said she’d gone from feeling withdrawn during her period to being totally unreachable and experiencing intense anxiety.

Maureen Whelihan, MD, a gynecologist in Palm Beach, Fla., said that, for the majority of her patients under 39 years of age, these feelings aren’t a hormone issue, but a stress and neuroreceptor issue. She says she’s seen approximately a 30% increase in mood disorders since the start of the pandemic. Even though many of her patients are cycling relatively normally, their anxiety and depression have been amplified.

Caroline Gurvich, PhD, a neuroscientist at Monash University in Melbourne, attributes this to the loss of typical coping mechanisms. “Having changes to the support system and routine and things that would keep them mentally healthy can exacerbate PMS,” she said in an interview. Dr. Gurvich’s advice is to build routines into the pandemic lifestyle. Normal wake and sleep times, healthy eating, and practices that bring happiness can be “crucial to keeping those PMS systems as controlled as possible.”

Telehealth has made it much easier to access some patients struggling with PMS and offer them the medication or counseling they need, Dr. Carlson said. But that approach doesn’t work for everyone. “I feel like there are a lot of silent sufferers,” she said.

This is where screening practices like the Patient Health Questionnaire-9 are so critical, according to Dr. Whelihan, who screens every patient as part of their routine iPad check-in process. Even in a normal year, “I think one-third of gynecology is psychiatry,” she said in an interview. She finds many of the patients struggling with excessive PMS symptoms, both during the pandemic and before, benefit from a child-sized dose of antidepressant. This may allow them to get to a place where they can make impactful routine decisions about exercise or sleep, and then taper off the antidepressant.

It may also be important for clinicians to help patients make the initial connection between their worsening mood or cognitive function and their period. Knowing their feelings of stress, irritability, fogginess, or being withdrawn are linked to their hormone cycle and possibly worsened by the stress of the pandemic can be helpful, Dr. Gurvich said. “If they become conscious of how they are feeling it can be helpful for management of these stressful symptoms,” she said.

Following a recent article in the Guardian, the Internet has erupted with tales of periods gone awry. The stress and loss of normalcy over the last year appears to have altered cycles and amplified the premenstrual syndrome (PMS) symptoms many women experience. And after the piece published, many responded on social media with the same sentiment: “So, it’s not just me?”

Women have experienced the loss of their period, excessive and prolonged bleeding, severe mood swings, and irritability, according to the Guardian article. London-based gynecologist Anita Mitra, MBChB, PhD, took an informal survey and found that 65% of 5,677 respondents had noticed a change in their menstrual cycle, the Guardian reported. Another survey, which was posted on medRxiv but hasn’t been peer reviewed yet, found 53% of the 749 respondents had noticed a change in their menstrual cycle, including increased cycle length.

“The pandemic in itself has made more stress for women,” said Karen Carlson, MD, obstetrician and gynecologist at Nebraska Medicine. There’s preliminary evidence that the cycling progesterone and estrogen experienced by reproductive age women actually offers a protective effect against COVID-19, which is good news. But Dr. Carlson said that because they are less likely than men and the elderly to become seriously ill, many women have taken on a lot of the additional responsibilities brought on by the pandemic. They often juggle homeschooling and elder care in addition to the ubiquitous stressors of isolation and concerns around personal health.

“Abnormal bleeding is the most common reason people present to the gynecologist,” Dr. Carlson said in an interview. But in recent months, Dr. Carlson said she’s seen a slight uptick in these issues, and there might have been even more women presenting to their physicians if the pandemic hadn’t also suppressed access to care.

Stress, or rather the cortisol it causes the body to produce, is the culprit for disrupted cycles. It can suppress pituitary hormones that stimulate ovulation. “Some women don’t feel right because they are stuck in the one phase of the cycle,” Dr. Carlson said. They may go months without a period and when they do eventually shed their uterine lining the bleeding goes on for a while.

Some irregularity in a person’s cycle is a normal response to stress and even likely, given the last year. However, bleeding for more than 2 weeks or irregularity for more than 3 months could point to something more serious like an infection or cancer, Dr. Carlson said. Getting a clear history so you know when you need to do blood and hormone workups is critical.
 

Anxiety and depression amplified

For some women it’s not bleeding that’s a problem, rather their PMS has become crippling. And some of their significant others have noticed drastic changes in their mood. In the Guardian article, one woman said she’d gone from feeling withdrawn during her period to being totally unreachable and experiencing intense anxiety.

Maureen Whelihan, MD, a gynecologist in Palm Beach, Fla., said that, for the majority of her patients under 39 years of age, these feelings aren’t a hormone issue, but a stress and neuroreceptor issue. She says she’s seen approximately a 30% increase in mood disorders since the start of the pandemic. Even though many of her patients are cycling relatively normally, their anxiety and depression have been amplified.

Caroline Gurvich, PhD, a neuroscientist at Monash University in Melbourne, attributes this to the loss of typical coping mechanisms. “Having changes to the support system and routine and things that would keep them mentally healthy can exacerbate PMS,” she said in an interview. Dr. Gurvich’s advice is to build routines into the pandemic lifestyle. Normal wake and sleep times, healthy eating, and practices that bring happiness can be “crucial to keeping those PMS systems as controlled as possible.”

Telehealth has made it much easier to access some patients struggling with PMS and offer them the medication or counseling they need, Dr. Carlson said. But that approach doesn’t work for everyone. “I feel like there are a lot of silent sufferers,” she said.

This is where screening practices like the Patient Health Questionnaire-9 are so critical, according to Dr. Whelihan, who screens every patient as part of their routine iPad check-in process. Even in a normal year, “I think one-third of gynecology is psychiatry,” she said in an interview. She finds many of the patients struggling with excessive PMS symptoms, both during the pandemic and before, benefit from a child-sized dose of antidepressant. This may allow them to get to a place where they can make impactful routine decisions about exercise or sleep, and then taper off the antidepressant.

It may also be important for clinicians to help patients make the initial connection between their worsening mood or cognitive function and their period. Knowing their feelings of stress, irritability, fogginess, or being withdrawn are linked to their hormone cycle and possibly worsened by the stress of the pandemic can be helpful, Dr. Gurvich said. “If they become conscious of how they are feeling it can be helpful for management of these stressful symptoms,” she said.

Patients being treated with infliximab had weakened immune responses to the first dose of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and BNT162b2 (Pfizer/BioNTech) vaccines, compared with patients on vedolizumab (Entyvio), although a very significant number of patients from both groups seroconverted after their second dose, according to a new U.K. study of patients with inflammatory bowel disease (IBD).

NoSystem images/Getty Images

“Antibody testing and adapted vaccine schedules should be considered to protect these at-risk patients,” Nicholas A. Kennedy, PhD, MBBS, of the University of Exeter (England) and colleagues wrote in a preprint published March 29 on MedRxiv.

Infliximab is an anti–tumor necrosis factor (anti-TNF) monoclonal antibody that’s approved to treat adult and pediatric Crohn’s disease and ulcerative colitis, as well as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, whereas vedolizumab, a gut selective anti-integrin alpha4beta7 monoclonal antibody that is not associated with impaired systemic immune responses, is approved to treat Crohn’s disease and ulcerative colitis in adults.

A previous study from Kennedy and colleagues revealed that IBD patients on infliximab showed a weakened COVID-19 antibody response compared with patients on vedolizumab. To determine if treatment with anti-TNF drugs impacted the efficacy of the first shot of these two-dose COVID-19 vaccines, the researchers used data from the CLARITY IBD study to assess 865 infliximab- and 428 vedolizumab-treated participants without evidence of prior SARS-CoV-2 infection who had received uninterrupted biologic therapy since being recruited between Sept. 22 and Dec. 23, 2020.

In the 3-10 weeks after initial vaccination, geometric mean concentrations for SARS-CoV-2 anti-spike protein receptor-binding protein antibodies were lower in patients on infliximab, compared with patients on vedolizumab for both the Pfizer (6.0 U/mL [5.9] versus 28.8 U/mL [5.4], P < .0001) and AstraZeneca (4.7 U/mL [4.9] versus 13.8 U/mL [5.9]; P < .0001) vaccines. The researchers’ multivariable models reinforced those findings, with antibody concentrations lower in infliximab-treated patients for both the Pfizer (fold change, 0.29; 95% confidence interval, 0.21-0.40; P < .0001) and AstraZeneca (FC, 0.39; 95% CI, 0.30-0.51; P < .0001) vaccines.

After second doses of the two-dose Pfizer vaccine, 85% of patients on infliximab and 86% of patients on vedolizumab seroconverted (P = .68); similarly high seroconversion rates were seen in patients who had been infected with SARS-CoV-2 prior to receiving either vaccine. Several patient characteristics were associated with lower antibody concentrations regardless of vaccine type: being 60 years or older, use of immunomodulators, having Crohn’s disease, and being a smoker. Alternatively, non-White ethnicity was associated with higher antibody concentrations.

Evidence has ‘unclear clinical significance’

“These data, which require peer review, do not change my opinion on the safety and efficacy of COVID-19 vaccines in patients taking TNF inhibitors such as infliximab as monotherapy for the treatment of psoriatic disease,” Joel M. Gelfand MD, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania, Philadelphia, said in an interview.

Courtesy Dr. Joel M. Gelfand

“First, two peer-reviewed studies found good antibody response in patients on TNF inhibitors receiving COVID-19 vaccines (doi: 10.1136/annrheumdis-2021-220289; 10.1136/annrheumdis-2021-220272). Second, antibody responses were robust in the small cohort that received the second dose of a COVID-19 vaccine. We already know that, for the two messenger RNA-based vaccines available under emergency use authorization in the U.S., a second dose is required for optimal efficacy. Thus, evidence of a reduced antibody response after just one dose is of unclear clinical significance. Third, antibody responses are only a surrogate marker, and a low antibody response doesn’t necessarily mean the patient will not be protected by the vaccine.”
 

Focus on the second dose of a two-dose regimen

“Tell me about the response in people who got both doses of a vaccine that you’re supposed to get both doses of,” Jeffrey Curtis, MD, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham, said in an interview. “The number of patients in that subset was small [n = 27] but in my opinion that’s the most clinically relevant analysis and the one that patients and clinicians want answered.”

Courtesy UAB Photo

He also emphasized the uncertainty around what ‘protection’ means in these early days of studying COVID-19 vaccine responses. “You can define seroprotection or seroconversion as some absolute level of an antibody response, but if you want to say ‘Mrs. Smith, your antibody level was X,’ on whatever arbitrary scale with whoever’s arbitrary lab test, nobody actually knows that Mrs. Smith is now protected from SARS-CoV-2, or how protected,” he said.

“What is not terribly controversial is: If you can’t detect antibodies, the vaccine didn’t ‘take,’ if you will. But if I tell you that the mean antibody level was X with one drug and then 2X with another drug, does that mean that you’re twice as protected? We don’t know that. I’m fearful that people are looking at these studies and thinking that more is better. It might be, but we don’t know that to be true.”
 

Debating the cause of weakened immune responses

“The biological plausibility of being on an anti-TNF affecting your immune reaction to a messenger RNA or even a replication-deficient viral vector vaccine doesn’t make sense,” David T. Rubin, MD, professor of medicine at the University of Chicago and chair of the National Scientific Advisory Committee of the Crohn’s and Colitis Foundation, said in an interview.

“I’m sure immunologists may differ with me on this, but given what we have come to appreciate about these vaccine mechanisms, this finding doesn’t make intuitive sense. So we need to make sure that, when this happens, we look to the next studies and try to understand, was there any other confounder that may have resulted in these findings that was not adequately adjusted for or addressed in some other way?

“When you have a study of this size, you argue, ‘Because it’s so large, any effect that was seen must be real,’ ” he added. “Alternatively, to have a study of this size, by its very nature you are limited in being able to control for certain other factors or differences between the groups.”

That said, he commended the authors for their study and acknowledged the potential questions it raises about the single-shot Johnson & Johnson vaccine. “If you only get one and you’re on infliximab, this study implies that maybe that’s not enough,” he said. “Despite the fact that Johnson & Johnson was approved as a single dose, it may be necessary to think about it as the first of two, or maybe it’s not the preferred vaccine in this group of patients.”

The study was supported by the Royal Devon and Exeter and Hull University Hospital Foundation NHS Trusts and unrestricted educational grants from Biogen (Switzerland), Celltrion Healthcare (South Korea), Galapagos NV (Belgium), and F. Hoffmann-La Roche (Switzerland). The authors acknowledged numerous potential conflicts of interest, including receiving grants, personal fees, and nonfinancial support from various pharmaceutical companies.

Patients being treated with infliximab had weakened immune responses to the first dose of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and BNT162b2 (Pfizer/BioNTech) vaccines, compared with patients on vedolizumab (Entyvio), although a very significant number of patients from both groups seroconverted after their second dose, according to a new U.K. study of patients with inflammatory bowel disease (IBD).

NoSystem images/Getty Images

“Antibody testing and adapted vaccine schedules should be considered to protect these at-risk patients,” Nicholas A. Kennedy, PhD, MBBS, of the University of Exeter (England) and colleagues wrote in a preprint published March 29 on MedRxiv.

Infliximab is an anti–tumor necrosis factor (anti-TNF) monoclonal antibody that’s approved to treat adult and pediatric Crohn’s disease and ulcerative colitis, as well as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, whereas vedolizumab, a gut selective anti-integrin alpha4beta7 monoclonal antibody that is not associated with impaired systemic immune responses, is approved to treat Crohn’s disease and ulcerative colitis in adults.

A previous study from Kennedy and colleagues revealed that IBD patients on infliximab showed a weakened COVID-19 antibody response compared with patients on vedolizumab. To determine if treatment with anti-TNF drugs impacted the efficacy of the first shot of these two-dose COVID-19 vaccines, the researchers used data from the CLARITY IBD study to assess 865 infliximab- and 428 vedolizumab-treated participants without evidence of prior SARS-CoV-2 infection who had received uninterrupted biologic therapy since being recruited between Sept. 22 and Dec. 23, 2020.

In the 3-10 weeks after initial vaccination, geometric mean concentrations for SARS-CoV-2 anti-spike protein receptor-binding protein antibodies were lower in patients on infliximab, compared with patients on vedolizumab for both the Pfizer (6.0 U/mL [5.9] versus 28.8 U/mL [5.4], P < .0001) and AstraZeneca (4.7 U/mL [4.9] versus 13.8 U/mL [5.9]; P < .0001) vaccines. The researchers’ multivariable models reinforced those findings, with antibody concentrations lower in infliximab-treated patients for both the Pfizer (fold change, 0.29; 95% confidence interval, 0.21-0.40; P < .0001) and AstraZeneca (FC, 0.39; 95% CI, 0.30-0.51; P < .0001) vaccines.

After second doses of the two-dose Pfizer vaccine, 85% of patients on infliximab and 86% of patients on vedolizumab seroconverted (P = .68); similarly high seroconversion rates were seen in patients who had been infected with SARS-CoV-2 prior to receiving either vaccine. Several patient characteristics were associated with lower antibody concentrations regardless of vaccine type: being 60 years or older, use of immunomodulators, having Crohn’s disease, and being a smoker. Alternatively, non-White ethnicity was associated with higher antibody concentrations.

Evidence has ‘unclear clinical significance’

“These data, which require peer review, do not change my opinion on the safety and efficacy of COVID-19 vaccines in patients taking TNF inhibitors such as infliximab as monotherapy for the treatment of psoriatic disease,” Joel M. Gelfand MD, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania, Philadelphia, said in an interview.

Courtesy Dr. Joel M. Gelfand

“First, two peer-reviewed studies found good antibody response in patients on TNF inhibitors receiving COVID-19 vaccines (doi: 10.1136/annrheumdis-2021-220289; 10.1136/annrheumdis-2021-220272). Second, antibody responses were robust in the small cohort that received the second dose of a COVID-19 vaccine. We already know that, for the two messenger RNA-based vaccines available under emergency use authorization in the U.S., a second dose is required for optimal efficacy. Thus, evidence of a reduced antibody response after just one dose is of unclear clinical significance. Third, antibody responses are only a surrogate marker, and a low antibody response doesn’t necessarily mean the patient will not be protected by the vaccine.”
 

Focus on the second dose of a two-dose regimen

“Tell me about the response in people who got both doses of a vaccine that you’re supposed to get both doses of,” Jeffrey Curtis, MD, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham, said in an interview. “The number of patients in that subset was small [n = 27] but in my opinion that’s the most clinically relevant analysis and the one that patients and clinicians want answered.”

Courtesy UAB Photo

He also emphasized the uncertainty around what ‘protection’ means in these early days of studying COVID-19 vaccine responses. “You can define seroprotection or seroconversion as some absolute level of an antibody response, but if you want to say ‘Mrs. Smith, your antibody level was X,’ on whatever arbitrary scale with whoever’s arbitrary lab test, nobody actually knows that Mrs. Smith is now protected from SARS-CoV-2, or how protected,” he said.

“What is not terribly controversial is: If you can’t detect antibodies, the vaccine didn’t ‘take,’ if you will. But if I tell you that the mean antibody level was X with one drug and then 2X with another drug, does that mean that you’re twice as protected? We don’t know that. I’m fearful that people are looking at these studies and thinking that more is better. It might be, but we don’t know that to be true.”
 

Debating the cause of weakened immune responses

“The biological plausibility of being on an anti-TNF affecting your immune reaction to a messenger RNA or even a replication-deficient viral vector vaccine doesn’t make sense,” David T. Rubin, MD, professor of medicine at the University of Chicago and chair of the National Scientific Advisory Committee of the Crohn’s and Colitis Foundation, said in an interview.

“I’m sure immunologists may differ with me on this, but given what we have come to appreciate about these vaccine mechanisms, this finding doesn’t make intuitive sense. So we need to make sure that, when this happens, we look to the next studies and try to understand, was there any other confounder that may have resulted in these findings that was not adequately adjusted for or addressed in some other way?

“When you have a study of this size, you argue, ‘Because it’s so large, any effect that was seen must be real,’ ” he added. “Alternatively, to have a study of this size, by its very nature you are limited in being able to control for certain other factors or differences between the groups.”

That said, he commended the authors for their study and acknowledged the potential questions it raises about the single-shot Johnson & Johnson vaccine. “If you only get one and you’re on infliximab, this study implies that maybe that’s not enough,” he said. “Despite the fact that Johnson & Johnson was approved as a single dose, it may be necessary to think about it as the first of two, or maybe it’s not the preferred vaccine in this group of patients.”

The study was supported by the Royal Devon and Exeter and Hull University Hospital Foundation NHS Trusts and unrestricted educational grants from Biogen (Switzerland), Celltrion Healthcare (South Korea), Galapagos NV (Belgium), and F. Hoffmann-La Roche (Switzerland). The authors acknowledged numerous potential conflicts of interest, including receiving grants, personal fees, and nonfinancial support from various pharmaceutical companies.

Patients being treated with infliximab had weakened immune responses to the first dose of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and BNT162b2 (Pfizer/BioNTech) vaccines, compared with patients on vedolizumab (Entyvio), although a very significant number of patients from both groups seroconverted after their second dose, according to a new U.K. study of patients with inflammatory bowel disease (IBD).

NoSystem images/Getty Images

“Antibody testing and adapted vaccine schedules should be considered to protect these at-risk patients,” Nicholas A. Kennedy, PhD, MBBS, of the University of Exeter (England) and colleagues wrote in a preprint published March 29 on MedRxiv.

Infliximab is an anti–tumor necrosis factor (anti-TNF) monoclonal antibody that’s approved to treat adult and pediatric Crohn’s disease and ulcerative colitis, as well as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, whereas vedolizumab, a gut selective anti-integrin alpha4beta7 monoclonal antibody that is not associated with impaired systemic immune responses, is approved to treat Crohn’s disease and ulcerative colitis in adults.

A previous study from Kennedy and colleagues revealed that IBD patients on infliximab showed a weakened COVID-19 antibody response compared with patients on vedolizumab. To determine if treatment with anti-TNF drugs impacted the efficacy of the first shot of these two-dose COVID-19 vaccines, the researchers used data from the CLARITY IBD study to assess 865 infliximab- and 428 vedolizumab-treated participants without evidence of prior SARS-CoV-2 infection who had received uninterrupted biologic therapy since being recruited between Sept. 22 and Dec. 23, 2020.

In the 3-10 weeks after initial vaccination, geometric mean concentrations for SARS-CoV-2 anti-spike protein receptor-binding protein antibodies were lower in patients on infliximab, compared with patients on vedolizumab for both the Pfizer (6.0 U/mL [5.9] versus 28.8 U/mL [5.4], P < .0001) and AstraZeneca (4.7 U/mL [4.9] versus 13.8 U/mL [5.9]; P < .0001) vaccines. The researchers’ multivariable models reinforced those findings, with antibody concentrations lower in infliximab-treated patients for both the Pfizer (fold change, 0.29; 95% confidence interval, 0.21-0.40; P < .0001) and AstraZeneca (FC, 0.39; 95% CI, 0.30-0.51; P < .0001) vaccines.

After second doses of the two-dose Pfizer vaccine, 85% of patients on infliximab and 86% of patients on vedolizumab seroconverted (P = .68); similarly high seroconversion rates were seen in patients who had been infected with SARS-CoV-2 prior to receiving either vaccine. Several patient characteristics were associated with lower antibody concentrations regardless of vaccine type: being 60 years or older, use of immunomodulators, having Crohn’s disease, and being a smoker. Alternatively, non-White ethnicity was associated with higher antibody concentrations.

Evidence has ‘unclear clinical significance’

“These data, which require peer review, do not change my opinion on the safety and efficacy of COVID-19 vaccines in patients taking TNF inhibitors such as infliximab as monotherapy for the treatment of psoriatic disease,” Joel M. Gelfand MD, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania, Philadelphia, said in an interview.

Courtesy Dr. Joel M. Gelfand

“First, two peer-reviewed studies found good antibody response in patients on TNF inhibitors receiving COVID-19 vaccines (doi: 10.1136/annrheumdis-2021-220289; 10.1136/annrheumdis-2021-220272). Second, antibody responses were robust in the small cohort that received the second dose of a COVID-19 vaccine. We already know that, for the two messenger RNA-based vaccines available under emergency use authorization in the U.S., a second dose is required for optimal efficacy. Thus, evidence of a reduced antibody response after just one dose is of unclear clinical significance. Third, antibody responses are only a surrogate marker, and a low antibody response doesn’t necessarily mean the patient will not be protected by the vaccine.”
 

Focus on the second dose of a two-dose regimen

“Tell me about the response in people who got both doses of a vaccine that you’re supposed to get both doses of,” Jeffrey Curtis, MD, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham, said in an interview. “The number of patients in that subset was small [n = 27] but in my opinion that’s the most clinically relevant analysis and the one that patients and clinicians want answered.”

Courtesy UAB Photo

He also emphasized the uncertainty around what ‘protection’ means in these early days of studying COVID-19 vaccine responses. “You can define seroprotection or seroconversion as some absolute level of an antibody response, but if you want to say ‘Mrs. Smith, your antibody level was X,’ on whatever arbitrary scale with whoever’s arbitrary lab test, nobody actually knows that Mrs. Smith is now protected from SARS-CoV-2, or how protected,” he said.

“What is not terribly controversial is: If you can’t detect antibodies, the vaccine didn’t ‘take,’ if you will. But if I tell you that the mean antibody level was X with one drug and then 2X with another drug, does that mean that you’re twice as protected? We don’t know that. I’m fearful that people are looking at these studies and thinking that more is better. It might be, but we don’t know that to be true.”
 

Debating the cause of weakened immune responses

“The biological plausibility of being on an anti-TNF affecting your immune reaction to a messenger RNA or even a replication-deficient viral vector vaccine doesn’t make sense,” David T. Rubin, MD, professor of medicine at the University of Chicago and chair of the National Scientific Advisory Committee of the Crohn’s and Colitis Foundation, said in an interview.

“I’m sure immunologists may differ with me on this, but given what we have come to appreciate about these vaccine mechanisms, this finding doesn’t make intuitive sense. So we need to make sure that, when this happens, we look to the next studies and try to understand, was there any other confounder that may have resulted in these findings that was not adequately adjusted for or addressed in some other way?

“When you have a study of this size, you argue, ‘Because it’s so large, any effect that was seen must be real,’ ” he added. “Alternatively, to have a study of this size, by its very nature you are limited in being able to control for certain other factors or differences between the groups.”

That said, he commended the authors for their study and acknowledged the potential questions it raises about the single-shot Johnson & Johnson vaccine. “If you only get one and you’re on infliximab, this study implies that maybe that’s not enough,” he said. “Despite the fact that Johnson & Johnson was approved as a single dose, it may be necessary to think about it as the first of two, or maybe it’s not the preferred vaccine in this group of patients.”

The study was supported by the Royal Devon and Exeter and Hull University Hospital Foundation NHS Trusts and unrestricted educational grants from Biogen (Switzerland), Celltrion Healthcare (South Korea), Galapagos NV (Belgium), and F. Hoffmann-La Roche (Switzerland). The authors acknowledged numerous potential conflicts of interest, including receiving grants, personal fees, and nonfinancial support from various pharmaceutical companies.

Children and adolescents with Prader-Willi syndrome (PWS) who received three daily, intranasal doses of carbetocin, an investigational, long-acting oxytocin analogue, had significant improvement in hyperphagia and anxiety during 8 weeks on treatment, compared with placebo in a multicenter, phase 3 trial with 119 patients.

The treatment also appeared safe during up to 56 additional weeks on active treatment, with no serious adverse effects nor “unexpected” events, and once completing the study about 95% of enrolled patients opted to remain on active treatment, Cheri L. Deal, MD, PhD, said at the annual meeting of the Endocrine Society.

Based on “the significant results for the placebo-controlled period, as well as for those finishing the 56-week extension, we may well have a new armament for helping these kids and their families deal with the unrelenting hunger of patients with PWS as well as some of the behavioral symptoms,” Dr. Deal, chief of endocrinology and diabetes at the Sainte-Justine Mother-Child University of Montreal Hospital, said in an interview. No treatment currently has labeling for addressing the hyperphagia or anxiety that is characteristic and often problematic for children and adolescents with PWS, an autosomal dominant genetic disease with an incidence of about 1 in 15,000 births and an estimated U.S. prevalence of about 9,000 cases, or about 1 case for every 37,000 people.
 

‘Gorgeous’ safety

“The results looked pretty positive, and we’re encouraged by what appears to be a good safety profile, so overall I think the PWS community is very excited by the results and is very interested in getting access to this drug,” commented Theresa V. Strong, PhD, director of research programs for the Foundation for Prader-Willi Research in Walnut, Calif., a group not involved with the study. Currently, “we have no effective treatments for these difficult behaviors” of hyperphagia and anxiety. Surveys and studies run by the foundation have documented that hyperphagia and anxiety “were the two most important symptoms that families would like to see treated,” Dr. Strong added in an interview.

PWS “is complex and affects almost every aspect of the lives of affected people and their families. Any treatment that can chip away at some of the problems these patients have can be a huge benefit to the patients and their families,” said Jennifer L. Miller, MD, a professor of pediatric endocrinology at the University of Florida, Gainesville, and a coinvestigator on the study.

But the finding that carbetocin appeared to address, at least in part, this unmet need while compiling a safety record that Dr. Miller called “gorgeous” and “remarkable,” also came with a few limitations.
 

Fewer patients than planned, and muddled outcomes

The CARE-PWS trial aimed to enroll 175 patients, but fell short once the COVID-19 pandemic hit. Plus the trial had two prespecified primary endpoints – improvements in a measure of hyperphagia, and in a measure of obsessive and compulsive behaviors – specifically in the 40 patients who received the higher of the two dosages studied, 9.6 mg t.i.d. intranasally. Neither endpoint showed significant improvement among the patients on this dosage, compared with the 40 patients who received placebo, although both outcomes trended in the right direction in the actively treated patients.

The study’s positive results came in a secondary treatment group, 39 patients who received 3.2 mg t.i.d., also intranasally. This subgroup had significant benefit, compared with placebo, for reducing hyperphagia symptoms as measured on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score. After the first 8 weeks on treatment, patients on the lower carbetocin dosage had an average reduction in their HQ-CT score of greater than 5 points, more than double the reduction seen among control patients who received placebo.

Those on the 3.2-mg t.i.d. dosage also showed significant improvements, compared with placebo, for anxiety, measured by the PWS Anxiety and Distress Questionnaire Total Score, as well as on measures of clinical global impression of severity, and of clinical global impression of change. Like the higher-dosage patients the lower-dosage subgroup did not show a significant difference compared with placebo for the other primary endpoint, change in obsessive and compulsive behaviors as measured by the Children’s Yale-Brown Obsessive-Compulsive Scale Total Score, although also like the higher dosage the effect from the lower dosage trended toward benefit.

A further limitation was that, at the time of her report, presented in abstract OR16-3 at the meeting, Dr. Deal could only present complete 64-week follow-up for 72 patients, although this reassuringly showed that, as time on the 9.6-mg t.i.d. dosage continued beyond 8 weeks, patients gradually improved their HQ-CT response so that by 64 weeks on treatment their hyperphagia score had improved as much as in the patients who received the lower dosage.

In short, documented benefits occurred on the lower dosage, especially for clinically meaningful symptoms like hyperphagia and anxiety, but the study’s overall results were not fully consistent by statistical criteria.

Benefiting an unmet need?

“While it is regrettable that we did not get to 175 patients because of COVID-19, the dataset is significant enough for me to feel that the FDA [Food and Drug Administration] needs to take a very serious look and consider approval,” Dr. Deal said in an interview. “Once safety is assured, which I think it is, I can only hope that regulatory officials understand their unmet needs of this rare disease community and will allow the drug to move to the next stage.”

“This is a very rare disease, and having families participate in trials is really challenging,” especially while the COVID-19 pandemic continues, Dr. Strong said. For the pediatric and adolescent patients targeted in this study “it will take a while for COVID to go away and for families to feel safe again being in a trial, so a real concern is that a need for more clinical trials is not terribly feasible now. Given that the safety profile looked good and one dose seemed to have good efficacy, as long as the long-term data continue to look good we’d love for the FDA to look at the existing data and see whether there is a path forward.”

Dr. Miller highlighted the limitations of what the CARE-PWS findings show.

“Given that it was only an 8-week trial of drug against placebo, and the fact that the primary outcomes weren’t met for the higher dose, my thought is that potentially we need to study more patients for a longer period at the 3.2-mg dose,” she said. She acknowledged that the metric used in the study to assess obsessive and compulsive behaviors is “very difficult” to apply to patients with PWS because of uncertainties in scoring obsessions in patients “who are not very good at telling you what they’re thinking.” Plus, “it’s absolutely not a problem that we did not see an effect on obsession and compulsions if the treatment potentially improves anxiety and hyperphagia, which are very common.” A treatment that reliably reduces these symptoms “would be amazing,” Dr. Miller added.

“PWS is very rare, so it’s very hard to do trials. Maybe the FDA will approve carbetocin because it was safe and gave a signal of efficacy at the lower dose. But my thought is that additional treatment trials are needed with only the lower dose and with longer duration,” she said.

CARE-PWS enrolled patients with nutritional phase 3 PWS who were aged 7-18 years at any of 24 sites in the United States, Canada, or Australia during 2018-2020. They averaged about 12 years of age, and 56% were girls.

The most common adverse effect from carbetocin was flushing, occurring in 14% of those on the lower dose and 21% on the higher dose, but not in any placebo patient. Other adverse effects more common on the lower dose than in the placebo group included headache in 16%, and diarrhea in 9%.

Carbetocin is not only long-lasting in circulation, it also has better affinity for oxytocin receptors than for vasopressin receptors, reducing the potential for causing hyponatremia. The idea to use it in patients with PWS followed prior studies with oxytocin, which had shown dopamine interactions that reduced anxiety and influenced food ingestion behavior. Brain autopsy studies had shown that patients with Prader-Willi syndrome have substantially fewer neurons than usual producing oxytocin. Treatment with intranasal carbetocin had shown efficacy for improving hyperphagia and behavior in a controlled phase 2 study with 37 patients.

Carbetocin is approved for use in reducing excessive bleeding after childbirth, particularly cesarean, in more than 20 countries outside the United States.

CARE-PWS was sponsored by Levo Therapeutics, the company developing carbetocin. Dr. Deal has been an adviser to Levo Therapeutics. Dr. Strong is an employee of the Foundation for Prader-Willi Research, which has received support from Levo Therapeutics as well as from other drug companies, but which receives most of its funding from individuals. Dr. Miller has received research funding from Levo Therapeutics and also from Harmony Biosciences, Rhythm Pharmaceuticals, and Soleno Therapeutics.

[email protected]

Children and adolescents with Prader-Willi syndrome (PWS) who received three daily, intranasal doses of carbetocin, an investigational, long-acting oxytocin analogue, had significant improvement in hyperphagia and anxiety during 8 weeks on treatment, compared with placebo in a multicenter, phase 3 trial with 119 patients.

The treatment also appeared safe during up to 56 additional weeks on active treatment, with no serious adverse effects nor “unexpected” events, and once completing the study about 95% of enrolled patients opted to remain on active treatment, Cheri L. Deal, MD, PhD, said at the annual meeting of the Endocrine Society.

Based on “the significant results for the placebo-controlled period, as well as for those finishing the 56-week extension, we may well have a new armament for helping these kids and their families deal with the unrelenting hunger of patients with PWS as well as some of the behavioral symptoms,” Dr. Deal, chief of endocrinology and diabetes at the Sainte-Justine Mother-Child University of Montreal Hospital, said in an interview. No treatment currently has labeling for addressing the hyperphagia or anxiety that is characteristic and often problematic for children and adolescents with PWS, an autosomal dominant genetic disease with an incidence of about 1 in 15,000 births and an estimated U.S. prevalence of about 9,000 cases, or about 1 case for every 37,000 people.
 

‘Gorgeous’ safety

“The results looked pretty positive, and we’re encouraged by what appears to be a good safety profile, so overall I think the PWS community is very excited by the results and is very interested in getting access to this drug,” commented Theresa V. Strong, PhD, director of research programs for the Foundation for Prader-Willi Research in Walnut, Calif., a group not involved with the study. Currently, “we have no effective treatments for these difficult behaviors” of hyperphagia and anxiety. Surveys and studies run by the foundation have documented that hyperphagia and anxiety “were the two most important symptoms that families would like to see treated,” Dr. Strong added in an interview.

PWS “is complex and affects almost every aspect of the lives of affected people and their families. Any treatment that can chip away at some of the problems these patients have can be a huge benefit to the patients and their families,” said Jennifer L. Miller, MD, a professor of pediatric endocrinology at the University of Florida, Gainesville, and a coinvestigator on the study.

But the finding that carbetocin appeared to address, at least in part, this unmet need while compiling a safety record that Dr. Miller called “gorgeous” and “remarkable,” also came with a few limitations.
 

Fewer patients than planned, and muddled outcomes

The CARE-PWS trial aimed to enroll 175 patients, but fell short once the COVID-19 pandemic hit. Plus the trial had two prespecified primary endpoints – improvements in a measure of hyperphagia, and in a measure of obsessive and compulsive behaviors – specifically in the 40 patients who received the higher of the two dosages studied, 9.6 mg t.i.d. intranasally. Neither endpoint showed significant improvement among the patients on this dosage, compared with the 40 patients who received placebo, although both outcomes trended in the right direction in the actively treated patients.

The study’s positive results came in a secondary treatment group, 39 patients who received 3.2 mg t.i.d., also intranasally. This subgroup had significant benefit, compared with placebo, for reducing hyperphagia symptoms as measured on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score. After the first 8 weeks on treatment, patients on the lower carbetocin dosage had an average reduction in their HQ-CT score of greater than 5 points, more than double the reduction seen among control patients who received placebo.

Those on the 3.2-mg t.i.d. dosage also showed significant improvements, compared with placebo, for anxiety, measured by the PWS Anxiety and Distress Questionnaire Total Score, as well as on measures of clinical global impression of severity, and of clinical global impression of change. Like the higher-dosage patients the lower-dosage subgroup did not show a significant difference compared with placebo for the other primary endpoint, change in obsessive and compulsive behaviors as measured by the Children’s Yale-Brown Obsessive-Compulsive Scale Total Score, although also like the higher dosage the effect from the lower dosage trended toward benefit.

A further limitation was that, at the time of her report, presented in abstract OR16-3 at the meeting, Dr. Deal could only present complete 64-week follow-up for 72 patients, although this reassuringly showed that, as time on the 9.6-mg t.i.d. dosage continued beyond 8 weeks, patients gradually improved their HQ-CT response so that by 64 weeks on treatment their hyperphagia score had improved as much as in the patients who received the lower dosage.

In short, documented benefits occurred on the lower dosage, especially for clinically meaningful symptoms like hyperphagia and anxiety, but the study’s overall results were not fully consistent by statistical criteria.

Benefiting an unmet need?

“While it is regrettable that we did not get to 175 patients because of COVID-19, the dataset is significant enough for me to feel that the FDA [Food and Drug Administration] needs to take a very serious look and consider approval,” Dr. Deal said in an interview. “Once safety is assured, which I think it is, I can only hope that regulatory officials understand their unmet needs of this rare disease community and will allow the drug to move to the next stage.”

“This is a very rare disease, and having families participate in trials is really challenging,” especially while the COVID-19 pandemic continues, Dr. Strong said. For the pediatric and adolescent patients targeted in this study “it will take a while for COVID to go away and for families to feel safe again being in a trial, so a real concern is that a need for more clinical trials is not terribly feasible now. Given that the safety profile looked good and one dose seemed to have good efficacy, as long as the long-term data continue to look good we’d love for the FDA to look at the existing data and see whether there is a path forward.”

Dr. Miller highlighted the limitations of what the CARE-PWS findings show.

“Given that it was only an 8-week trial of drug against placebo, and the fact that the primary outcomes weren’t met for the higher dose, my thought is that potentially we need to study more patients for a longer period at the 3.2-mg dose,” she said. She acknowledged that the metric used in the study to assess obsessive and compulsive behaviors is “very difficult” to apply to patients with PWS because of uncertainties in scoring obsessions in patients “who are not very good at telling you what they’re thinking.” Plus, “it’s absolutely not a problem that we did not see an effect on obsession and compulsions if the treatment potentially improves anxiety and hyperphagia, which are very common.” A treatment that reliably reduces these symptoms “would be amazing,” Dr. Miller added.

“PWS is very rare, so it’s very hard to do trials. Maybe the FDA will approve carbetocin because it was safe and gave a signal of efficacy at the lower dose. But my thought is that additional treatment trials are needed with only the lower dose and with longer duration,” she said.

CARE-PWS enrolled patients with nutritional phase 3 PWS who were aged 7-18 years at any of 24 sites in the United States, Canada, or Australia during 2018-2020. They averaged about 12 years of age, and 56% were girls.

The most common adverse effect from carbetocin was flushing, occurring in 14% of those on the lower dose and 21% on the higher dose, but not in any placebo patient. Other adverse effects more common on the lower dose than in the placebo group included headache in 16%, and diarrhea in 9%.

Carbetocin is not only long-lasting in circulation, it also has better affinity for oxytocin receptors than for vasopressin receptors, reducing the potential for causing hyponatremia. The idea to use it in patients with PWS followed prior studies with oxytocin, which had shown dopamine interactions that reduced anxiety and influenced food ingestion behavior. Brain autopsy studies had shown that patients with Prader-Willi syndrome have substantially fewer neurons than usual producing oxytocin. Treatment with intranasal carbetocin had shown efficacy for improving hyperphagia and behavior in a controlled phase 2 study with 37 patients.

Carbetocin is approved for use in reducing excessive bleeding after childbirth, particularly cesarean, in more than 20 countries outside the United States.

CARE-PWS was sponsored by Levo Therapeutics, the company developing carbetocin. Dr. Deal has been an adviser to Levo Therapeutics. Dr. Strong is an employee of the Foundation for Prader-Willi Research, which has received support from Levo Therapeutics as well as from other drug companies, but which receives most of its funding from individuals. Dr. Miller has received research funding from Levo Therapeutics and also from Harmony Biosciences, Rhythm Pharmaceuticals, and Soleno Therapeutics.

[email protected]

Children and adolescents with Prader-Willi syndrome (PWS) who received three daily, intranasal doses of carbetocin, an investigational, long-acting oxytocin analogue, had significant improvement in hyperphagia and anxiety during 8 weeks on treatment, compared with placebo in a multicenter, phase 3 trial with 119 patients.

The treatment also appeared safe during up to 56 additional weeks on active treatment, with no serious adverse effects nor “unexpected” events, and once completing the study about 95% of enrolled patients opted to remain on active treatment, Cheri L. Deal, MD, PhD, said at the annual meeting of the Endocrine Society.

Based on “the significant results for the placebo-controlled period, as well as for those finishing the 56-week extension, we may well have a new armament for helping these kids and their families deal with the unrelenting hunger of patients with PWS as well as some of the behavioral symptoms,” Dr. Deal, chief of endocrinology and diabetes at the Sainte-Justine Mother-Child University of Montreal Hospital, said in an interview. No treatment currently has labeling for addressing the hyperphagia or anxiety that is characteristic and often problematic for children and adolescents with PWS, an autosomal dominant genetic disease with an incidence of about 1 in 15,000 births and an estimated U.S. prevalence of about 9,000 cases, or about 1 case for every 37,000 people.
 

‘Gorgeous’ safety

“The results looked pretty positive, and we’re encouraged by what appears to be a good safety profile, so overall I think the PWS community is very excited by the results and is very interested in getting access to this drug,” commented Theresa V. Strong, PhD, director of research programs for the Foundation for Prader-Willi Research in Walnut, Calif., a group not involved with the study. Currently, “we have no effective treatments for these difficult behaviors” of hyperphagia and anxiety. Surveys and studies run by the foundation have documented that hyperphagia and anxiety “were the two most important symptoms that families would like to see treated,” Dr. Strong added in an interview.

PWS “is complex and affects almost every aspect of the lives of affected people and their families. Any treatment that can chip away at some of the problems these patients have can be a huge benefit to the patients and their families,” said Jennifer L. Miller, MD, a professor of pediatric endocrinology at the University of Florida, Gainesville, and a coinvestigator on the study.

But the finding that carbetocin appeared to address, at least in part, this unmet need while compiling a safety record that Dr. Miller called “gorgeous” and “remarkable,” also came with a few limitations.
 

Fewer patients than planned, and muddled outcomes

The CARE-PWS trial aimed to enroll 175 patients, but fell short once the COVID-19 pandemic hit. Plus the trial had two prespecified primary endpoints – improvements in a measure of hyperphagia, and in a measure of obsessive and compulsive behaviors – specifically in the 40 patients who received the higher of the two dosages studied, 9.6 mg t.i.d. intranasally. Neither endpoint showed significant improvement among the patients on this dosage, compared with the 40 patients who received placebo, although both outcomes trended in the right direction in the actively treated patients.

The study’s positive results came in a secondary treatment group, 39 patients who received 3.2 mg t.i.d., also intranasally. This subgroup had significant benefit, compared with placebo, for reducing hyperphagia symptoms as measured on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score. After the first 8 weeks on treatment, patients on the lower carbetocin dosage had an average reduction in their HQ-CT score of greater than 5 points, more than double the reduction seen among control patients who received placebo.

Those on the 3.2-mg t.i.d. dosage also showed significant improvements, compared with placebo, for anxiety, measured by the PWS Anxiety and Distress Questionnaire Total Score, as well as on measures of clinical global impression of severity, and of clinical global impression of change. Like the higher-dosage patients the lower-dosage subgroup did not show a significant difference compared with placebo for the other primary endpoint, change in obsessive and compulsive behaviors as measured by the Children’s Yale-Brown Obsessive-Compulsive Scale Total Score, although also like the higher dosage the effect from the lower dosage trended toward benefit.

A further limitation was that, at the time of her report, presented in abstract OR16-3 at the meeting, Dr. Deal could only present complete 64-week follow-up for 72 patients, although this reassuringly showed that, as time on the 9.6-mg t.i.d. dosage continued beyond 8 weeks, patients gradually improved their HQ-CT response so that by 64 weeks on treatment their hyperphagia score had improved as much as in the patients who received the lower dosage.

In short, documented benefits occurred on the lower dosage, especially for clinically meaningful symptoms like hyperphagia and anxiety, but the study’s overall results were not fully consistent by statistical criteria.

Benefiting an unmet need?

“While it is regrettable that we did not get to 175 patients because of COVID-19, the dataset is significant enough for me to feel that the FDA [Food and Drug Administration] needs to take a very serious look and consider approval,” Dr. Deal said in an interview. “Once safety is assured, which I think it is, I can only hope that regulatory officials understand their unmet needs of this rare disease community and will allow the drug to move to the next stage.”

“This is a very rare disease, and having families participate in trials is really challenging,” especially while the COVID-19 pandemic continues, Dr. Strong said. For the pediatric and adolescent patients targeted in this study “it will take a while for COVID to go away and for families to feel safe again being in a trial, so a real concern is that a need for more clinical trials is not terribly feasible now. Given that the safety profile looked good and one dose seemed to have good efficacy, as long as the long-term data continue to look good we’d love for the FDA to look at the existing data and see whether there is a path forward.”

Dr. Miller highlighted the limitations of what the CARE-PWS findings show.

“Given that it was only an 8-week trial of drug against placebo, and the fact that the primary outcomes weren’t met for the higher dose, my thought is that potentially we need to study more patients for a longer period at the 3.2-mg dose,” she said. She acknowledged that the metric used in the study to assess obsessive and compulsive behaviors is “very difficult” to apply to patients with PWS because of uncertainties in scoring obsessions in patients “who are not very good at telling you what they’re thinking.” Plus, “it’s absolutely not a problem that we did not see an effect on obsession and compulsions if the treatment potentially improves anxiety and hyperphagia, which are very common.” A treatment that reliably reduces these symptoms “would be amazing,” Dr. Miller added.

“PWS is very rare, so it’s very hard to do trials. Maybe the FDA will approve carbetocin because it was safe and gave a signal of efficacy at the lower dose. But my thought is that additional treatment trials are needed with only the lower dose and with longer duration,” she said.

CARE-PWS enrolled patients with nutritional phase 3 PWS who were aged 7-18 years at any of 24 sites in the United States, Canada, or Australia during 2018-2020. They averaged about 12 years of age, and 56% were girls.

The most common adverse effect from carbetocin was flushing, occurring in 14% of those on the lower dose and 21% on the higher dose, but not in any placebo patient. Other adverse effects more common on the lower dose than in the placebo group included headache in 16%, and diarrhea in 9%.

Carbetocin is not only long-lasting in circulation, it also has better affinity for oxytocin receptors than for vasopressin receptors, reducing the potential for causing hyponatremia. The idea to use it in patients with PWS followed prior studies with oxytocin, which had shown dopamine interactions that reduced anxiety and influenced food ingestion behavior. Brain autopsy studies had shown that patients with Prader-Willi syndrome have substantially fewer neurons than usual producing oxytocin. Treatment with intranasal carbetocin had shown efficacy for improving hyperphagia and behavior in a controlled phase 2 study with 37 patients.

Carbetocin is approved for use in reducing excessive bleeding after childbirth, particularly cesarean, in more than 20 countries outside the United States.

CARE-PWS was sponsored by Levo Therapeutics, the company developing carbetocin. Dr. Deal has been an adviser to Levo Therapeutics. Dr. Strong is an employee of the Foundation for Prader-Willi Research, which has received support from Levo Therapeutics as well as from other drug companies, but which receives most of its funding from individuals. Dr. Miller has received research funding from Levo Therapeutics and also from Harmony Biosciences, Rhythm Pharmaceuticals, and Soleno Therapeutics.

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