When Margot Gage-Witvliet began feeling run down after her family returned from a trip to the Netherlands in late February 2020, she initially chalked up her symptoms to jet lag. Three days later, however, her situation went from concerning to alarming as she struggled to breathe. “It felt like there was an elephant sitting on my chest,” she said.

Her husband and daughters also became ill with COVID-19, but Ms. Gage-Witvliet was the only one in her family who didn’t get better. After an early improvement, a rare coronavirus-induced tonic-clonic seizure in early April sent her spiraling back down. Ms. Gage-Witvliet spent the next several weeks in bed with the curtains drawn, unable to tolerate light or sound.

Today, Ms. Gage-Witvliet’s life looks nothing like it did 6 months ago when she first got sick. As one of COVID-19’s so called long-haulers, she continues to struggle with crushing fatigue, brain fog, and headaches – symptoms that worsen when she pushes herself to do more. Across the country, as many as 1 in 10 COVID-19 patients are reporting illnesses that continue for weeks and months after their initial diagnosis. Nearly all report neurologic issues like Ms. Gage-Witvliet, as well as shortness of breath and psychiatric concerns.

For Avindra Nath, MD, a neurologist at the National Institutes of Health, the experience of these long-haul COVID-19 patients feels familiar and reminds him of myalgic encephalomyelitis, also known as chronic fatigue syndrome.

Dr. Nath has long been interested in the lingering neurologic issues connected to chronic fatigue. An estimated three-quarters of all patients with chronic fatigue syndrome report that their symptoms started after a viral infection, and they suffer unrelenting exhaustion, difficulties regulating pulse and blood pressure, aches and pains, and brain fog. When Dr. Nath first read about the novel coronavirus, he began to worry that the virus would trigger symptoms in a subset of those infected. Hearing about the experiences of long-haulers like Ms. Gage-Witvliet raised his suspicions even more.

Unlike COVID-19 long-haulers, however, many patients with chronic fatigue syndrome go at least a year with these symptoms before receiving a diagnosis, according to a British survey. That means researchers have had few opportunities to study the early stages of the syndrome. “When we see patients with myalgic encephalomyelitis, whatever infection they might have had occurred in the remote past, so there’s no way for us to know how they got infected with it, what the infection was, or what the effects of it were in that early phase. We’re seeing them 2 years afterward,” Dr. Nath said.

Dr. Nath quickly realized that studying patients like Ms. Gage-Witvliet would give physicians and scientists a unique opportunity to understand not only long-term outcomes of COVID-19 infections, but also other postviral syndromes, including chronic fatigue syndrome at their earliest stages. It’s why Dr. Nath has spent the past several months scrambling to launch two NIH studies to examine the phenomenon.

Although Dr. Nath said that the parallels between COVID-19 long-haulers and those with chronic fatigue syndrome are obvious, he cautions against assuming that they are the same phenomenon. Some long-haulers might simply be taking a much slower path to recovery, or they might have a condition that looks similar on the surface but differs from chronic fatigue syndrome on a molecular level. But even if Dr. Nath fails to see links to chronic fatigue syndrome, with more than 92.5 million documented cases of COVID-19 around the world, the work will be relevant to the substantial number of infected individuals who don’t recover quickly.

“With so many people having exposure to the same virus over a similar time period, we really have the opportunity to look at these manifestations and at the very least to understand postviral syndromes,” said Mady Hornig, MD, a psychiatrist at Columbia University, New York.

The origins of chronic fatigue syndrome date back to 1985, when the Centers for Disease Control and Prevention received a request from two physicians – Paul Cheney, MD, and Daniel Peterson, MD – to investigate a mysterious disease outbreak in Nevada. In November 1984, residents in and around the idyllic vacation spot of Incline Village, a small town tucked into the north shore of Lake Tahoe, had begun reporting flu-like symptoms that persisted for weeks, even months. The doctors had searched high and low for a cause, but they couldn’t figure out what was making their patients sick.

They reported a range of symptoms – including muscle aches and pains, low-grade fevers, sore throats, and headaches – but everyone said that crippling fatigue was the most debilitating issue. This wasn’t the kind of fatigue that could be cured by a nap or even a long holiday. No matter how much their patients slept – and some were almost completely bedbound – their fatigue didn’t abate. What’s more, the fatigue got worse whenever they tried to push themselves to do more. Puzzled, the CDC sent two epidemic intelligence service (EIS) officers to try to get to the bottom of what might be happening.


 

Muscle aches and pains with crippling fatigue

After their visit to Incline Village, however, the CDC was just as perplexed as Dr. Cheney and Dr. Peterson. Many of the people with the condition reported flu-like symptoms right around the time they first got sick, and the physicians’ leading hypothesis was that the outbreak and its lasting symptoms were caused by chronic Epstein-Barr virus infection. But neither the CDC nor anyone else could identify the infection or any other microbial cause. The two EIS officers duly wrote up a report for the CDC’s flagship publication, Morbidity and Mortality Weekly ReportI, titled “Chronic Fatigue Possibly Related to Epstein-Barr Virus – Nevada”.

That investigators focused on the fatigue aspect made sense, says Leonard A. Jason, PhD, professor of psychology at DePaul University and director of the Center for Community Research, both in Chicago, because it was one of the few symptoms shared by all the individuals studied and it was also the most debilitating. But that focus – and the name “chronic fatigue syndrome” – led to broad public dismissal of the condition’s severity, as did an editorial note in MMWR urging physicians to look for “more definable, and possibly treatable, conditions.” Subsequent research failed to confirm a specific link to the Epstein-Barr virus, which only added to the condition’s phony reputation. Rather than being considered a potentially disabling illness, it was disregarded as a “yuppie flu” or a fancy name for malingering.

“It’s not a surprise that patients are being dismissed because there’s already this sort of grandfathered-in sense that fatigue is not real,” said Jennifer Frankovich, MD, a pediatric rheumatologist at Stanford (Calif.) University’s Lucile Packard Children’s Hospital in Palo Alto. “I’m sure that’s frustrating for them to be tired and then to have the clinician not believe them or dismiss them or think they’re making it up. It would be more helpful to the families to say: ‘You know what, we don’t know, we do not have the answer, and we believe you.’ ”
 

A syndrome’s shame

As time passed, patient advocacy groups began pushing back against the negative way the condition was being perceived. This criticism came as organizations like the CDC worked to develop a set of diagnostic criteria that researchers and clinicians dealing with chronic fatigue syndrome could use. With such a heterogeneous group of patients and symptoms, the task was no small challenge. The discussions, which took place over nearly 2 decades, played a key role in helping scientists home in on the single factor that was central to chronic fatigue: postexertional malaise.

“This is quite unique for chronic fatigue syndrome. With other diseases, yes, you may have fatigue as one of the components of the disease, but postexertional fatigue is very specific,” said Alain Moreau, PhD, a molecular biologist at the University of Montreal.

Of course, plenty of people have pushed themselves too hard physically and paid the price the next day. But those with chronic fatigue syndrome weren’t running marathons. To them, exertion could be anything from getting the mail to reading a book. Nor could the resulting exhaustion be resolved by an afternoon on the couch or a long vacation.

“If they do these activities, they can crash for weeks, even months,” Dr. Moreau said. It was deep, persistent, and – for 40% of those with chronic fatigue syndrome – disabling. In 2015, a study group from the Institute of Medicine proposed renaming chronic fatigue to “systemic exercise intolerance disease” because of the centrality of this symptom. Although that effort mostly stalled, their report did bring the condition out of its historic place as a scientific backwater. What resulted was an uptick in research on chronic fatigue syndrome, which helped define some of the physiological issues that either contribute to or result from the condition.

Researchers had long known about the link between infection and fatigue, said Dr. Frankovich. Work included mysterious outbreaks like the one in Lake Tahoe and well-documented issues like the wave of encephalitis lethargica (a condition that leaves patients in an almost vegetative state) that followed the 1918 H1N1 influenza pandemic.

“As a clinician, when you see someone who comes in with a chronic infection, they’re tired. I think that’s why, in the chronic-fatigue world, people are desperately looking for the infection so we can treat it, and maybe these poor suffering people will feel better,” Dr. Frankovich added. Then the pandemic struck, giving him yet another opportunity to study postviral syndromes.
 

Immunologic symptoms

Given the close link between a nonspecific viral illness and the onset of symptoms in chronic fatigue syndrome, scientists like Dr. Hornig opted to focus on immunologic symptoms. In a 2015 analysis published in Science, Dr. Hornig and colleagues showed that immune problems can be found in the earliest stages of chronic fatigue syndrome, and that they change as the illness progresses. Patients who had been sick for less than 3 years showed significant increases in levels of both pro- and anti-inflammatory cytokines, and the factor most strongly correlated to this inability to regulate cytokine levels was the duration of symptoms, not their severity. A series of other studies also revealed problems with regulation of the immune system, although no one could show what might have set these problems in motion.

Other researchers found signs of mitochondrial dysfunction in those with chronic fatigue syndrome. Because mitochondria make energy for cells, it wasn’t an intellectual stretch to believe that glitches in this process could contribute to fatigue. As early as 1991, scientists had discovered signs of mitochondrial degeneration in muscle biopsies from people with chronic fatigue syndrome. Subsequent studies showed that those affected by chronic fatigue were missing segments of mitochondrial DNA and had significantly reduced levels of mitochondrial activity. Although exercise normally improves mitochondrial functioning, the opposite appears to happen in chronic fatigue.

To Dr. Nath, these dual hypotheses aren’t necessarily mutually exclusive. Some studies have hinted that infection with the common human herpesvirus–6 (HHV-6) can lead to an autoimmune condition in which the body makes antibodies against the mitochondria. Mitochondria also play a key role in the ability of the innate immune system to produce interferon and other proinflammatory cytokines. It might also be that the link between immune and mitochondrial problems is more convoluted than originally thought, or that the two systems are affected independent of one another, Dr. Nath said.

Finding answers, especially those that could lead to potential treatments, wouldn’t be easy, however. In 2016, the NIH launched an in-depth study of a small number of individuals with chronic fatigue, hoping to find clues about what the condition was and how it might be treated.

For scientists like Dr. Nath, the NIH study provided a way to get at the underlying biology of chronic fatigue syndrome. Then the pandemic struck, giving him yet another opportunity to study postviral syndromes.
 

Chronic post-SARS syndrome

In March 2020, retired physician Harvey Moldofsky, MD, began receiving inquiries about a 2011 study he and his colleague, John Patcai, MD, had published in BMC Neurology about something they dubbed “chronic post-SARS syndrome.” The small case-control study, which involved mainly health care workers in Toronto, received little attention when it was first published, but with COVID-19, it was suddenly relevant.

Early clusters of similar cases in Miami made local physicians desperate for Dr. Moldofsky’s expertise. Luckily, he was nearby; he had fled the frigid Canadian winter for the warmth of Sarasota, Fla.

“I had people from various countries around the world writing to me and asking what they should do. And of course I don’t have any answers,” he said. But the study contained one of the world’s only references to the syndrome.

In 2003, a woman arrived in Toronto from Hong Kong. She didn’t know it at the time, but her preairport stay at the Hotel Metropole had infected her with the first SARS (severe acute respiratory syndrome) coronavirus. Her subsequent hospitalization in Toronto sparked a city-wide outbreak of SARS in which 273 people became ill and 44 died. Many of those affected were health care workers, including nurses and respiratory therapists. Although most eventually returned to work, a subset couldn’t. They complained of energy-sapping fatigue, poor sleep, brain fog, and assorted body aches and pains that persisted for more than 18 months. The aches and pains brought them to the attention of Dr. Moldofsky, then director of the Centre for the Study of Pain at the University of Toronto.

His primary interest at the time was fibromyalgia, which caused symptoms similar to those reported by the original SARS long-haulers. Intrigued, Dr. Moldofsky agreed to take a look. Their chest x-rays were clear and the nurses showed no signs of lingering viral infection. Dr. Moldofsky could see that the nurses were ill and suffering, but no lab tests or anything else could identify what was causing their symptoms.

In 2011, Dr. Moldofsky and Dr. Patcai found a strong overlap between chronic SARS, fibromyalgia, and chronic fatigue syndrome when they compared 22 patients with long-term SARS issues with 21 who had fibromyalgia. “Their problems are exactly the same. They have strange symptoms and nobody can figure out what they’re about. And these symptoms are aches and pains, and they have trouble thinking and concentrating,” Dr. Moldofsky said. Reports of COVID-19 long-haulers didn’t surprise Dr. Moldofsky, and he immediately recognized that Nath’s intention to follow these patients could provide insights into both fibromyalgia and chronic fatigue syndrome.

That’s exactly what Dr. Nath is proposing with the two NIH studies. One will focus solely on the neurologic impacts of COVID-19, including stroke, loss of taste and smell, and brain fog. The other will bring patients who have had COVID-19 symptoms for at least 6 months to the NIH Clinical Center for an inpatient stay during which they will undergo detailed physiologic tests.

Scientists around the world are launching their own post–COVID-19 studies. Dr. Moreau’s group in Montreal has laid the groundwork for such an endeavor, and the CoroNerve group in the United Kingdom is monitoring neurologic complications from the coronavirus. Many of them have the same goals as the NIH studies: Leverage the large number of COVID-19 long-haulers to better understand the earliest stages of postviral syndrome.

“At this juncture, after all the reports that we’ve seen so far, I think it’s very unlikely that there will be no relationship whatsoever between COVID-19 and chronic fatigue syndrome,” Dr. Hornig said. “I think there certainly will be some, but again, what’s the scope, what’s the size? And then, of course, even more importantly, if it is happening, what is the mechanism and how is it happening?”

For people like Ms. Gage-Witvliet, the answers can’t come soon enough. For the first time in more than a decade, the full-time professor of epidemiology didn’t prepare to teach this year because she simply can’t. It’s too taxing for her brain to deal with impromptu student questions. Ms. Gage-Witvliet hopes that, by sharing her own experiences with post COVID-19, she can help others.

“In my work, I use data to give a voice to people who don’t have a voice,” she said. “Now, I am one of those people.”

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

When Margot Gage-Witvliet began feeling run down after her family returned from a trip to the Netherlands in late February 2020, she initially chalked up her symptoms to jet lag. Three days later, however, her situation went from concerning to alarming as she struggled to breathe. “It felt like there was an elephant sitting on my chest,” she said.

Her husband and daughters also became ill with COVID-19, but Ms. Gage-Witvliet was the only one in her family who didn’t get better. After an early improvement, a rare coronavirus-induced tonic-clonic seizure in early April sent her spiraling back down. Ms. Gage-Witvliet spent the next several weeks in bed with the curtains drawn, unable to tolerate light or sound.

Today, Ms. Gage-Witvliet’s life looks nothing like it did 6 months ago when she first got sick. As one of COVID-19’s so called long-haulers, she continues to struggle with crushing fatigue, brain fog, and headaches – symptoms that worsen when she pushes herself to do more. Across the country, as many as 1 in 10 COVID-19 patients are reporting illnesses that continue for weeks and months after their initial diagnosis. Nearly all report neurologic issues like Ms. Gage-Witvliet, as well as shortness of breath and psychiatric concerns.

For Avindra Nath, MD, a neurologist at the National Institutes of Health, the experience of these long-haul COVID-19 patients feels familiar and reminds him of myalgic encephalomyelitis, also known as chronic fatigue syndrome.

Dr. Nath has long been interested in the lingering neurologic issues connected to chronic fatigue. An estimated three-quarters of all patients with chronic fatigue syndrome report that their symptoms started after a viral infection, and they suffer unrelenting exhaustion, difficulties regulating pulse and blood pressure, aches and pains, and brain fog. When Dr. Nath first read about the novel coronavirus, he began to worry that the virus would trigger symptoms in a subset of those infected. Hearing about the experiences of long-haulers like Ms. Gage-Witvliet raised his suspicions even more.

Unlike COVID-19 long-haulers, however, many patients with chronic fatigue syndrome go at least a year with these symptoms before receiving a diagnosis, according to a British survey. That means researchers have had few opportunities to study the early stages of the syndrome. “When we see patients with myalgic encephalomyelitis, whatever infection they might have had occurred in the remote past, so there’s no way for us to know how they got infected with it, what the infection was, or what the effects of it were in that early phase. We’re seeing them 2 years afterward,” Dr. Nath said.

Dr. Nath quickly realized that studying patients like Ms. Gage-Witvliet would give physicians and scientists a unique opportunity to understand not only long-term outcomes of COVID-19 infections, but also other postviral syndromes, including chronic fatigue syndrome at their earliest stages. It’s why Dr. Nath has spent the past several months scrambling to launch two NIH studies to examine the phenomenon.

Although Dr. Nath said that the parallels between COVID-19 long-haulers and those with chronic fatigue syndrome are obvious, he cautions against assuming that they are the same phenomenon. Some long-haulers might simply be taking a much slower path to recovery, or they might have a condition that looks similar on the surface but differs from chronic fatigue syndrome on a molecular level. But even if Dr. Nath fails to see links to chronic fatigue syndrome, with more than 92.5 million documented cases of COVID-19 around the world, the work will be relevant to the substantial number of infected individuals who don’t recover quickly.

“With so many people having exposure to the same virus over a similar time period, we really have the opportunity to look at these manifestations and at the very least to understand postviral syndromes,” said Mady Hornig, MD, a psychiatrist at Columbia University, New York.

The origins of chronic fatigue syndrome date back to 1985, when the Centers for Disease Control and Prevention received a request from two physicians – Paul Cheney, MD, and Daniel Peterson, MD – to investigate a mysterious disease outbreak in Nevada. In November 1984, residents in and around the idyllic vacation spot of Incline Village, a small town tucked into the north shore of Lake Tahoe, had begun reporting flu-like symptoms that persisted for weeks, even months. The doctors had searched high and low for a cause, but they couldn’t figure out what was making their patients sick.

They reported a range of symptoms – including muscle aches and pains, low-grade fevers, sore throats, and headaches – but everyone said that crippling fatigue was the most debilitating issue. This wasn’t the kind of fatigue that could be cured by a nap or even a long holiday. No matter how much their patients slept – and some were almost completely bedbound – their fatigue didn’t abate. What’s more, the fatigue got worse whenever they tried to push themselves to do more. Puzzled, the CDC sent two epidemic intelligence service (EIS) officers to try to get to the bottom of what might be happening.


 

Muscle aches and pains with crippling fatigue

After their visit to Incline Village, however, the CDC was just as perplexed as Dr. Cheney and Dr. Peterson. Many of the people with the condition reported flu-like symptoms right around the time they first got sick, and the physicians’ leading hypothesis was that the outbreak and its lasting symptoms were caused by chronic Epstein-Barr virus infection. But neither the CDC nor anyone else could identify the infection or any other microbial cause. The two EIS officers duly wrote up a report for the CDC’s flagship publication, Morbidity and Mortality Weekly ReportI, titled “Chronic Fatigue Possibly Related to Epstein-Barr Virus – Nevada”.

That investigators focused on the fatigue aspect made sense, says Leonard A. Jason, PhD, professor of psychology at DePaul University and director of the Center for Community Research, both in Chicago, because it was one of the few symptoms shared by all the individuals studied and it was also the most debilitating. But that focus – and the name “chronic fatigue syndrome” – led to broad public dismissal of the condition’s severity, as did an editorial note in MMWR urging physicians to look for “more definable, and possibly treatable, conditions.” Subsequent research failed to confirm a specific link to the Epstein-Barr virus, which only added to the condition’s phony reputation. Rather than being considered a potentially disabling illness, it was disregarded as a “yuppie flu” or a fancy name for malingering.

“It’s not a surprise that patients are being dismissed because there’s already this sort of grandfathered-in sense that fatigue is not real,” said Jennifer Frankovich, MD, a pediatric rheumatologist at Stanford (Calif.) University’s Lucile Packard Children’s Hospital in Palo Alto. “I’m sure that’s frustrating for them to be tired and then to have the clinician not believe them or dismiss them or think they’re making it up. It would be more helpful to the families to say: ‘You know what, we don’t know, we do not have the answer, and we believe you.’ ”
 

A syndrome’s shame

As time passed, patient advocacy groups began pushing back against the negative way the condition was being perceived. This criticism came as organizations like the CDC worked to develop a set of diagnostic criteria that researchers and clinicians dealing with chronic fatigue syndrome could use. With such a heterogeneous group of patients and symptoms, the task was no small challenge. The discussions, which took place over nearly 2 decades, played a key role in helping scientists home in on the single factor that was central to chronic fatigue: postexertional malaise.

“This is quite unique for chronic fatigue syndrome. With other diseases, yes, you may have fatigue as one of the components of the disease, but postexertional fatigue is very specific,” said Alain Moreau, PhD, a molecular biologist at the University of Montreal.

Of course, plenty of people have pushed themselves too hard physically and paid the price the next day. But those with chronic fatigue syndrome weren’t running marathons. To them, exertion could be anything from getting the mail to reading a book. Nor could the resulting exhaustion be resolved by an afternoon on the couch or a long vacation.

“If they do these activities, they can crash for weeks, even months,” Dr. Moreau said. It was deep, persistent, and – for 40% of those with chronic fatigue syndrome – disabling. In 2015, a study group from the Institute of Medicine proposed renaming chronic fatigue to “systemic exercise intolerance disease” because of the centrality of this symptom. Although that effort mostly stalled, their report did bring the condition out of its historic place as a scientific backwater. What resulted was an uptick in research on chronic fatigue syndrome, which helped define some of the physiological issues that either contribute to or result from the condition.

Researchers had long known about the link between infection and fatigue, said Dr. Frankovich. Work included mysterious outbreaks like the one in Lake Tahoe and well-documented issues like the wave of encephalitis lethargica (a condition that leaves patients in an almost vegetative state) that followed the 1918 H1N1 influenza pandemic.

“As a clinician, when you see someone who comes in with a chronic infection, they’re tired. I think that’s why, in the chronic-fatigue world, people are desperately looking for the infection so we can treat it, and maybe these poor suffering people will feel better,” Dr. Frankovich added. Then the pandemic struck, giving him yet another opportunity to study postviral syndromes.
 

Immunologic symptoms

Given the close link between a nonspecific viral illness and the onset of symptoms in chronic fatigue syndrome, scientists like Dr. Hornig opted to focus on immunologic symptoms. In a 2015 analysis published in Science, Dr. Hornig and colleagues showed that immune problems can be found in the earliest stages of chronic fatigue syndrome, and that they change as the illness progresses. Patients who had been sick for less than 3 years showed significant increases in levels of both pro- and anti-inflammatory cytokines, and the factor most strongly correlated to this inability to regulate cytokine levels was the duration of symptoms, not their severity. A series of other studies also revealed problems with regulation of the immune system, although no one could show what might have set these problems in motion.

Other researchers found signs of mitochondrial dysfunction in those with chronic fatigue syndrome. Because mitochondria make energy for cells, it wasn’t an intellectual stretch to believe that glitches in this process could contribute to fatigue. As early as 1991, scientists had discovered signs of mitochondrial degeneration in muscle biopsies from people with chronic fatigue syndrome. Subsequent studies showed that those affected by chronic fatigue were missing segments of mitochondrial DNA and had significantly reduced levels of mitochondrial activity. Although exercise normally improves mitochondrial functioning, the opposite appears to happen in chronic fatigue.

To Dr. Nath, these dual hypotheses aren’t necessarily mutually exclusive. Some studies have hinted that infection with the common human herpesvirus–6 (HHV-6) can lead to an autoimmune condition in which the body makes antibodies against the mitochondria. Mitochondria also play a key role in the ability of the innate immune system to produce interferon and other proinflammatory cytokines. It might also be that the link between immune and mitochondrial problems is more convoluted than originally thought, or that the two systems are affected independent of one another, Dr. Nath said.

Finding answers, especially those that could lead to potential treatments, wouldn’t be easy, however. In 2016, the NIH launched an in-depth study of a small number of individuals with chronic fatigue, hoping to find clues about what the condition was and how it might be treated.

For scientists like Dr. Nath, the NIH study provided a way to get at the underlying biology of chronic fatigue syndrome. Then the pandemic struck, giving him yet another opportunity to study postviral syndromes.
 

Chronic post-SARS syndrome

In March 2020, retired physician Harvey Moldofsky, MD, began receiving inquiries about a 2011 study he and his colleague, John Patcai, MD, had published in BMC Neurology about something they dubbed “chronic post-SARS syndrome.” The small case-control study, which involved mainly health care workers in Toronto, received little attention when it was first published, but with COVID-19, it was suddenly relevant.

Early clusters of similar cases in Miami made local physicians desperate for Dr. Moldofsky’s expertise. Luckily, he was nearby; he had fled the frigid Canadian winter for the warmth of Sarasota, Fla.

“I had people from various countries around the world writing to me and asking what they should do. And of course I don’t have any answers,” he said. But the study contained one of the world’s only references to the syndrome.

In 2003, a woman arrived in Toronto from Hong Kong. She didn’t know it at the time, but her preairport stay at the Hotel Metropole had infected her with the first SARS (severe acute respiratory syndrome) coronavirus. Her subsequent hospitalization in Toronto sparked a city-wide outbreak of SARS in which 273 people became ill and 44 died. Many of those affected were health care workers, including nurses and respiratory therapists. Although most eventually returned to work, a subset couldn’t. They complained of energy-sapping fatigue, poor sleep, brain fog, and assorted body aches and pains that persisted for more than 18 months. The aches and pains brought them to the attention of Dr. Moldofsky, then director of the Centre for the Study of Pain at the University of Toronto.

His primary interest at the time was fibromyalgia, which caused symptoms similar to those reported by the original SARS long-haulers. Intrigued, Dr. Moldofsky agreed to take a look. Their chest x-rays were clear and the nurses showed no signs of lingering viral infection. Dr. Moldofsky could see that the nurses were ill and suffering, but no lab tests or anything else could identify what was causing their symptoms.

In 2011, Dr. Moldofsky and Dr. Patcai found a strong overlap between chronic SARS, fibromyalgia, and chronic fatigue syndrome when they compared 22 patients with long-term SARS issues with 21 who had fibromyalgia. “Their problems are exactly the same. They have strange symptoms and nobody can figure out what they’re about. And these symptoms are aches and pains, and they have trouble thinking and concentrating,” Dr. Moldofsky said. Reports of COVID-19 long-haulers didn’t surprise Dr. Moldofsky, and he immediately recognized that Nath’s intention to follow these patients could provide insights into both fibromyalgia and chronic fatigue syndrome.

That’s exactly what Dr. Nath is proposing with the two NIH studies. One will focus solely on the neurologic impacts of COVID-19, including stroke, loss of taste and smell, and brain fog. The other will bring patients who have had COVID-19 symptoms for at least 6 months to the NIH Clinical Center for an inpatient stay during which they will undergo detailed physiologic tests.

Scientists around the world are launching their own post–COVID-19 studies. Dr. Moreau’s group in Montreal has laid the groundwork for such an endeavor, and the CoroNerve group in the United Kingdom is monitoring neurologic complications from the coronavirus. Many of them have the same goals as the NIH studies: Leverage the large number of COVID-19 long-haulers to better understand the earliest stages of postviral syndrome.

“At this juncture, after all the reports that we’ve seen so far, I think it’s very unlikely that there will be no relationship whatsoever between COVID-19 and chronic fatigue syndrome,” Dr. Hornig said. “I think there certainly will be some, but again, what’s the scope, what’s the size? And then, of course, even more importantly, if it is happening, what is the mechanism and how is it happening?”

For people like Ms. Gage-Witvliet, the answers can’t come soon enough. For the first time in more than a decade, the full-time professor of epidemiology didn’t prepare to teach this year because she simply can’t. It’s too taxing for her brain to deal with impromptu student questions. Ms. Gage-Witvliet hopes that, by sharing her own experiences with post COVID-19, she can help others.

“In my work, I use data to give a voice to people who don’t have a voice,” she said. “Now, I am one of those people.”

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

When Margot Gage-Witvliet began feeling run down after her family returned from a trip to the Netherlands in late February 2020, she initially chalked up her symptoms to jet lag. Three days later, however, her situation went from concerning to alarming as she struggled to breathe. “It felt like there was an elephant sitting on my chest,” she said.

Her husband and daughters also became ill with COVID-19, but Ms. Gage-Witvliet was the only one in her family who didn’t get better. After an early improvement, a rare coronavirus-induced tonic-clonic seizure in early April sent her spiraling back down. Ms. Gage-Witvliet spent the next several weeks in bed with the curtains drawn, unable to tolerate light or sound.

Today, Ms. Gage-Witvliet’s life looks nothing like it did 6 months ago when she first got sick. As one of COVID-19’s so called long-haulers, she continues to struggle with crushing fatigue, brain fog, and headaches – symptoms that worsen when she pushes herself to do more. Across the country, as many as 1 in 10 COVID-19 patients are reporting illnesses that continue for weeks and months after their initial diagnosis. Nearly all report neurologic issues like Ms. Gage-Witvliet, as well as shortness of breath and psychiatric concerns.

For Avindra Nath, MD, a neurologist at the National Institutes of Health, the experience of these long-haul COVID-19 patients feels familiar and reminds him of myalgic encephalomyelitis, also known as chronic fatigue syndrome.

Dr. Nath has long been interested in the lingering neurologic issues connected to chronic fatigue. An estimated three-quarters of all patients with chronic fatigue syndrome report that their symptoms started after a viral infection, and they suffer unrelenting exhaustion, difficulties regulating pulse and blood pressure, aches and pains, and brain fog. When Dr. Nath first read about the novel coronavirus, he began to worry that the virus would trigger symptoms in a subset of those infected. Hearing about the experiences of long-haulers like Ms. Gage-Witvliet raised his suspicions even more.

Unlike COVID-19 long-haulers, however, many patients with chronic fatigue syndrome go at least a year with these symptoms before receiving a diagnosis, according to a British survey. That means researchers have had few opportunities to study the early stages of the syndrome. “When we see patients with myalgic encephalomyelitis, whatever infection they might have had occurred in the remote past, so there’s no way for us to know how they got infected with it, what the infection was, or what the effects of it were in that early phase. We’re seeing them 2 years afterward,” Dr. Nath said.

Dr. Nath quickly realized that studying patients like Ms. Gage-Witvliet would give physicians and scientists a unique opportunity to understand not only long-term outcomes of COVID-19 infections, but also other postviral syndromes, including chronic fatigue syndrome at their earliest stages. It’s why Dr. Nath has spent the past several months scrambling to launch two NIH studies to examine the phenomenon.

Although Dr. Nath said that the parallels between COVID-19 long-haulers and those with chronic fatigue syndrome are obvious, he cautions against assuming that they are the same phenomenon. Some long-haulers might simply be taking a much slower path to recovery, or they might have a condition that looks similar on the surface but differs from chronic fatigue syndrome on a molecular level. But even if Dr. Nath fails to see links to chronic fatigue syndrome, with more than 92.5 million documented cases of COVID-19 around the world, the work will be relevant to the substantial number of infected individuals who don’t recover quickly.

“With so many people having exposure to the same virus over a similar time period, we really have the opportunity to look at these manifestations and at the very least to understand postviral syndromes,” said Mady Hornig, MD, a psychiatrist at Columbia University, New York.

The origins of chronic fatigue syndrome date back to 1985, when the Centers for Disease Control and Prevention received a request from two physicians – Paul Cheney, MD, and Daniel Peterson, MD – to investigate a mysterious disease outbreak in Nevada. In November 1984, residents in and around the idyllic vacation spot of Incline Village, a small town tucked into the north shore of Lake Tahoe, had begun reporting flu-like symptoms that persisted for weeks, even months. The doctors had searched high and low for a cause, but they couldn’t figure out what was making their patients sick.

They reported a range of symptoms – including muscle aches and pains, low-grade fevers, sore throats, and headaches – but everyone said that crippling fatigue was the most debilitating issue. This wasn’t the kind of fatigue that could be cured by a nap or even a long holiday. No matter how much their patients slept – and some were almost completely bedbound – their fatigue didn’t abate. What’s more, the fatigue got worse whenever they tried to push themselves to do more. Puzzled, the CDC sent two epidemic intelligence service (EIS) officers to try to get to the bottom of what might be happening.


 

Muscle aches and pains with crippling fatigue

After their visit to Incline Village, however, the CDC was just as perplexed as Dr. Cheney and Dr. Peterson. Many of the people with the condition reported flu-like symptoms right around the time they first got sick, and the physicians’ leading hypothesis was that the outbreak and its lasting symptoms were caused by chronic Epstein-Barr virus infection. But neither the CDC nor anyone else could identify the infection or any other microbial cause. The two EIS officers duly wrote up a report for the CDC’s flagship publication, Morbidity and Mortality Weekly ReportI, titled “Chronic Fatigue Possibly Related to Epstein-Barr Virus – Nevada”.

That investigators focused on the fatigue aspect made sense, says Leonard A. Jason, PhD, professor of psychology at DePaul University and director of the Center for Community Research, both in Chicago, because it was one of the few symptoms shared by all the individuals studied and it was also the most debilitating. But that focus – and the name “chronic fatigue syndrome” – led to broad public dismissal of the condition’s severity, as did an editorial note in MMWR urging physicians to look for “more definable, and possibly treatable, conditions.” Subsequent research failed to confirm a specific link to the Epstein-Barr virus, which only added to the condition’s phony reputation. Rather than being considered a potentially disabling illness, it was disregarded as a “yuppie flu” or a fancy name for malingering.

“It’s not a surprise that patients are being dismissed because there’s already this sort of grandfathered-in sense that fatigue is not real,” said Jennifer Frankovich, MD, a pediatric rheumatologist at Stanford (Calif.) University’s Lucile Packard Children’s Hospital in Palo Alto. “I’m sure that’s frustrating for them to be tired and then to have the clinician not believe them or dismiss them or think they’re making it up. It would be more helpful to the families to say: ‘You know what, we don’t know, we do not have the answer, and we believe you.’ ”
 

A syndrome’s shame

As time passed, patient advocacy groups began pushing back against the negative way the condition was being perceived. This criticism came as organizations like the CDC worked to develop a set of diagnostic criteria that researchers and clinicians dealing with chronic fatigue syndrome could use. With such a heterogeneous group of patients and symptoms, the task was no small challenge. The discussions, which took place over nearly 2 decades, played a key role in helping scientists home in on the single factor that was central to chronic fatigue: postexertional malaise.

“This is quite unique for chronic fatigue syndrome. With other diseases, yes, you may have fatigue as one of the components of the disease, but postexertional fatigue is very specific,” said Alain Moreau, PhD, a molecular biologist at the University of Montreal.

Of course, plenty of people have pushed themselves too hard physically and paid the price the next day. But those with chronic fatigue syndrome weren’t running marathons. To them, exertion could be anything from getting the mail to reading a book. Nor could the resulting exhaustion be resolved by an afternoon on the couch or a long vacation.

“If they do these activities, they can crash for weeks, even months,” Dr. Moreau said. It was deep, persistent, and – for 40% of those with chronic fatigue syndrome – disabling. In 2015, a study group from the Institute of Medicine proposed renaming chronic fatigue to “systemic exercise intolerance disease” because of the centrality of this symptom. Although that effort mostly stalled, their report did bring the condition out of its historic place as a scientific backwater. What resulted was an uptick in research on chronic fatigue syndrome, which helped define some of the physiological issues that either contribute to or result from the condition.

Researchers had long known about the link between infection and fatigue, said Dr. Frankovich. Work included mysterious outbreaks like the one in Lake Tahoe and well-documented issues like the wave of encephalitis lethargica (a condition that leaves patients in an almost vegetative state) that followed the 1918 H1N1 influenza pandemic.

“As a clinician, when you see someone who comes in with a chronic infection, they’re tired. I think that’s why, in the chronic-fatigue world, people are desperately looking for the infection so we can treat it, and maybe these poor suffering people will feel better,” Dr. Frankovich added. Then the pandemic struck, giving him yet another opportunity to study postviral syndromes.
 

Immunologic symptoms

Given the close link between a nonspecific viral illness and the onset of symptoms in chronic fatigue syndrome, scientists like Dr. Hornig opted to focus on immunologic symptoms. In a 2015 analysis published in Science, Dr. Hornig and colleagues showed that immune problems can be found in the earliest stages of chronic fatigue syndrome, and that they change as the illness progresses. Patients who had been sick for less than 3 years showed significant increases in levels of both pro- and anti-inflammatory cytokines, and the factor most strongly correlated to this inability to regulate cytokine levels was the duration of symptoms, not their severity. A series of other studies also revealed problems with regulation of the immune system, although no one could show what might have set these problems in motion.

Other researchers found signs of mitochondrial dysfunction in those with chronic fatigue syndrome. Because mitochondria make energy for cells, it wasn’t an intellectual stretch to believe that glitches in this process could contribute to fatigue. As early as 1991, scientists had discovered signs of mitochondrial degeneration in muscle biopsies from people with chronic fatigue syndrome. Subsequent studies showed that those affected by chronic fatigue were missing segments of mitochondrial DNA and had significantly reduced levels of mitochondrial activity. Although exercise normally improves mitochondrial functioning, the opposite appears to happen in chronic fatigue.

To Dr. Nath, these dual hypotheses aren’t necessarily mutually exclusive. Some studies have hinted that infection with the common human herpesvirus–6 (HHV-6) can lead to an autoimmune condition in which the body makes antibodies against the mitochondria. Mitochondria also play a key role in the ability of the innate immune system to produce interferon and other proinflammatory cytokines. It might also be that the link between immune and mitochondrial problems is more convoluted than originally thought, or that the two systems are affected independent of one another, Dr. Nath said.

Finding answers, especially those that could lead to potential treatments, wouldn’t be easy, however. In 2016, the NIH launched an in-depth study of a small number of individuals with chronic fatigue, hoping to find clues about what the condition was and how it might be treated.

For scientists like Dr. Nath, the NIH study provided a way to get at the underlying biology of chronic fatigue syndrome. Then the pandemic struck, giving him yet another opportunity to study postviral syndromes.
 

Chronic post-SARS syndrome

In March 2020, retired physician Harvey Moldofsky, MD, began receiving inquiries about a 2011 study he and his colleague, John Patcai, MD, had published in BMC Neurology about something they dubbed “chronic post-SARS syndrome.” The small case-control study, which involved mainly health care workers in Toronto, received little attention when it was first published, but with COVID-19, it was suddenly relevant.

Early clusters of similar cases in Miami made local physicians desperate for Dr. Moldofsky’s expertise. Luckily, he was nearby; he had fled the frigid Canadian winter for the warmth of Sarasota, Fla.

“I had people from various countries around the world writing to me and asking what they should do. And of course I don’t have any answers,” he said. But the study contained one of the world’s only references to the syndrome.

In 2003, a woman arrived in Toronto from Hong Kong. She didn’t know it at the time, but her preairport stay at the Hotel Metropole had infected her with the first SARS (severe acute respiratory syndrome) coronavirus. Her subsequent hospitalization in Toronto sparked a city-wide outbreak of SARS in which 273 people became ill and 44 died. Many of those affected were health care workers, including nurses and respiratory therapists. Although most eventually returned to work, a subset couldn’t. They complained of energy-sapping fatigue, poor sleep, brain fog, and assorted body aches and pains that persisted for more than 18 months. The aches and pains brought them to the attention of Dr. Moldofsky, then director of the Centre for the Study of Pain at the University of Toronto.

His primary interest at the time was fibromyalgia, which caused symptoms similar to those reported by the original SARS long-haulers. Intrigued, Dr. Moldofsky agreed to take a look. Their chest x-rays were clear and the nurses showed no signs of lingering viral infection. Dr. Moldofsky could see that the nurses were ill and suffering, but no lab tests or anything else could identify what was causing their symptoms.

In 2011, Dr. Moldofsky and Dr. Patcai found a strong overlap between chronic SARS, fibromyalgia, and chronic fatigue syndrome when they compared 22 patients with long-term SARS issues with 21 who had fibromyalgia. “Their problems are exactly the same. They have strange symptoms and nobody can figure out what they’re about. And these symptoms are aches and pains, and they have trouble thinking and concentrating,” Dr. Moldofsky said. Reports of COVID-19 long-haulers didn’t surprise Dr. Moldofsky, and he immediately recognized that Nath’s intention to follow these patients could provide insights into both fibromyalgia and chronic fatigue syndrome.

That’s exactly what Dr. Nath is proposing with the two NIH studies. One will focus solely on the neurologic impacts of COVID-19, including stroke, loss of taste and smell, and brain fog. The other will bring patients who have had COVID-19 symptoms for at least 6 months to the NIH Clinical Center for an inpatient stay during which they will undergo detailed physiologic tests.

Scientists around the world are launching their own post–COVID-19 studies. Dr. Moreau’s group in Montreal has laid the groundwork for such an endeavor, and the CoroNerve group in the United Kingdom is monitoring neurologic complications from the coronavirus. Many of them have the same goals as the NIH studies: Leverage the large number of COVID-19 long-haulers to better understand the earliest stages of postviral syndrome.

“At this juncture, after all the reports that we’ve seen so far, I think it’s very unlikely that there will be no relationship whatsoever between COVID-19 and chronic fatigue syndrome,” Dr. Hornig said. “I think there certainly will be some, but again, what’s the scope, what’s the size? And then, of course, even more importantly, if it is happening, what is the mechanism and how is it happening?”

For people like Ms. Gage-Witvliet, the answers can’t come soon enough. For the first time in more than a decade, the full-time professor of epidemiology didn’t prepare to teach this year because she simply can’t. It’s too taxing for her brain to deal with impromptu student questions. Ms. Gage-Witvliet hopes that, by sharing her own experiences with post COVID-19, she can help others.

“In my work, I use data to give a voice to people who don’t have a voice,” she said. “Now, I am one of those people.”

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

Among the multiple vaccine candidates around the globe, next up in the arsenal against COVID-19 is likely the single-dose Ad26.COV2.S vaccine in development from Johnson & Johnson/Janssen, infectious disease experts predict.

And it got closer with promising interim phase 1/2a trial results, published online Jan. 13 in The New England Journal of Medicine.

A single Ad26.COV2.S dose was associated with S-binding and neutralizing antibodies in more than 90% of the participants. The finding was observed in both adults aged 18-55 years and participants 65 and older, as well as for participants given low-dose or high-dose vaccinations.

The results also suggest a durable vaccine response. “The take-home message [includes] a high neutralizing antibody responder rate to a single dose of our Ad26.COV2.S COVID-19 vaccine candidate. In addition, we see that these responses and antibody titers are stable for at least 71 days,” senior study author Hanneke Schuitemaker, PhD, global head of viral vaccine discovery and translational medicine at Johnson & Johnson in Leiden, the Netherlands, said in an interview.

If the single-dose Johnson & Johnson product gains Food and Drug Administration emergency use authorization (EUA), it could significantly boost the number of overall immunizations available. Less stringent storage requirements – only regular refrigeration vs. a need to freeze the Pfizer/BioNTech and Moderna COVID-19 vaccines – is another potential advantage. The Ad26.COV2.S vaccine can be refrigerated for up to 3 months at 36°-46 °F (2°-8 °C).

“Phase 1-2 trial data on the J&J vaccine: If it works as well as the mRNA options, it will have substantial advantages,” Jeremy Faust, MD, an emergency room physician affiliated with Brigham & Women’s Hospital and Harvard Medical School, Boston, tweeted on Jan. 13.

Unlike the Pfizer/BioNTech and Moderna messenger RNA vaccines, the Johnson & Johnson product is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike (S) protein.
 

Phase 3 efficacy/safety results pending

Under normal circumstances, phase 3 trial results would not be anticipated within weeks of phase 1/2a trial findings. However, the urgency of the COVID-19 pandemic accelerated the vaccine development process, so preclinical trials were conducted simultaneously and not sequentially. For this reason, phase 3 interim results for the Johnson & Johnson vaccine are expected within weeks, and a company executive told Reuters that the rollout is on track for March.

“We hope to report data from our first phase 3 study, ENSEMBLE, in which we are testing the protective efficacy of a single dose of Ad26.COV2.S, by the end of this month or early February,” Dr. Schuitemaker said. 

In the meantime, the phase 1/2a ongoing, multicenter, randomized, double-blind, and placebo-controlled trial interim results have drawn positive reactions.

“Data is highly encouraging and supports the single inoculation approach that makes this vaccine unique,” Carlos del Rio, executive associate dean for Emory University at Grady in Atlanta, wrote in a tweet on Jan. 13.

“Encouraging COVID vaccine data from J&J published [Jan. 13]. Solid antibody, CD4 T cell, and CD8 T cell responses – a nice trifecta of vaccine immune responses to see! And safe!” tweeted Shane Crotty, PhD, vaccine scientist and professor at the La Jolla (Calif.) Institute for Immunology.

 

First results in 800+ participants

At baseline for the phase 1/2a trial, 2% of the younger group and 1% of the 65+ group were seropositive for SARS-CoV-2 S-specific antibodies.

A total of 402 people in the younger age cohort and 403 in the 65 and older group received a first dose of the Johnson & Johnson vaccine. Many participants also received a second dose 56 days later for a separate trial, ENSEMBLE2, designed to compare safety and efficacy between single- and double-dose regimens. Results of that trial are still pending.
 

Safety profile

A single dose was associated with a higher incidence of solicited systemic adverse events in the higher vaccine dose group. They also found that grade 3 adverse events decreased with increasing age.

Injection site pain on the day of immunization or the next day was the most common local reaction. The pain generally resolved within 24 hours. Fever was reported by 15% of the low-dose vaccine group and 39% of the high-dose cohort. Fatigue, headache, and myalgia were the most common grade 1 or 2 solicited systemic adverse events reported.

Five serious adverse events were reported, including four that investigators deemed unrelated to vaccination: hypotension, bilateral nephrolithiasis, legionella pneumonia, and one case of worsening of multiple sclerosis. The vaccine-related serious adverse event was a fever that resulted in hospitalization because of suspicion of COVID-19. The patient recovered within 12 hours.

“These data confirm our previous experience with vaccine candidates based on our Ad26 viral vector platform in the younger age group. The almost similar performance in older adults is promising,” Dr. Schuitemaker said.

A potential limitation of the phase 1/2a trial is “the lack of representation of minority groups,” the researchers noted. Johnson & Johnson is working on improving the diversity of study participants “with respect to groups that seem to be affected most by the COVID-19 pandemic.”
 

AstraZeneca/Oxford vaccine status

The AstraZeneca/Oxford AZD1222 vaccine in development received approval for use in the United Kingdom on Dec. 30. The approval came after Public Health England said the country was facing “unprecedented” levels of infections, the BBC reported. AstraZeneca applied for European Medical Agency approval earlier in the week of Jan. 10, which could lead to more widespread use across Europe.

The status of the vaccine remains uncertain in the United States. A phase 3 trial that started in August was paused for about 6 weeks in September and October after an adverse event in a British volunteer halted studies worldwide. On Oct. 23, the FDA permitted researchers to continue the trial with approximately 40,000 participants.

There was some suggestion in the clinical trials that a half dose of the AstraZeneca vaccine was more effective than a full dose, 90% vs. 62%, but some irregularities in the research require further investigation.

Although the AstraZeneca vaccine is delivered to cells by an adenovirus – as with the Johnson & Johnson product – it is designed to be delivered in two doses 28 days apart, like the administration schedule of the Moderna mRNA vaccine.
 

A need for speed, and more doses

Regardless of which vaccine product is next to gain an EUA in the United States, many experts agree the COVID-19 vaccine rollouts so far have been problematic, at a time when cases are climbing to record-breaking levels, and likely more related to logistics over administration of the vaccine than production of the doses.

“Lots of doses being manufactured. In December 20 million, January 40 million, February 80 million and J&J hopefully soon to add to the count. The shortage is the number arms not getting vaccinated. Freezers do not get COVID. They do not need all those vaccines,” Daniel Griffin, MD, PhD, an infectious disease expert in Port Washington, N.Y., tweeted on Jan. 12.

“Unfortunately, the rollout has not gone smoothly, partly due to a lack of resources for this distribution phase we’re in,” Andrew T. Pavia, MD, chief of the division of pediatric infectious diseases at the University of Utah, Salt Lake City, said during a media briefing Jan. 14 sponsored by the Infectious Diseases Society of America (IDSA).

“We’re concerned about the mismatch between the number of people who are being told they are eligible and the amount of vaccine that is being distributed,” he said.

Complicating the rollout is a directive from U.S. Health and Human Services Secretary Alex Azar that states should start vaccinating everyone 65 and older as well as those with underlying conditions.

Expanding distribution to the 15% of Americans in just this age group is a big challenge, Dr. Pavia said. “We have enough vaccine maybe to vaccinate 40 million by the end of this month. There is a huge disconnect, and that creates a lot of problems.”

“One of the biggest problems is we are trying to do this mass vaccination program in the middle of the biggest surge we’ve ever seen,” Julie Vaishampayan, MD, MPH, chair of the IDSA Public Health Committee, said during the briefing. Without sufficient time for public health officials to plan for vaccinating a larger population, “people will come and stand in extremely long lines.”

Trying to expand immunization access without a proportionate increase in available doses prompted Dr. Vaishampayan to share an analogy from a colleague: “We are trying to fill a lake with a garden hose. Rather than making the lake bigger, what we really need is more water.”

Dr. Pavia emphasized that infectious disease experts “know the measures that work.” Not using masks, physical distancing, and hand hygiene, he said, “is a bit like knowing that really good shark repellents will be available in summer, so I’m going to jump into the ocean covered in blood while the great whites are swimming around.”

An official at the World Health Organization agreed. “Vaccines are coming online and I do believe vaccines will make a huge difference. But they are not here yet in enough quantities and in enough people to make that difference,” Michael Ryan, MB, WHO executive director of health emergencies, said during an online media briefing Jan. 13, held in conjunction with Emory University.

Dr. Ryan predicted that “we’ve got weeks if not months ahead of us in which our weapon is our knowledge ... what we know about this virus, its transmission, and stopping that transmission.

“And as the vaccines roll in, we can hopefully end this horrific pandemic.”

Dr. Schuitemaker reports grants from BARDA during the conduct of the study; personal fees and other from Janssen Vaccines and Prevention, a J&J company, outside the submitted work. Johnson & Johnson and the Biomedical Advanced Research and Development Authority of the Department of Health and Human Services funded the phase 1/2a study.

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

Among the multiple vaccine candidates around the globe, next up in the arsenal against COVID-19 is likely the single-dose Ad26.COV2.S vaccine in development from Johnson & Johnson/Janssen, infectious disease experts predict.

And it got closer with promising interim phase 1/2a trial results, published online Jan. 13 in The New England Journal of Medicine.

A single Ad26.COV2.S dose was associated with S-binding and neutralizing antibodies in more than 90% of the participants. The finding was observed in both adults aged 18-55 years and participants 65 and older, as well as for participants given low-dose or high-dose vaccinations.

The results also suggest a durable vaccine response. “The take-home message [includes] a high neutralizing antibody responder rate to a single dose of our Ad26.COV2.S COVID-19 vaccine candidate. In addition, we see that these responses and antibody titers are stable for at least 71 days,” senior study author Hanneke Schuitemaker, PhD, global head of viral vaccine discovery and translational medicine at Johnson & Johnson in Leiden, the Netherlands, said in an interview.

If the single-dose Johnson & Johnson product gains Food and Drug Administration emergency use authorization (EUA), it could significantly boost the number of overall immunizations available. Less stringent storage requirements – only regular refrigeration vs. a need to freeze the Pfizer/BioNTech and Moderna COVID-19 vaccines – is another potential advantage. The Ad26.COV2.S vaccine can be refrigerated for up to 3 months at 36°-46 °F (2°-8 °C).

“Phase 1-2 trial data on the J&J vaccine: If it works as well as the mRNA options, it will have substantial advantages,” Jeremy Faust, MD, an emergency room physician affiliated with Brigham & Women’s Hospital and Harvard Medical School, Boston, tweeted on Jan. 13.

Unlike the Pfizer/BioNTech and Moderna messenger RNA vaccines, the Johnson & Johnson product is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike (S) protein.
 

Phase 3 efficacy/safety results pending

Under normal circumstances, phase 3 trial results would not be anticipated within weeks of phase 1/2a trial findings. However, the urgency of the COVID-19 pandemic accelerated the vaccine development process, so preclinical trials were conducted simultaneously and not sequentially. For this reason, phase 3 interim results for the Johnson & Johnson vaccine are expected within weeks, and a company executive told Reuters that the rollout is on track for March.

“We hope to report data from our first phase 3 study, ENSEMBLE, in which we are testing the protective efficacy of a single dose of Ad26.COV2.S, by the end of this month or early February,” Dr. Schuitemaker said. 

In the meantime, the phase 1/2a ongoing, multicenter, randomized, double-blind, and placebo-controlled trial interim results have drawn positive reactions.

“Data is highly encouraging and supports the single inoculation approach that makes this vaccine unique,” Carlos del Rio, executive associate dean for Emory University at Grady in Atlanta, wrote in a tweet on Jan. 13.

“Encouraging COVID vaccine data from J&J published [Jan. 13]. Solid antibody, CD4 T cell, and CD8 T cell responses – a nice trifecta of vaccine immune responses to see! And safe!” tweeted Shane Crotty, PhD, vaccine scientist and professor at the La Jolla (Calif.) Institute for Immunology.

 

First results in 800+ participants

At baseline for the phase 1/2a trial, 2% of the younger group and 1% of the 65+ group were seropositive for SARS-CoV-2 S-specific antibodies.

A total of 402 people in the younger age cohort and 403 in the 65 and older group received a first dose of the Johnson & Johnson vaccine. Many participants also received a second dose 56 days later for a separate trial, ENSEMBLE2, designed to compare safety and efficacy between single- and double-dose regimens. Results of that trial are still pending.
 

Safety profile

A single dose was associated with a higher incidence of solicited systemic adverse events in the higher vaccine dose group. They also found that grade 3 adverse events decreased with increasing age.

Injection site pain on the day of immunization or the next day was the most common local reaction. The pain generally resolved within 24 hours. Fever was reported by 15% of the low-dose vaccine group and 39% of the high-dose cohort. Fatigue, headache, and myalgia were the most common grade 1 or 2 solicited systemic adverse events reported.

Five serious adverse events were reported, including four that investigators deemed unrelated to vaccination: hypotension, bilateral nephrolithiasis, legionella pneumonia, and one case of worsening of multiple sclerosis. The vaccine-related serious adverse event was a fever that resulted in hospitalization because of suspicion of COVID-19. The patient recovered within 12 hours.

“These data confirm our previous experience with vaccine candidates based on our Ad26 viral vector platform in the younger age group. The almost similar performance in older adults is promising,” Dr. Schuitemaker said.

A potential limitation of the phase 1/2a trial is “the lack of representation of minority groups,” the researchers noted. Johnson & Johnson is working on improving the diversity of study participants “with respect to groups that seem to be affected most by the COVID-19 pandemic.”
 

AstraZeneca/Oxford vaccine status

The AstraZeneca/Oxford AZD1222 vaccine in development received approval for use in the United Kingdom on Dec. 30. The approval came after Public Health England said the country was facing “unprecedented” levels of infections, the BBC reported. AstraZeneca applied for European Medical Agency approval earlier in the week of Jan. 10, which could lead to more widespread use across Europe.

The status of the vaccine remains uncertain in the United States. A phase 3 trial that started in August was paused for about 6 weeks in September and October after an adverse event in a British volunteer halted studies worldwide. On Oct. 23, the FDA permitted researchers to continue the trial with approximately 40,000 participants.

There was some suggestion in the clinical trials that a half dose of the AstraZeneca vaccine was more effective than a full dose, 90% vs. 62%, but some irregularities in the research require further investigation.

Although the AstraZeneca vaccine is delivered to cells by an adenovirus – as with the Johnson & Johnson product – it is designed to be delivered in two doses 28 days apart, like the administration schedule of the Moderna mRNA vaccine.
 

A need for speed, and more doses

Regardless of which vaccine product is next to gain an EUA in the United States, many experts agree the COVID-19 vaccine rollouts so far have been problematic, at a time when cases are climbing to record-breaking levels, and likely more related to logistics over administration of the vaccine than production of the doses.

“Lots of doses being manufactured. In December 20 million, January 40 million, February 80 million and J&J hopefully soon to add to the count. The shortage is the number arms not getting vaccinated. Freezers do not get COVID. They do not need all those vaccines,” Daniel Griffin, MD, PhD, an infectious disease expert in Port Washington, N.Y., tweeted on Jan. 12.

“Unfortunately, the rollout has not gone smoothly, partly due to a lack of resources for this distribution phase we’re in,” Andrew T. Pavia, MD, chief of the division of pediatric infectious diseases at the University of Utah, Salt Lake City, said during a media briefing Jan. 14 sponsored by the Infectious Diseases Society of America (IDSA).

“We’re concerned about the mismatch between the number of people who are being told they are eligible and the amount of vaccine that is being distributed,” he said.

Complicating the rollout is a directive from U.S. Health and Human Services Secretary Alex Azar that states should start vaccinating everyone 65 and older as well as those with underlying conditions.

Expanding distribution to the 15% of Americans in just this age group is a big challenge, Dr. Pavia said. “We have enough vaccine maybe to vaccinate 40 million by the end of this month. There is a huge disconnect, and that creates a lot of problems.”

“One of the biggest problems is we are trying to do this mass vaccination program in the middle of the biggest surge we’ve ever seen,” Julie Vaishampayan, MD, MPH, chair of the IDSA Public Health Committee, said during the briefing. Without sufficient time for public health officials to plan for vaccinating a larger population, “people will come and stand in extremely long lines.”

Trying to expand immunization access without a proportionate increase in available doses prompted Dr. Vaishampayan to share an analogy from a colleague: “We are trying to fill a lake with a garden hose. Rather than making the lake bigger, what we really need is more water.”

Dr. Pavia emphasized that infectious disease experts “know the measures that work.” Not using masks, physical distancing, and hand hygiene, he said, “is a bit like knowing that really good shark repellents will be available in summer, so I’m going to jump into the ocean covered in blood while the great whites are swimming around.”

An official at the World Health Organization agreed. “Vaccines are coming online and I do believe vaccines will make a huge difference. But they are not here yet in enough quantities and in enough people to make that difference,” Michael Ryan, MB, WHO executive director of health emergencies, said during an online media briefing Jan. 13, held in conjunction with Emory University.

Dr. Ryan predicted that “we’ve got weeks if not months ahead of us in which our weapon is our knowledge ... what we know about this virus, its transmission, and stopping that transmission.

“And as the vaccines roll in, we can hopefully end this horrific pandemic.”

Dr. Schuitemaker reports grants from BARDA during the conduct of the study; personal fees and other from Janssen Vaccines and Prevention, a J&J company, outside the submitted work. Johnson & Johnson and the Biomedical Advanced Research and Development Authority of the Department of Health and Human Services funded the phase 1/2a study.

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

Among the multiple vaccine candidates around the globe, next up in the arsenal against COVID-19 is likely the single-dose Ad26.COV2.S vaccine in development from Johnson & Johnson/Janssen, infectious disease experts predict.

And it got closer with promising interim phase 1/2a trial results, published online Jan. 13 in The New England Journal of Medicine.

A single Ad26.COV2.S dose was associated with S-binding and neutralizing antibodies in more than 90% of the participants. The finding was observed in both adults aged 18-55 years and participants 65 and older, as well as for participants given low-dose or high-dose vaccinations.

The results also suggest a durable vaccine response. “The take-home message [includes] a high neutralizing antibody responder rate to a single dose of our Ad26.COV2.S COVID-19 vaccine candidate. In addition, we see that these responses and antibody titers are stable for at least 71 days,” senior study author Hanneke Schuitemaker, PhD, global head of viral vaccine discovery and translational medicine at Johnson & Johnson in Leiden, the Netherlands, said in an interview.

If the single-dose Johnson & Johnson product gains Food and Drug Administration emergency use authorization (EUA), it could significantly boost the number of overall immunizations available. Less stringent storage requirements – only regular refrigeration vs. a need to freeze the Pfizer/BioNTech and Moderna COVID-19 vaccines – is another potential advantage. The Ad26.COV2.S vaccine can be refrigerated for up to 3 months at 36°-46 °F (2°-8 °C).

“Phase 1-2 trial data on the J&J vaccine: If it works as well as the mRNA options, it will have substantial advantages,” Jeremy Faust, MD, an emergency room physician affiliated with Brigham & Women’s Hospital and Harvard Medical School, Boston, tweeted on Jan. 13.

Unlike the Pfizer/BioNTech and Moderna messenger RNA vaccines, the Johnson & Johnson product is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike (S) protein.
 

Phase 3 efficacy/safety results pending

Under normal circumstances, phase 3 trial results would not be anticipated within weeks of phase 1/2a trial findings. However, the urgency of the COVID-19 pandemic accelerated the vaccine development process, so preclinical trials were conducted simultaneously and not sequentially. For this reason, phase 3 interim results for the Johnson & Johnson vaccine are expected within weeks, and a company executive told Reuters that the rollout is on track for March.

“We hope to report data from our first phase 3 study, ENSEMBLE, in which we are testing the protective efficacy of a single dose of Ad26.COV2.S, by the end of this month or early February,” Dr. Schuitemaker said. 

In the meantime, the phase 1/2a ongoing, multicenter, randomized, double-blind, and placebo-controlled trial interim results have drawn positive reactions.

“Data is highly encouraging and supports the single inoculation approach that makes this vaccine unique,” Carlos del Rio, executive associate dean for Emory University at Grady in Atlanta, wrote in a tweet on Jan. 13.

“Encouraging COVID vaccine data from J&J published [Jan. 13]. Solid antibody, CD4 T cell, and CD8 T cell responses – a nice trifecta of vaccine immune responses to see! And safe!” tweeted Shane Crotty, PhD, vaccine scientist and professor at the La Jolla (Calif.) Institute for Immunology.

 

First results in 800+ participants

At baseline for the phase 1/2a trial, 2% of the younger group and 1% of the 65+ group were seropositive for SARS-CoV-2 S-specific antibodies.

A total of 402 people in the younger age cohort and 403 in the 65 and older group received a first dose of the Johnson & Johnson vaccine. Many participants also received a second dose 56 days later for a separate trial, ENSEMBLE2, designed to compare safety and efficacy between single- and double-dose regimens. Results of that trial are still pending.
 

Safety profile

A single dose was associated with a higher incidence of solicited systemic adverse events in the higher vaccine dose group. They also found that grade 3 adverse events decreased with increasing age.

Injection site pain on the day of immunization or the next day was the most common local reaction. The pain generally resolved within 24 hours. Fever was reported by 15% of the low-dose vaccine group and 39% of the high-dose cohort. Fatigue, headache, and myalgia were the most common grade 1 or 2 solicited systemic adverse events reported.

Five serious adverse events were reported, including four that investigators deemed unrelated to vaccination: hypotension, bilateral nephrolithiasis, legionella pneumonia, and one case of worsening of multiple sclerosis. The vaccine-related serious adverse event was a fever that resulted in hospitalization because of suspicion of COVID-19. The patient recovered within 12 hours.

“These data confirm our previous experience with vaccine candidates based on our Ad26 viral vector platform in the younger age group. The almost similar performance in older adults is promising,” Dr. Schuitemaker said.

A potential limitation of the phase 1/2a trial is “the lack of representation of minority groups,” the researchers noted. Johnson & Johnson is working on improving the diversity of study participants “with respect to groups that seem to be affected most by the COVID-19 pandemic.”
 

AstraZeneca/Oxford vaccine status

The AstraZeneca/Oxford AZD1222 vaccine in development received approval for use in the United Kingdom on Dec. 30. The approval came after Public Health England said the country was facing “unprecedented” levels of infections, the BBC reported. AstraZeneca applied for European Medical Agency approval earlier in the week of Jan. 10, which could lead to more widespread use across Europe.

The status of the vaccine remains uncertain in the United States. A phase 3 trial that started in August was paused for about 6 weeks in September and October after an adverse event in a British volunteer halted studies worldwide. On Oct. 23, the FDA permitted researchers to continue the trial with approximately 40,000 participants.

There was some suggestion in the clinical trials that a half dose of the AstraZeneca vaccine was more effective than a full dose, 90% vs. 62%, but some irregularities in the research require further investigation.

Although the AstraZeneca vaccine is delivered to cells by an adenovirus – as with the Johnson & Johnson product – it is designed to be delivered in two doses 28 days apart, like the administration schedule of the Moderna mRNA vaccine.
 

A need for speed, and more doses

Regardless of which vaccine product is next to gain an EUA in the United States, many experts agree the COVID-19 vaccine rollouts so far have been problematic, at a time when cases are climbing to record-breaking levels, and likely more related to logistics over administration of the vaccine than production of the doses.

“Lots of doses being manufactured. In December 20 million, January 40 million, February 80 million and J&J hopefully soon to add to the count. The shortage is the number arms not getting vaccinated. Freezers do not get COVID. They do not need all those vaccines,” Daniel Griffin, MD, PhD, an infectious disease expert in Port Washington, N.Y., tweeted on Jan. 12.

“Unfortunately, the rollout has not gone smoothly, partly due to a lack of resources for this distribution phase we’re in,” Andrew T. Pavia, MD, chief of the division of pediatric infectious diseases at the University of Utah, Salt Lake City, said during a media briefing Jan. 14 sponsored by the Infectious Diseases Society of America (IDSA).

“We’re concerned about the mismatch between the number of people who are being told they are eligible and the amount of vaccine that is being distributed,” he said.

Complicating the rollout is a directive from U.S. Health and Human Services Secretary Alex Azar that states should start vaccinating everyone 65 and older as well as those with underlying conditions.

Expanding distribution to the 15% of Americans in just this age group is a big challenge, Dr. Pavia said. “We have enough vaccine maybe to vaccinate 40 million by the end of this month. There is a huge disconnect, and that creates a lot of problems.”

“One of the biggest problems is we are trying to do this mass vaccination program in the middle of the biggest surge we’ve ever seen,” Julie Vaishampayan, MD, MPH, chair of the IDSA Public Health Committee, said during the briefing. Without sufficient time for public health officials to plan for vaccinating a larger population, “people will come and stand in extremely long lines.”

Trying to expand immunization access without a proportionate increase in available doses prompted Dr. Vaishampayan to share an analogy from a colleague: “We are trying to fill a lake with a garden hose. Rather than making the lake bigger, what we really need is more water.”

Dr. Pavia emphasized that infectious disease experts “know the measures that work.” Not using masks, physical distancing, and hand hygiene, he said, “is a bit like knowing that really good shark repellents will be available in summer, so I’m going to jump into the ocean covered in blood while the great whites are swimming around.”

An official at the World Health Organization agreed. “Vaccines are coming online and I do believe vaccines will make a huge difference. But they are not here yet in enough quantities and in enough people to make that difference,” Michael Ryan, MB, WHO executive director of health emergencies, said during an online media briefing Jan. 13, held in conjunction with Emory University.

Dr. Ryan predicted that “we’ve got weeks if not months ahead of us in which our weapon is our knowledge ... what we know about this virus, its transmission, and stopping that transmission.

“And as the vaccines roll in, we can hopefully end this horrific pandemic.”

Dr. Schuitemaker reports grants from BARDA during the conduct of the study; personal fees and other from Janssen Vaccines and Prevention, a J&J company, outside the submitted work. Johnson & Johnson and the Biomedical Advanced Research and Development Authority of the Department of Health and Human Services funded the phase 1/2a study.

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

Background: Chronic kidney disease (CKD) is both a prothrombotic state and a condition with an elevated bleeding risk that increases in a linear fashion as estimated glomerular filtration rate (eGFR) decreases. These features of the disease along with the exclusion of patients with CKD from most anticoagulation trials have resulted in uncertainty about overall risks and benefits of anticoagulant use in this population.

The most compelling data were seen in the management of atrial fibrillation in early-stage CKD (five studies representing 11,332 patients) in which high-dose DOACs were associated with a lower risk for stroke or systemic embolism (risk ratio, 0.79; 95% confidence interval, 0.66-0.92), hemorrhagic stroke (RR, 0.48; 95% CI, 0.30-0.76), and all-cause death (RR, 0.88; 95% CI, 0.78-0.99). Overall stroke reduction was primarily hemorrhagic, and DOACs were equivalent to vitamin K antagonists (VKAs) for ischemic stroke risk.

The analysis also suggests that, in CKD, DOACs may reduce major bleeding when compared with VKAs across a variety of indications, though that finding was not statistically significant.

Efficacy of DOACs, compared with VKAs, in treatment of venous thromboembolism was uncertain, and patients with end-stage kidney disease and advanced CKD (creatinine clearance, less than 25 mL/min) were excluded from all trials comparing DOACs with VKAs, with limited overall data in these populations.

Bottom line: For patients with atrial fibrillation and early-stage CKD, direct oral anticoagulants show a promising risk-benefit profile when compared with vitamin K antagonists. Very few data are available on the safety and efficacy of anticoagulants in patients with advanced CKD and end-stage kidney disease.

Citation: Ha JT et al. Benefits and harms of oral anticoagulant therapy in chronic kidney disease. Ann Intern Med. 2019 Aug 6;171(3):181-9.

Dr. Herrle is a hospitalist at Maine Medical Center in Portland and at Stephens Memorial Hospital in Norway, Maine.

Background: Chronic kidney disease (CKD) is both a prothrombotic state and a condition with an elevated bleeding risk that increases in a linear fashion as estimated glomerular filtration rate (eGFR) decreases. These features of the disease along with the exclusion of patients with CKD from most anticoagulation trials have resulted in uncertainty about overall risks and benefits of anticoagulant use in this population.

The most compelling data were seen in the management of atrial fibrillation in early-stage CKD (five studies representing 11,332 patients) in which high-dose DOACs were associated with a lower risk for stroke or systemic embolism (risk ratio, 0.79; 95% confidence interval, 0.66-0.92), hemorrhagic stroke (RR, 0.48; 95% CI, 0.30-0.76), and all-cause death (RR, 0.88; 95% CI, 0.78-0.99). Overall stroke reduction was primarily hemorrhagic, and DOACs were equivalent to vitamin K antagonists (VKAs) for ischemic stroke risk.

The analysis also suggests that, in CKD, DOACs may reduce major bleeding when compared with VKAs across a variety of indications, though that finding was not statistically significant.

Efficacy of DOACs, compared with VKAs, in treatment of venous thromboembolism was uncertain, and patients with end-stage kidney disease and advanced CKD (creatinine clearance, less than 25 mL/min) were excluded from all trials comparing DOACs with VKAs, with limited overall data in these populations.

Bottom line: For patients with atrial fibrillation and early-stage CKD, direct oral anticoagulants show a promising risk-benefit profile when compared with vitamin K antagonists. Very few data are available on the safety and efficacy of anticoagulants in patients with advanced CKD and end-stage kidney disease.

Citation: Ha JT et al. Benefits and harms of oral anticoagulant therapy in chronic kidney disease. Ann Intern Med. 2019 Aug 6;171(3):181-9.

Dr. Herrle is a hospitalist at Maine Medical Center in Portland and at Stephens Memorial Hospital in Norway, Maine.

Background: Chronic kidney disease (CKD) is both a prothrombotic state and a condition with an elevated bleeding risk that increases in a linear fashion as estimated glomerular filtration rate (eGFR) decreases. These features of the disease along with the exclusion of patients with CKD from most anticoagulation trials have resulted in uncertainty about overall risks and benefits of anticoagulant use in this population.

The most compelling data were seen in the management of atrial fibrillation in early-stage CKD (five studies representing 11,332 patients) in which high-dose DOACs were associated with a lower risk for stroke or systemic embolism (risk ratio, 0.79; 95% confidence interval, 0.66-0.92), hemorrhagic stroke (RR, 0.48; 95% CI, 0.30-0.76), and all-cause death (RR, 0.88; 95% CI, 0.78-0.99). Overall stroke reduction was primarily hemorrhagic, and DOACs were equivalent to vitamin K antagonists (VKAs) for ischemic stroke risk.

The analysis also suggests that, in CKD, DOACs may reduce major bleeding when compared with VKAs across a variety of indications, though that finding was not statistically significant.

Efficacy of DOACs, compared with VKAs, in treatment of venous thromboembolism was uncertain, and patients with end-stage kidney disease and advanced CKD (creatinine clearance, less than 25 mL/min) were excluded from all trials comparing DOACs with VKAs, with limited overall data in these populations.

Bottom line: For patients with atrial fibrillation and early-stage CKD, direct oral anticoagulants show a promising risk-benefit profile when compared with vitamin K antagonists. Very few data are available on the safety and efficacy of anticoagulants in patients with advanced CKD and end-stage kidney disease.

Citation: Ha JT et al. Benefits and harms of oral anticoagulant therapy in chronic kidney disease. Ann Intern Med. 2019 Aug 6;171(3):181-9.

Dr. Herrle is a hospitalist at Maine Medical Center in Portland and at Stephens Memorial Hospital in Norway, Maine.

Pregnancy complications in women with pityriasis rosea (PR) were relatively minor, and included no cases of miscarriage, abortion, or fetal death, according to a review of 33 patients.

“Though generally considered benign, PR may be associated with an increased risk of birth complications if acquired during pregnancy,” and previous studies have shown increased rates of complications including miscarriage and neonatal hypotonia in these patients, wrote Julian Stashower of the University of Virginia, Charlottesville, and colleagues.

In a retrospective study published in the Journal of the American Academy of Dermatology, the researchers assessed pregnancy outcomes in women who developed PR during pregnancy. They were identified from medical records at three institutions between September 2010 and June 2020. Diagnosis of PR, a papulosquamous skin eruption associated with human herpesvirus (HHV)–6/7 reactivation, was based on history and physical examination.

Overall, 8 of the 33 women (24%) had birth complications; the rates of preterm delivery, spontaneous pregnancy loss in clinically detectable pregnancies, and oligohydramnios were 6%, 0%, and 3%, respectively. The average onset of PR during pregnancy was earlier among women with complications, compared with those without complications (10.75 weeks’ gestation vs. 15.21 weeks’ gestation), but the difference was not statistically significant.

The researchers noted that their findings differed from the most recent study of PR in pregnancy, which included 60 patients and found a notably higher incidence of overall birth complications (50%), as well as higher incidence of neonatal hypotonia (25%), and miscarriage (13%).

The previous study also showed an increased risk of birth complications when PR onset occurred prior to 15 weeks’ gestation, but the current study did not reflect that finding, they wrote.

The current study findings were limited by several factors including the small sample size, retrospective design, and lack of confirmation of PR with HHV-6/7 testing, as well as lack of exclusion of atypical PR cases, the researchers noted. However, the results suggest that birth complications associated with PR may be lower than previously reported. “Further research is needed to guide future care and fully elucidate this possible association, which has important implications for both pregnant women with PR and their providers.”

The study received no outside funding. The researchers had no financial conflict to disclose.

Pregnancy complications in women with pityriasis rosea (PR) were relatively minor, and included no cases of miscarriage, abortion, or fetal death, according to a review of 33 patients.

“Though generally considered benign, PR may be associated with an increased risk of birth complications if acquired during pregnancy,” and previous studies have shown increased rates of complications including miscarriage and neonatal hypotonia in these patients, wrote Julian Stashower of the University of Virginia, Charlottesville, and colleagues.

In a retrospective study published in the Journal of the American Academy of Dermatology, the researchers assessed pregnancy outcomes in women who developed PR during pregnancy. They were identified from medical records at three institutions between September 2010 and June 2020. Diagnosis of PR, a papulosquamous skin eruption associated with human herpesvirus (HHV)–6/7 reactivation, was based on history and physical examination.

Overall, 8 of the 33 women (24%) had birth complications; the rates of preterm delivery, spontaneous pregnancy loss in clinically detectable pregnancies, and oligohydramnios were 6%, 0%, and 3%, respectively. The average onset of PR during pregnancy was earlier among women with complications, compared with those without complications (10.75 weeks’ gestation vs. 15.21 weeks’ gestation), but the difference was not statistically significant.

The researchers noted that their findings differed from the most recent study of PR in pregnancy, which included 60 patients and found a notably higher incidence of overall birth complications (50%), as well as higher incidence of neonatal hypotonia (25%), and miscarriage (13%).

The previous study also showed an increased risk of birth complications when PR onset occurred prior to 15 weeks’ gestation, but the current study did not reflect that finding, they wrote.

The current study findings were limited by several factors including the small sample size, retrospective design, and lack of confirmation of PR with HHV-6/7 testing, as well as lack of exclusion of atypical PR cases, the researchers noted. However, the results suggest that birth complications associated with PR may be lower than previously reported. “Further research is needed to guide future care and fully elucidate this possible association, which has important implications for both pregnant women with PR and their providers.”

The study received no outside funding. The researchers had no financial conflict to disclose.

Pregnancy complications in women with pityriasis rosea (PR) were relatively minor, and included no cases of miscarriage, abortion, or fetal death, according to a review of 33 patients.

“Though generally considered benign, PR may be associated with an increased risk of birth complications if acquired during pregnancy,” and previous studies have shown increased rates of complications including miscarriage and neonatal hypotonia in these patients, wrote Julian Stashower of the University of Virginia, Charlottesville, and colleagues.

In a retrospective study published in the Journal of the American Academy of Dermatology, the researchers assessed pregnancy outcomes in women who developed PR during pregnancy. They were identified from medical records at three institutions between September 2010 and June 2020. Diagnosis of PR, a papulosquamous skin eruption associated with human herpesvirus (HHV)–6/7 reactivation, was based on history and physical examination.

Overall, 8 of the 33 women (24%) had birth complications; the rates of preterm delivery, spontaneous pregnancy loss in clinically detectable pregnancies, and oligohydramnios were 6%, 0%, and 3%, respectively. The average onset of PR during pregnancy was earlier among women with complications, compared with those without complications (10.75 weeks’ gestation vs. 15.21 weeks’ gestation), but the difference was not statistically significant.

The researchers noted that their findings differed from the most recent study of PR in pregnancy, which included 60 patients and found a notably higher incidence of overall birth complications (50%), as well as higher incidence of neonatal hypotonia (25%), and miscarriage (13%).

The previous study also showed an increased risk of birth complications when PR onset occurred prior to 15 weeks’ gestation, but the current study did not reflect that finding, they wrote.

The current study findings were limited by several factors including the small sample size, retrospective design, and lack of confirmation of PR with HHV-6/7 testing, as well as lack of exclusion of atypical PR cases, the researchers noted. However, the results suggest that birth complications associated with PR may be lower than previously reported. “Further research is needed to guide future care and fully elucidate this possible association, which has important implications for both pregnant women with PR and their providers.”

The study received no outside funding. The researchers had no financial conflict to disclose.

In an effort to counteract alarming trends in rising hepatitis infections, the U.S. Department of Health and Human Services has developed and released its Viral Hepatitis National Strategic Plan 2021-2025, which aims to eliminate viral hepatitis infection in the United States by 2030.

sarathsasidharan/Thinkstock

An estimated 3.3 million people in the United States were chronically infected with hepatitis B (HBV) and hepatitis C (HCV) as of 2016. In addition, the country “is currently facing unprecedented hepatitis A (HAV) outbreaks, while progress in preventing hepatitis B has stalled, and hepatitis C rates nearly tripled from 2011 to 2018,” according to the HHS.

The new plan, “A Roadmap to Elimination for the United States,” builds upon previous initiatives the HHS has made to tackle the diseases and was coordinated by the Office of the Assistant Secretary for Health through the Office of Infectious Disease and HIV/AIDS Policy.

The plan focuses on HAV, HBV, and HCV, which have the largest impact on the health of the nation, according to the HHS. The plan addresses populations with the highest burden of viral hepatitis based on nationwide data so that resources can be focused there to achieve the greatest impact. Persons who inject drugs are a priority population for all three hepatitis viruses. HAV efforts will also include a focus on the homeless population. HBV efforts will also focus on Asian and Pacific Islander and the Black, non-Hispanic populations, while HCV efforts will include a focus on Black, non-Hispanic people, people born during 1945-1965, people with HIV, and the American Indian/Alaska Native population.
 

Goal-setting

There are five main goals outlined in the plan, according to the HHS:

• Prevent new hepatitis infections.
• Improve hepatitis-related health outcomes of people with viral hepatitis.
• Reduce hepatitis-related disparities and health inequities.
• Improve hepatitis surveillance and data use.
• Achieve integrated, coordinated efforts that address the viral hepatitis epidemics among all partners and stakeholders.

“The United States will be a place where new viral hepatitis infections are prevented, every person knows their status, and every person with viral hepatitis has high-quality health care and treatment and lives free from stigma and discrimination. This vision includes all people, regardless of age, sex, gender identity, sexual orientation, race, ethnicity, religion, disability, geographic location, or socioeconomic circumstance,” according to the HHS vision statement.

[email protected]

In an effort to counteract alarming trends in rising hepatitis infections, the U.S. Department of Health and Human Services has developed and released its Viral Hepatitis National Strategic Plan 2021-2025, which aims to eliminate viral hepatitis infection in the United States by 2030.

sarathsasidharan/Thinkstock

An estimated 3.3 million people in the United States were chronically infected with hepatitis B (HBV) and hepatitis C (HCV) as of 2016. In addition, the country “is currently facing unprecedented hepatitis A (HAV) outbreaks, while progress in preventing hepatitis B has stalled, and hepatitis C rates nearly tripled from 2011 to 2018,” according to the HHS.

The new plan, “A Roadmap to Elimination for the United States,” builds upon previous initiatives the HHS has made to tackle the diseases and was coordinated by the Office of the Assistant Secretary for Health through the Office of Infectious Disease and HIV/AIDS Policy.

The plan focuses on HAV, HBV, and HCV, which have the largest impact on the health of the nation, according to the HHS. The plan addresses populations with the highest burden of viral hepatitis based on nationwide data so that resources can be focused there to achieve the greatest impact. Persons who inject drugs are a priority population for all three hepatitis viruses. HAV efforts will also include a focus on the homeless population. HBV efforts will also focus on Asian and Pacific Islander and the Black, non-Hispanic populations, while HCV efforts will include a focus on Black, non-Hispanic people, people born during 1945-1965, people with HIV, and the American Indian/Alaska Native population.
 

Goal-setting

There are five main goals outlined in the plan, according to the HHS:

• Prevent new hepatitis infections.
• Improve hepatitis-related health outcomes of people with viral hepatitis.
• Reduce hepatitis-related disparities and health inequities.
• Improve hepatitis surveillance and data use.
• Achieve integrated, coordinated efforts that address the viral hepatitis epidemics among all partners and stakeholders.

“The United States will be a place where new viral hepatitis infections are prevented, every person knows their status, and every person with viral hepatitis has high-quality health care and treatment and lives free from stigma and discrimination. This vision includes all people, regardless of age, sex, gender identity, sexual orientation, race, ethnicity, religion, disability, geographic location, or socioeconomic circumstance,” according to the HHS vision statement.

[email protected]

In an effort to counteract alarming trends in rising hepatitis infections, the U.S. Department of Health and Human Services has developed and released its Viral Hepatitis National Strategic Plan 2021-2025, which aims to eliminate viral hepatitis infection in the United States by 2030.

sarathsasidharan/Thinkstock

An estimated 3.3 million people in the United States were chronically infected with hepatitis B (HBV) and hepatitis C (HCV) as of 2016. In addition, the country “is currently facing unprecedented hepatitis A (HAV) outbreaks, while progress in preventing hepatitis B has stalled, and hepatitis C rates nearly tripled from 2011 to 2018,” according to the HHS.

The new plan, “A Roadmap to Elimination for the United States,” builds upon previous initiatives the HHS has made to tackle the diseases and was coordinated by the Office of the Assistant Secretary for Health through the Office of Infectious Disease and HIV/AIDS Policy.

The plan focuses on HAV, HBV, and HCV, which have the largest impact on the health of the nation, according to the HHS. The plan addresses populations with the highest burden of viral hepatitis based on nationwide data so that resources can be focused there to achieve the greatest impact. Persons who inject drugs are a priority population for all three hepatitis viruses. HAV efforts will also include a focus on the homeless population. HBV efforts will also focus on Asian and Pacific Islander and the Black, non-Hispanic populations, while HCV efforts will include a focus on Black, non-Hispanic people, people born during 1945-1965, people with HIV, and the American Indian/Alaska Native population.
 

Goal-setting

There are five main goals outlined in the plan, according to the HHS:

• Prevent new hepatitis infections.
• Improve hepatitis-related health outcomes of people with viral hepatitis.
• Reduce hepatitis-related disparities and health inequities.
• Improve hepatitis surveillance and data use.
• Achieve integrated, coordinated efforts that address the viral hepatitis epidemics among all partners and stakeholders.

“The United States will be a place where new viral hepatitis infections are prevented, every person knows their status, and every person with viral hepatitis has high-quality health care and treatment and lives free from stigma and discrimination. This vision includes all people, regardless of age, sex, gender identity, sexual orientation, race, ethnicity, religion, disability, geographic location, or socioeconomic circumstance,” according to the HHS vision statement.

[email protected]

Health care professionals miss an important opportunity if they do not use a holistic patient-centered approach in providing support to their postpartum patients, advised Alison M. Stuebe, MD, MSc, of the division of maternal-fetal medicine at the University of North Carolina at Chapel Hill, and colleagues.

Too often, the emphasis for health care professionals is on less common, highly morbid complications, while their patients’ needs are focused more on daily functioning.

More than half of maternal deaths occur not during delivery, but in the days, weeks, and months following birth. Many serious complications and management of less-emergent conditions such as flu-like symptoms go unnoticed or result in treatment delays. Routinely asking women who present for care whether they have been pregnant during the past year could go a long way in helping clinicians connect the dots for conditions they might not otherwise consider, suggested Dr. Stuebe and colleagues.

In response to what is becoming a growing burden of postpartum maternal morbidity and mortality in the United States, Dr. Stuebe and associates, in coordination with the Alliance of Innovation in Maternal Health, prepared a comprehensive consensus statement on postpartum care basics. The work came out of a day-long planning meeting of an interdisciplinary work group funded by AIMH to develop the maternal safety bundle, which established 28 goals across four phases – readiness, recognition and prevention, response, and reporting. Each phase is intended to occur as part of a coordinated effort between women experiencing pregnancy and their health care providers, with involvement from multiple clinical settings and health systems.
 

America needs to change the way it treats its new mothers

In a separate interview, Dr. Stuebe shared additional insights into the development of the consensus statement: “This article is part of a broader movement to change the way America treats new mothers. For too long, we’ve lavished attention on women in the weeks before birth and then left them alone to manage recovery, plunging hormones, sleepless nights, and new baby care. If the baby is the candy, and the mother is the wrapper, once the candy is out of the wrapper, we’ve tossed the wrapper aside. The goal of this article is to set out the ways that we can better support women in this critical transition period.

“We need to start during pregnancy, by working with women to plan for the fourth trimester and identify a care team that will support her and her baby. After birth, we need to adapt those plans and make sure she has the emotional and material support she needs to navigate the coming months. Many of these decisions are deeply personal, and we need to center the values and preferences of the woman and her family.”

Dr. Stuebe also spotlighted a new University of North Carolina–based program designed to support shared decision-making. Their Trimester Project team partnered with mothers to design NewMomHealth.com, the first national postpartum resource designed by and for new mothers, which is in the process of launching a culturally adapted Spanish-language site, saludmadre.com, in partnership with Urban Strategies.
 

Readiness prepares mothers, HCPs, and clinical settings for the fourth trimester

In the first phase, Readiness, there are three key parties involved: the woman experiencing pregnancy, the health care providers (HCPs) supporting her, and the clinical settings involved in her care. Each player has specific goals to achieve in this phase, women are responsible for four goals, health care providers have two goals, and clinical settings have five.

Prenatally, every woman should work with health care providers to develop a comprehensive, individualized postpartum care plan that designates a postpartum clinical “home” for addressing any care needed between birth and the “comprehensive postpartum visit.” The plan encourages the patient and her health care team give attention to social support, birth recovery, infant care and feeding plans, thoughts concerning future pregnancies, and specifically use of contraception, as well as any chronic health concerns and overall emotional well-being.

The plan should consist of a postpartum care team that includes friends and family and ensures that medical, material, and social support are available in the weeks following birth for both mother and baby.

The authors emphasized the importance for clinicians to develop a keen awareness of “reproductive justice,” which respects a woman’s right “to maintain personal bodily autonomy, have children, not have children, and parent the children we have in safe and sustainable communities.” They encouraged adopting a sensitivity to concerns deeply rooted in the history of family planning, which is perceived to have been “fraught by coercive tactics to incentivize sterilization and contraceptive implants among marginalized groups.” With this in mind, they urged clinicians to respectfully ask about the patient’s intentions before making any suggestions concerning future births and family planning preferences.

HCP readiness ensures that each woman “has a documented postpartum care plan and care team identified in the prenatal period.” HCPs are also responsible for developing and maintaining “a working knowledge of evidence-based evaluation and management of common issues facing the mother-infant dyad.”

Clinical setting readiness ensures that woman-centered postpartum care and education have been developed and optimized using adult learning principles whenever possible. Diversity of family structures, cultural traditions, and parenting practices are fully embraced. Dr. Stuebe and colleagues emphasized that traditional top-down teaching methods are ineffective and should be avoided.

Clinical setting readiness also ensures that systems are developed to pair families with community-based resources that provide medical follow-up as well as social and material support. Clinical protocols and reimbursement options should be available that give women easy access to preferred contraception. Systems should be in place that facilitate prompt, pertinent communication between in- and outpatient providers. Lastly, and perhaps most importantly, clinical setting readiness demands the development of protocols to screen and treat key postpartum concerns, such as depression, substance use disorders, family violence, and even incontinence in coordination with locally identified specialists.

Recognition and prevention promotes accountability and establishes key guidelines

Recognition and prevention require coordinated participation between women experiencing pregnancy and the clinical environments supporting their care. In this phase, women are responsible for three goals; clinical environments have four goals.

Women are to be identified and respected as the expert most knowledgeable of their own needs, cautioned the authors. They should also be empowered to trust their instincts, seeking care as early and as often as needed in the weeks after they give birth. Postpartum care needs to be viewed as an ongoing process, not just a singular encounter.

Women also need to take ownership for their postpartum care plan, reviewing and revising it as needed in coordination with their health care providers before maternity discharge is complete. Every plan should include a comprehensive list of warning signs and recommended action plans when faced with life-threatening complications, a list of resources for lactation support, and a “first-call” phone number that identifies the postpartum medical providers available to address breastfeeding issues and for postpartum care visits, including prescheduled dates and times.

Lastly, women are to take responsibility for attending their postpartum visit. Although new guidance suggests that the comprehensive visit take place no later than 12 weeks post partum, it also recognizes multiple visits may be required to address individual needs. All women should have contact with a maternal care provider within 3 weeks post partum, the American College of Obstetricians and Gynecologists recommends.

Responsibility for recognition and prevention in the clinical setting begins with determining guidelines for early postpartum visits, considering chronic conditions such as hypertension, diabetes, or substance abuse disorder and risk for postpartum conditions such as wound complications or postpartum depression, the authors wrote. Ongoing care between inpatient and outpatient settings as well as between maternal and infant care providers is coordinated to ensure health and well-being of both patients. Screening and treatment of common comorbidities such as mental health issues, smoking, and substance use as well as issues related to unstable housing and food insecurities are also addressed in the clinical environment. Lastly, clinicians are tasked with ensuring that every patient has selected a primary care provider for ongoing care.

Response ensures key parties and resources are connected at every step

In the response phase, clinical settings and health care providers are the key participants and they have two goals each.

Every clinical setting is tasked with implementing treatment protocols and providing needed care or facilitating referral in a timely fashion. The importance of a “warm hand-off” and “face-to-face introduction to the specialist to whom the patient is being referred” is encouraged. They are also responsible for keeping an updated inventory of community resources on hand for such unmet needs as 24-hour hotlines, food banks, diaper banks, lactation support groups, and home-visiting programs.

Every health care provider is tasked with developing strategies designed to reach women who do not attend their comprehensive postpartum visit. They are also responsible for assessing the severity of identified needs, and arranging immediate transportation to appropriate facilities in life-threatening circumstances. In nonacute cases, the woman and her care providers work with her to make appropriate decisions.

Reporting gives health systems the opportunity to assess and improve

Sole responsibility in the reporting phase falls to every health system. In this phase, they have a total of six goals.

Health systems are ideally organized to convene strategy-sharing sessions with inpatient as well as outpatient professionals to evaluate successes and opportunities for improvement. They are equally qualified to identify and monitor such quality measures as postpartum emergency department utilization and readmission rates. They are tasked with working toward quality metrics that compare postpartum outcomes and prenatal intentions, including patient receipt of preferred contraception or completion of planned breastfeeding duration.

Health systems are expected to conduct quality improvement measures designed to reduce postpartum morbidity when preventable. They are also the logical choice for maintaining a clearinghouse for resources, in collaboration with the community, that is designed to meet the postpartum needs of women.

Lastly, they play an important role in ensuring that reimbursement policies are structured such that they do not disincentivize postpartum visits.
 

The consensus bundle encourages change in the way America treats its new mothers

Angela Bianco, MD, maternal and fetal medicine specialist at Mount Sinai Hospital, New York, also interviewed separately, noted: “I think the fact that ACOG has created a postpartum bundle for providers to use for guidance is long overdue. The current prenatal care paradigm focuses on numerous/intensive prenatal visits but only a single postpartum visit. Many women report feeling ill-equipped to navigate the challenges that arise post delivery, including self-care, newborn care, and breastfeeding. In addition, most women experience the impact of dramatic hormonal fluctuations resulting in mood alterations. Add profound sleep deprivation to this and the result is often some degree of postpartum blues and/or depression. The importance of anticipatory guidance for our patients cannot be underestimated. Helping to facilitate potential social support structures be in place prior to the birth is optimal. Providers should reinforce the importance of access to a variety of tools, including digital apps, community support groups, and 24/7 web access services. Moving forward, it should be considered unconscionable to send a new mother home without ensuring the appropriate resources are in place. Postpartum care should be tailored to a woman’s needs and may require multiple visits and/or referrals.”

Dr. Stuebe and colleagues, as well as Dr. Bianco, disclosed receiving honoraria for various projects. Funding for the study was supported by the Alliance for Innovation on Maternal and Child Health, which is funded by a grant from the Health Resources and Services Administration.

Health care professionals miss an important opportunity if they do not use a holistic patient-centered approach in providing support to their postpartum patients, advised Alison M. Stuebe, MD, MSc, of the division of maternal-fetal medicine at the University of North Carolina at Chapel Hill, and colleagues.

Too often, the emphasis for health care professionals is on less common, highly morbid complications, while their patients’ needs are focused more on daily functioning.

More than half of maternal deaths occur not during delivery, but in the days, weeks, and months following birth. Many serious complications and management of less-emergent conditions such as flu-like symptoms go unnoticed or result in treatment delays. Routinely asking women who present for care whether they have been pregnant during the past year could go a long way in helping clinicians connect the dots for conditions they might not otherwise consider, suggested Dr. Stuebe and colleagues.

In response to what is becoming a growing burden of postpartum maternal morbidity and mortality in the United States, Dr. Stuebe and associates, in coordination with the Alliance of Innovation in Maternal Health, prepared a comprehensive consensus statement on postpartum care basics. The work came out of a day-long planning meeting of an interdisciplinary work group funded by AIMH to develop the maternal safety bundle, which established 28 goals across four phases – readiness, recognition and prevention, response, and reporting. Each phase is intended to occur as part of a coordinated effort between women experiencing pregnancy and their health care providers, with involvement from multiple clinical settings and health systems.
 

America needs to change the way it treats its new mothers

In a separate interview, Dr. Stuebe shared additional insights into the development of the consensus statement: “This article is part of a broader movement to change the way America treats new mothers. For too long, we’ve lavished attention on women in the weeks before birth and then left them alone to manage recovery, plunging hormones, sleepless nights, and new baby care. If the baby is the candy, and the mother is the wrapper, once the candy is out of the wrapper, we’ve tossed the wrapper aside. The goal of this article is to set out the ways that we can better support women in this critical transition period.

“We need to start during pregnancy, by working with women to plan for the fourth trimester and identify a care team that will support her and her baby. After birth, we need to adapt those plans and make sure she has the emotional and material support she needs to navigate the coming months. Many of these decisions are deeply personal, and we need to center the values and preferences of the woman and her family.”

Dr. Stuebe also spotlighted a new University of North Carolina–based program designed to support shared decision-making. Their Trimester Project team partnered with mothers to design NewMomHealth.com, the first national postpartum resource designed by and for new mothers, which is in the process of launching a culturally adapted Spanish-language site, saludmadre.com, in partnership with Urban Strategies.
 

Readiness prepares mothers, HCPs, and clinical settings for the fourth trimester

In the first phase, Readiness, there are three key parties involved: the woman experiencing pregnancy, the health care providers (HCPs) supporting her, and the clinical settings involved in her care. Each player has specific goals to achieve in this phase, women are responsible for four goals, health care providers have two goals, and clinical settings have five.

Prenatally, every woman should work with health care providers to develop a comprehensive, individualized postpartum care plan that designates a postpartum clinical “home” for addressing any care needed between birth and the “comprehensive postpartum visit.” The plan encourages the patient and her health care team give attention to social support, birth recovery, infant care and feeding plans, thoughts concerning future pregnancies, and specifically use of contraception, as well as any chronic health concerns and overall emotional well-being.

The plan should consist of a postpartum care team that includes friends and family and ensures that medical, material, and social support are available in the weeks following birth for both mother and baby.

The authors emphasized the importance for clinicians to develop a keen awareness of “reproductive justice,” which respects a woman’s right “to maintain personal bodily autonomy, have children, not have children, and parent the children we have in safe and sustainable communities.” They encouraged adopting a sensitivity to concerns deeply rooted in the history of family planning, which is perceived to have been “fraught by coercive tactics to incentivize sterilization and contraceptive implants among marginalized groups.” With this in mind, they urged clinicians to respectfully ask about the patient’s intentions before making any suggestions concerning future births and family planning preferences.

HCP readiness ensures that each woman “has a documented postpartum care plan and care team identified in the prenatal period.” HCPs are also responsible for developing and maintaining “a working knowledge of evidence-based evaluation and management of common issues facing the mother-infant dyad.”

Clinical setting readiness ensures that woman-centered postpartum care and education have been developed and optimized using adult learning principles whenever possible. Diversity of family structures, cultural traditions, and parenting practices are fully embraced. Dr. Stuebe and colleagues emphasized that traditional top-down teaching methods are ineffective and should be avoided.

Clinical setting readiness also ensures that systems are developed to pair families with community-based resources that provide medical follow-up as well as social and material support. Clinical protocols and reimbursement options should be available that give women easy access to preferred contraception. Systems should be in place that facilitate prompt, pertinent communication between in- and outpatient providers. Lastly, and perhaps most importantly, clinical setting readiness demands the development of protocols to screen and treat key postpartum concerns, such as depression, substance use disorders, family violence, and even incontinence in coordination with locally identified specialists.

Recognition and prevention promotes accountability and establishes key guidelines

Recognition and prevention require coordinated participation between women experiencing pregnancy and the clinical environments supporting their care. In this phase, women are responsible for three goals; clinical environments have four goals.

Women are to be identified and respected as the expert most knowledgeable of their own needs, cautioned the authors. They should also be empowered to trust their instincts, seeking care as early and as often as needed in the weeks after they give birth. Postpartum care needs to be viewed as an ongoing process, not just a singular encounter.

Women also need to take ownership for their postpartum care plan, reviewing and revising it as needed in coordination with their health care providers before maternity discharge is complete. Every plan should include a comprehensive list of warning signs and recommended action plans when faced with life-threatening complications, a list of resources for lactation support, and a “first-call” phone number that identifies the postpartum medical providers available to address breastfeeding issues and for postpartum care visits, including prescheduled dates and times.

Lastly, women are to take responsibility for attending their postpartum visit. Although new guidance suggests that the comprehensive visit take place no later than 12 weeks post partum, it also recognizes multiple visits may be required to address individual needs. All women should have contact with a maternal care provider within 3 weeks post partum, the American College of Obstetricians and Gynecologists recommends.

Responsibility for recognition and prevention in the clinical setting begins with determining guidelines for early postpartum visits, considering chronic conditions such as hypertension, diabetes, or substance abuse disorder and risk for postpartum conditions such as wound complications or postpartum depression, the authors wrote. Ongoing care between inpatient and outpatient settings as well as between maternal and infant care providers is coordinated to ensure health and well-being of both patients. Screening and treatment of common comorbidities such as mental health issues, smoking, and substance use as well as issues related to unstable housing and food insecurities are also addressed in the clinical environment. Lastly, clinicians are tasked with ensuring that every patient has selected a primary care provider for ongoing care.

Response ensures key parties and resources are connected at every step

In the response phase, clinical settings and health care providers are the key participants and they have two goals each.

Every clinical setting is tasked with implementing treatment protocols and providing needed care or facilitating referral in a timely fashion. The importance of a “warm hand-off” and “face-to-face introduction to the specialist to whom the patient is being referred” is encouraged. They are also responsible for keeping an updated inventory of community resources on hand for such unmet needs as 24-hour hotlines, food banks, diaper banks, lactation support groups, and home-visiting programs.

Every health care provider is tasked with developing strategies designed to reach women who do not attend their comprehensive postpartum visit. They are also responsible for assessing the severity of identified needs, and arranging immediate transportation to appropriate facilities in life-threatening circumstances. In nonacute cases, the woman and her care providers work with her to make appropriate decisions.

Reporting gives health systems the opportunity to assess and improve

Sole responsibility in the reporting phase falls to every health system. In this phase, they have a total of six goals.

Health systems are ideally organized to convene strategy-sharing sessions with inpatient as well as outpatient professionals to evaluate successes and opportunities for improvement. They are equally qualified to identify and monitor such quality measures as postpartum emergency department utilization and readmission rates. They are tasked with working toward quality metrics that compare postpartum outcomes and prenatal intentions, including patient receipt of preferred contraception or completion of planned breastfeeding duration.

Health systems are expected to conduct quality improvement measures designed to reduce postpartum morbidity when preventable. They are also the logical choice for maintaining a clearinghouse for resources, in collaboration with the community, that is designed to meet the postpartum needs of women.

Lastly, they play an important role in ensuring that reimbursement policies are structured such that they do not disincentivize postpartum visits.
 

The consensus bundle encourages change in the way America treats its new mothers

Angela Bianco, MD, maternal and fetal medicine specialist at Mount Sinai Hospital, New York, also interviewed separately, noted: “I think the fact that ACOG has created a postpartum bundle for providers to use for guidance is long overdue. The current prenatal care paradigm focuses on numerous/intensive prenatal visits but only a single postpartum visit. Many women report feeling ill-equipped to navigate the challenges that arise post delivery, including self-care, newborn care, and breastfeeding. In addition, most women experience the impact of dramatic hormonal fluctuations resulting in mood alterations. Add profound sleep deprivation to this and the result is often some degree of postpartum blues and/or depression. The importance of anticipatory guidance for our patients cannot be underestimated. Helping to facilitate potential social support structures be in place prior to the birth is optimal. Providers should reinforce the importance of access to a variety of tools, including digital apps, community support groups, and 24/7 web access services. Moving forward, it should be considered unconscionable to send a new mother home without ensuring the appropriate resources are in place. Postpartum care should be tailored to a woman’s needs and may require multiple visits and/or referrals.”

Dr. Stuebe and colleagues, as well as Dr. Bianco, disclosed receiving honoraria for various projects. Funding for the study was supported by the Alliance for Innovation on Maternal and Child Health, which is funded by a grant from the Health Resources and Services Administration.

Health care professionals miss an important opportunity if they do not use a holistic patient-centered approach in providing support to their postpartum patients, advised Alison M. Stuebe, MD, MSc, of the division of maternal-fetal medicine at the University of North Carolina at Chapel Hill, and colleagues.

Too often, the emphasis for health care professionals is on less common, highly morbid complications, while their patients’ needs are focused more on daily functioning.

More than half of maternal deaths occur not during delivery, but in the days, weeks, and months following birth. Many serious complications and management of less-emergent conditions such as flu-like symptoms go unnoticed or result in treatment delays. Routinely asking women who present for care whether they have been pregnant during the past year could go a long way in helping clinicians connect the dots for conditions they might not otherwise consider, suggested Dr. Stuebe and colleagues.

In response to what is becoming a growing burden of postpartum maternal morbidity and mortality in the United States, Dr. Stuebe and associates, in coordination with the Alliance of Innovation in Maternal Health, prepared a comprehensive consensus statement on postpartum care basics. The work came out of a day-long planning meeting of an interdisciplinary work group funded by AIMH to develop the maternal safety bundle, which established 28 goals across four phases – readiness, recognition and prevention, response, and reporting. Each phase is intended to occur as part of a coordinated effort between women experiencing pregnancy and their health care providers, with involvement from multiple clinical settings and health systems.
 

America needs to change the way it treats its new mothers

In a separate interview, Dr. Stuebe shared additional insights into the development of the consensus statement: “This article is part of a broader movement to change the way America treats new mothers. For too long, we’ve lavished attention on women in the weeks before birth and then left them alone to manage recovery, plunging hormones, sleepless nights, and new baby care. If the baby is the candy, and the mother is the wrapper, once the candy is out of the wrapper, we’ve tossed the wrapper aside. The goal of this article is to set out the ways that we can better support women in this critical transition period.

“We need to start during pregnancy, by working with women to plan for the fourth trimester and identify a care team that will support her and her baby. After birth, we need to adapt those plans and make sure she has the emotional and material support she needs to navigate the coming months. Many of these decisions are deeply personal, and we need to center the values and preferences of the woman and her family.”

Dr. Stuebe also spotlighted a new University of North Carolina–based program designed to support shared decision-making. Their Trimester Project team partnered with mothers to design NewMomHealth.com, the first national postpartum resource designed by and for new mothers, which is in the process of launching a culturally adapted Spanish-language site, saludmadre.com, in partnership with Urban Strategies.
 

Readiness prepares mothers, HCPs, and clinical settings for the fourth trimester

In the first phase, Readiness, there are three key parties involved: the woman experiencing pregnancy, the health care providers (HCPs) supporting her, and the clinical settings involved in her care. Each player has specific goals to achieve in this phase, women are responsible for four goals, health care providers have two goals, and clinical settings have five.

Prenatally, every woman should work with health care providers to develop a comprehensive, individualized postpartum care plan that designates a postpartum clinical “home” for addressing any care needed between birth and the “comprehensive postpartum visit.” The plan encourages the patient and her health care team give attention to social support, birth recovery, infant care and feeding plans, thoughts concerning future pregnancies, and specifically use of contraception, as well as any chronic health concerns and overall emotional well-being.

The plan should consist of a postpartum care team that includes friends and family and ensures that medical, material, and social support are available in the weeks following birth for both mother and baby.

The authors emphasized the importance for clinicians to develop a keen awareness of “reproductive justice,” which respects a woman’s right “to maintain personal bodily autonomy, have children, not have children, and parent the children we have in safe and sustainable communities.” They encouraged adopting a sensitivity to concerns deeply rooted in the history of family planning, which is perceived to have been “fraught by coercive tactics to incentivize sterilization and contraceptive implants among marginalized groups.” With this in mind, they urged clinicians to respectfully ask about the patient’s intentions before making any suggestions concerning future births and family planning preferences.

HCP readiness ensures that each woman “has a documented postpartum care plan and care team identified in the prenatal period.” HCPs are also responsible for developing and maintaining “a working knowledge of evidence-based evaluation and management of common issues facing the mother-infant dyad.”

Clinical setting readiness ensures that woman-centered postpartum care and education have been developed and optimized using adult learning principles whenever possible. Diversity of family structures, cultural traditions, and parenting practices are fully embraced. Dr. Stuebe and colleagues emphasized that traditional top-down teaching methods are ineffective and should be avoided.

Clinical setting readiness also ensures that systems are developed to pair families with community-based resources that provide medical follow-up as well as social and material support. Clinical protocols and reimbursement options should be available that give women easy access to preferred contraception. Systems should be in place that facilitate prompt, pertinent communication between in- and outpatient providers. Lastly, and perhaps most importantly, clinical setting readiness demands the development of protocols to screen and treat key postpartum concerns, such as depression, substance use disorders, family violence, and even incontinence in coordination with locally identified specialists.

Recognition and prevention promotes accountability and establishes key guidelines

Recognition and prevention require coordinated participation between women experiencing pregnancy and the clinical environments supporting their care. In this phase, women are responsible for three goals; clinical environments have four goals.

Women are to be identified and respected as the expert most knowledgeable of their own needs, cautioned the authors. They should also be empowered to trust their instincts, seeking care as early and as often as needed in the weeks after they give birth. Postpartum care needs to be viewed as an ongoing process, not just a singular encounter.

Women also need to take ownership for their postpartum care plan, reviewing and revising it as needed in coordination with their health care providers before maternity discharge is complete. Every plan should include a comprehensive list of warning signs and recommended action plans when faced with life-threatening complications, a list of resources for lactation support, and a “first-call” phone number that identifies the postpartum medical providers available to address breastfeeding issues and for postpartum care visits, including prescheduled dates and times.

Lastly, women are to take responsibility for attending their postpartum visit. Although new guidance suggests that the comprehensive visit take place no later than 12 weeks post partum, it also recognizes multiple visits may be required to address individual needs. All women should have contact with a maternal care provider within 3 weeks post partum, the American College of Obstetricians and Gynecologists recommends.

Responsibility for recognition and prevention in the clinical setting begins with determining guidelines for early postpartum visits, considering chronic conditions such as hypertension, diabetes, or substance abuse disorder and risk for postpartum conditions such as wound complications or postpartum depression, the authors wrote. Ongoing care between inpatient and outpatient settings as well as between maternal and infant care providers is coordinated to ensure health and well-being of both patients. Screening and treatment of common comorbidities such as mental health issues, smoking, and substance use as well as issues related to unstable housing and food insecurities are also addressed in the clinical environment. Lastly, clinicians are tasked with ensuring that every patient has selected a primary care provider for ongoing care.

Response ensures key parties and resources are connected at every step

In the response phase, clinical settings and health care providers are the key participants and they have two goals each.

Every clinical setting is tasked with implementing treatment protocols and providing needed care or facilitating referral in a timely fashion. The importance of a “warm hand-off” and “face-to-face introduction to the specialist to whom the patient is being referred” is encouraged. They are also responsible for keeping an updated inventory of community resources on hand for such unmet needs as 24-hour hotlines, food banks, diaper banks, lactation support groups, and home-visiting programs.

Every health care provider is tasked with developing strategies designed to reach women who do not attend their comprehensive postpartum visit. They are also responsible for assessing the severity of identified needs, and arranging immediate transportation to appropriate facilities in life-threatening circumstances. In nonacute cases, the woman and her care providers work with her to make appropriate decisions.

Reporting gives health systems the opportunity to assess and improve

Sole responsibility in the reporting phase falls to every health system. In this phase, they have a total of six goals.

Health systems are ideally organized to convene strategy-sharing sessions with inpatient as well as outpatient professionals to evaluate successes and opportunities for improvement. They are equally qualified to identify and monitor such quality measures as postpartum emergency department utilization and readmission rates. They are tasked with working toward quality metrics that compare postpartum outcomes and prenatal intentions, including patient receipt of preferred contraception or completion of planned breastfeeding duration.

Health systems are expected to conduct quality improvement measures designed to reduce postpartum morbidity when preventable. They are also the logical choice for maintaining a clearinghouse for resources, in collaboration with the community, that is designed to meet the postpartum needs of women.

Lastly, they play an important role in ensuring that reimbursement policies are structured such that they do not disincentivize postpartum visits.
 

The consensus bundle encourages change in the way America treats its new mothers

Angela Bianco, MD, maternal and fetal medicine specialist at Mount Sinai Hospital, New York, also interviewed separately, noted: “I think the fact that ACOG has created a postpartum bundle for providers to use for guidance is long overdue. The current prenatal care paradigm focuses on numerous/intensive prenatal visits but only a single postpartum visit. Many women report feeling ill-equipped to navigate the challenges that arise post delivery, including self-care, newborn care, and breastfeeding. In addition, most women experience the impact of dramatic hormonal fluctuations resulting in mood alterations. Add profound sleep deprivation to this and the result is often some degree of postpartum blues and/or depression. The importance of anticipatory guidance for our patients cannot be underestimated. Helping to facilitate potential social support structures be in place prior to the birth is optimal. Providers should reinforce the importance of access to a variety of tools, including digital apps, community support groups, and 24/7 web access services. Moving forward, it should be considered unconscionable to send a new mother home without ensuring the appropriate resources are in place. Postpartum care should be tailored to a woman’s needs and may require multiple visits and/or referrals.”

Dr. Stuebe and colleagues, as well as Dr. Bianco, disclosed receiving honoraria for various projects. Funding for the study was supported by the Alliance for Innovation on Maternal and Child Health, which is funded by a grant from the Health Resources and Services Administration.

Most patients with normal findings on functional luminal imaging probe (FLIP) showed no clinical evidence of a major esophageal motor disorder, even when their high-resolution manometry (HRM) test results were abnormal, according to the results of a single-center retrospective cohort study.

Among 111 study participants with normal FLIP findings, 79% also showed no evidence of a major esophageal motor disorder on esophageal high-resolution manometry (HRM), wrote Alexandra J. Baumann, DO, of Northwestern University, Chicago, and associates. “Among the remaining 21% with apparent disagreement with HRM, [those] with normal FLIP panometry carried overall clinical impressions of not having a major esophageal motor disorder and subsequently were treated conservatively without the need for surgical interventions,” they reported. For patients with normal upper endoscopy and normal FLIP panometry, “the initial clinical management strategy could be directed toward addressing gastroesophageal reflux or a functional syndrome,” they wrote in Clinical Gastroenterology and Hepatology.

FLIP uses high-resolution impedance planimetry to evaluate esophageal lumen parameters, distensibility, and contractility in response to distension. Although HRM is standard for evaluating esophageal motility, false negatives and positives can result from challenges with interpreting outflow obstructions and normal lower-esophageal sphincter relaxation pressures among patients with clinical achalasia.

Hence, the researchers evaluated correlations between FLIP and HRM in 111 patients with esophageal symptoms and nonobstructive endoscopy findings who were evaluated at the Esophageal Center of Northwestern University between 2012 and 2019. Gastroenterologists performed additional studies, such as barium esophagrams, at their discretion. By study design, all patients had normal FLIP results, defined as an esophagogastric junction distensibility index above 3.0 mm² per mm Hg and a normal contractile response (that is, normal repetitive retrograde contractions and a repetitive antegrade contraction pattern that met the Rule-of-6s). Three clinicians evaluated and reached consensus on each FLIP study. Esophageal HRM data were interpreted based on the Chicago classification system (version 3.0).

Patients with normal FLIP panometry findings “did not have a clinical impression of a major esophageal motor disorder,” the researchers reported. In all, 23 (21%) patients with normal FLIP results had discrepant (abnormal) HRM findings, most of which were false positives or equivocal.

For example, among 20 patients whose HRM suggested an esophagogastric junction outflow obstruction, 17 showed normal bolus transit on supine swallows and 16 showed normalization of integrated relaxation pressure after adjunctive maneuvers. Similarly, among 10 patients who underwent a barium esophagram, 8 showed normal emptying, 1 showed a temporary delay but no retention, and 1 had an incomplete study. “The overall clinical impression was not of an achalasia variant in any of these 20 patients with [esophagogastric junction outflow obstruction] on HRM, and thus none underwent botulinum toxin injection, pneumatic dilation, or lower-esophageal sphincter myotomy at our center,” the researchers wrote. Among 17 patients who were available for clinical follow-up, 4 underwent empiric dilation, of whom none had mucosal disruption. One patient was diagnosed with dysphagia lusoria based on cross-sectional imaging, while the rest were managed conservatively.

Similarly, among 10 patients with at least 50% ineffective swallows on HRM, 5 showed normal barium emptying and 9 were managed conservatively (the remaining patient underwent cricopharyngeal dilation for concurrent oropharyngeal dysphagia). The strong correlation between HRM and esophagrams in this study indicates that“[n]ormal findings from FLIP panometry can be used to exclude esophageal motility disorders at the time of endoscopy, possibly reducing the need for high-resolution manometry evaluation of some patients,” the investigators concluded. “However, further longitudinal studies are needed to support this approach.”

The work was supported by the Public Health Service and the American College of Gastroenterology. Dr. Baumann reported having no conflicts of interest. Four coinvestigators disclosed relevant ties to Crospon, Given Imaging, Ironwood, Medtronic, Sandhill Scientific, Torax, and other companies..

SOURCE: Baumann AJ et al. Clin Gastroenterol Hepatol 2020 Mar 20. doi: 10.1016/j.cgh.2020.03.040.

Most patients with normal findings on functional luminal imaging probe (FLIP) showed no clinical evidence of a major esophageal motor disorder, even when their high-resolution manometry (HRM) test results were abnormal, according to the results of a single-center retrospective cohort study.

Among 111 study participants with normal FLIP findings, 79% also showed no evidence of a major esophageal motor disorder on esophageal high-resolution manometry (HRM), wrote Alexandra J. Baumann, DO, of Northwestern University, Chicago, and associates. “Among the remaining 21% with apparent disagreement with HRM, [those] with normal FLIP panometry carried overall clinical impressions of not having a major esophageal motor disorder and subsequently were treated conservatively without the need for surgical interventions,” they reported. For patients with normal upper endoscopy and normal FLIP panometry, “the initial clinical management strategy could be directed toward addressing gastroesophageal reflux or a functional syndrome,” they wrote in Clinical Gastroenterology and Hepatology.

FLIP uses high-resolution impedance planimetry to evaluate esophageal lumen parameters, distensibility, and contractility in response to distension. Although HRM is standard for evaluating esophageal motility, false negatives and positives can result from challenges with interpreting outflow obstructions and normal lower-esophageal sphincter relaxation pressures among patients with clinical achalasia.

Hence, the researchers evaluated correlations between FLIP and HRM in 111 patients with esophageal symptoms and nonobstructive endoscopy findings who were evaluated at the Esophageal Center of Northwestern University between 2012 and 2019. Gastroenterologists performed additional studies, such as barium esophagrams, at their discretion. By study design, all patients had normal FLIP results, defined as an esophagogastric junction distensibility index above 3.0 mm² per mm Hg and a normal contractile response (that is, normal repetitive retrograde contractions and a repetitive antegrade contraction pattern that met the Rule-of-6s). Three clinicians evaluated and reached consensus on each FLIP study. Esophageal HRM data were interpreted based on the Chicago classification system (version 3.0).

Patients with normal FLIP panometry findings “did not have a clinical impression of a major esophageal motor disorder,” the researchers reported. In all, 23 (21%) patients with normal FLIP results had discrepant (abnormal) HRM findings, most of which were false positives or equivocal.

For example, among 20 patients whose HRM suggested an esophagogastric junction outflow obstruction, 17 showed normal bolus transit on supine swallows and 16 showed normalization of integrated relaxation pressure after adjunctive maneuvers. Similarly, among 10 patients who underwent a barium esophagram, 8 showed normal emptying, 1 showed a temporary delay but no retention, and 1 had an incomplete study. “The overall clinical impression was not of an achalasia variant in any of these 20 patients with [esophagogastric junction outflow obstruction] on HRM, and thus none underwent botulinum toxin injection, pneumatic dilation, or lower-esophageal sphincter myotomy at our center,” the researchers wrote. Among 17 patients who were available for clinical follow-up, 4 underwent empiric dilation, of whom none had mucosal disruption. One patient was diagnosed with dysphagia lusoria based on cross-sectional imaging, while the rest were managed conservatively.

Similarly, among 10 patients with at least 50% ineffective swallows on HRM, 5 showed normal barium emptying and 9 were managed conservatively (the remaining patient underwent cricopharyngeal dilation for concurrent oropharyngeal dysphagia). The strong correlation between HRM and esophagrams in this study indicates that“[n]ormal findings from FLIP panometry can be used to exclude esophageal motility disorders at the time of endoscopy, possibly reducing the need for high-resolution manometry evaluation of some patients,” the investigators concluded. “However, further longitudinal studies are needed to support this approach.”

The work was supported by the Public Health Service and the American College of Gastroenterology. Dr. Baumann reported having no conflicts of interest. Four coinvestigators disclosed relevant ties to Crospon, Given Imaging, Ironwood, Medtronic, Sandhill Scientific, Torax, and other companies..

SOURCE: Baumann AJ et al. Clin Gastroenterol Hepatol 2020 Mar 20. doi: 10.1016/j.cgh.2020.03.040.

Most patients with normal findings on functional luminal imaging probe (FLIP) showed no clinical evidence of a major esophageal motor disorder, even when their high-resolution manometry (HRM) test results were abnormal, according to the results of a single-center retrospective cohort study.

Among 111 study participants with normal FLIP findings, 79% also showed no evidence of a major esophageal motor disorder on esophageal high-resolution manometry (HRM), wrote Alexandra J. Baumann, DO, of Northwestern University, Chicago, and associates. “Among the remaining 21% with apparent disagreement with HRM, [those] with normal FLIP panometry carried overall clinical impressions of not having a major esophageal motor disorder and subsequently were treated conservatively without the need for surgical interventions,” they reported. For patients with normal upper endoscopy and normal FLIP panometry, “the initial clinical management strategy could be directed toward addressing gastroesophageal reflux or a functional syndrome,” they wrote in Clinical Gastroenterology and Hepatology.

FLIP uses high-resolution impedance planimetry to evaluate esophageal lumen parameters, distensibility, and contractility in response to distension. Although HRM is standard for evaluating esophageal motility, false negatives and positives can result from challenges with interpreting outflow obstructions and normal lower-esophageal sphincter relaxation pressures among patients with clinical achalasia.

Hence, the researchers evaluated correlations between FLIP and HRM in 111 patients with esophageal symptoms and nonobstructive endoscopy findings who were evaluated at the Esophageal Center of Northwestern University between 2012 and 2019. Gastroenterologists performed additional studies, such as barium esophagrams, at their discretion. By study design, all patients had normal FLIP results, defined as an esophagogastric junction distensibility index above 3.0 mm² per mm Hg and a normal contractile response (that is, normal repetitive retrograde contractions and a repetitive antegrade contraction pattern that met the Rule-of-6s). Three clinicians evaluated and reached consensus on each FLIP study. Esophageal HRM data were interpreted based on the Chicago classification system (version 3.0).

Patients with normal FLIP panometry findings “did not have a clinical impression of a major esophageal motor disorder,” the researchers reported. In all, 23 (21%) patients with normal FLIP results had discrepant (abnormal) HRM findings, most of which were false positives or equivocal.

For example, among 20 patients whose HRM suggested an esophagogastric junction outflow obstruction, 17 showed normal bolus transit on supine swallows and 16 showed normalization of integrated relaxation pressure after adjunctive maneuvers. Similarly, among 10 patients who underwent a barium esophagram, 8 showed normal emptying, 1 showed a temporary delay but no retention, and 1 had an incomplete study. “The overall clinical impression was not of an achalasia variant in any of these 20 patients with [esophagogastric junction outflow obstruction] on HRM, and thus none underwent botulinum toxin injection, pneumatic dilation, or lower-esophageal sphincter myotomy at our center,” the researchers wrote. Among 17 patients who were available for clinical follow-up, 4 underwent empiric dilation, of whom none had mucosal disruption. One patient was diagnosed with dysphagia lusoria based on cross-sectional imaging, while the rest were managed conservatively.

Similarly, among 10 patients with at least 50% ineffective swallows on HRM, 5 showed normal barium emptying and 9 were managed conservatively (the remaining patient underwent cricopharyngeal dilation for concurrent oropharyngeal dysphagia). The strong correlation between HRM and esophagrams in this study indicates that“[n]ormal findings from FLIP panometry can be used to exclude esophageal motility disorders at the time of endoscopy, possibly reducing the need for high-resolution manometry evaluation of some patients,” the investigators concluded. “However, further longitudinal studies are needed to support this approach.”

The work was supported by the Public Health Service and the American College of Gastroenterology. Dr. Baumann reported having no conflicts of interest. Four coinvestigators disclosed relevant ties to Crospon, Given Imaging, Ironwood, Medtronic, Sandhill Scientific, Torax, and other companies..

SOURCE: Baumann AJ et al. Clin Gastroenterol Hepatol 2020 Mar 20. doi: 10.1016/j.cgh.2020.03.040.

Use of linked-color imaging for upper gastrointestinal tract endoscopy improves the detection of neoplasms in comparison with conventional white-light imaging, according to results from a randomized trial involving more than 1,500 patients.

Linked-color imaging (LCI) is an advanced illumination technique that combines white light with narrow-band short-wavelength light to enhance the contrast of red and white hues during endoscopy, making it easier to recognize subtle differences in mucosal color.

At present, LCI is available only on systems manufactured by Fujifilm (that is, the Lasereo endoscopic system marketed in Japan and the Eluxeo system in the United States and Europe). The system includes the light source and a processor and can be used with various endoscopes.

“Combined with previous studies that show the efficacy of LCI in detecting large intestinal neoplasia, our findings make a strong case for wider adoption of this modality in surveillance of the entire endoscopically accessible digestive tract,” senior investigator and gastroenterologist Mototsugu Kato, MD, of the Hakodate National Hospital, Hokkaido, Japan, said in a press release.

The randomized trial was conducted at 19 Japanese hospitals by 58 expert endoscopists, all of whom were experienced with LCI.

“We need further research to confirm [LCI’s] efficacy in the hands of general clinicians for upper GI screening” of an average-risk population, Dr. Kato said.

Results from the trial were published in Annals of Internal Medicine.

Approached for comment, gastroenterologist Marvin Ryou, MD, director of endoscopic innovation at Brigham and Women’s Hospital, Boston, said that he has used Fujifilm’s LCI technology mostly for polyp detection on colonoscopy and has found it useful.

LCI “has been shown to be helpful for the detection of colonic neoplasia, and this Japanese multicenter study provides additional evidence of utility in foregut neoplasm detection. I would look forward to future studies of LCI in an average-risk population,” he said.
 

Details of the randomized trial

All of the trial participants had previous or current gastrointestinal cancer and were undergoing upper GI endoscopic surveillance. Patients were a little older than 70 years on average, and more than 75% were men.

The patients underwent two examinations during their endoscopy sessions, one performed with LCI, and the other with conventional white-light imaging (WLI). The endoscopy system used in the study allowed the scope to switch between the two modalities, as well as others.

Overall, 750 patients were randomly assigned to undergo LCI first and then WLI; 752 underwent WLI first and then LCI.

In both groups, lesions were most common in the stomach, followed by the esophagus and the pharynx.

Neoplastic lesions in the pharynx, esophagus, or stomach – confirmed by histology – were detected in 60 patients (8%) with LCI versus 36 patients (4.8%) with WLI. This translated to a 1.67 times higher rate of detection.

First-pass WLI missed 26 lesions that were picked up by second-pass LCI. Five lesions were missed by LCI and were subsequently detected by WLI, which translated to a greater than 80% reduction in missed lesions with LCI.

Procedure time was longer with LCI than WLI, but mean differences were less than 20 seconds.

The investigators said that there is a possibility of overdiagnosis with both systems, but perhaps more so with LCI. Overall, WLI detected 121 lesions on first pass, 30.6% of which were neoplastic; first-pass LCI detected 185 lesions, 35.7% of which were neoplastic.

The trial was funded by Fujifilm. One investigator has received a grant and another has received research funding from Fujifilm. Dr. Ryou is a consultant for the company.

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

Use of linked-color imaging for upper gastrointestinal tract endoscopy improves the detection of neoplasms in comparison with conventional white-light imaging, according to results from a randomized trial involving more than 1,500 patients.

Linked-color imaging (LCI) is an advanced illumination technique that combines white light with narrow-band short-wavelength light to enhance the contrast of red and white hues during endoscopy, making it easier to recognize subtle differences in mucosal color.

At present, LCI is available only on systems manufactured by Fujifilm (that is, the Lasereo endoscopic system marketed in Japan and the Eluxeo system in the United States and Europe). The system includes the light source and a processor and can be used with various endoscopes.

“Combined with previous studies that show the efficacy of LCI in detecting large intestinal neoplasia, our findings make a strong case for wider adoption of this modality in surveillance of the entire endoscopically accessible digestive tract,” senior investigator and gastroenterologist Mototsugu Kato, MD, of the Hakodate National Hospital, Hokkaido, Japan, said in a press release.

The randomized trial was conducted at 19 Japanese hospitals by 58 expert endoscopists, all of whom were experienced with LCI.

“We need further research to confirm [LCI’s] efficacy in the hands of general clinicians for upper GI screening” of an average-risk population, Dr. Kato said.

Results from the trial were published in Annals of Internal Medicine.

Approached for comment, gastroenterologist Marvin Ryou, MD, director of endoscopic innovation at Brigham and Women’s Hospital, Boston, said that he has used Fujifilm’s LCI technology mostly for polyp detection on colonoscopy and has found it useful.

LCI “has been shown to be helpful for the detection of colonic neoplasia, and this Japanese multicenter study provides additional evidence of utility in foregut neoplasm detection. I would look forward to future studies of LCI in an average-risk population,” he said.
 

Details of the randomized trial

All of the trial participants had previous or current gastrointestinal cancer and were undergoing upper GI endoscopic surveillance. Patients were a little older than 70 years on average, and more than 75% were men.

The patients underwent two examinations during their endoscopy sessions, one performed with LCI, and the other with conventional white-light imaging (WLI). The endoscopy system used in the study allowed the scope to switch between the two modalities, as well as others.

Overall, 750 patients were randomly assigned to undergo LCI first and then WLI; 752 underwent WLI first and then LCI.

In both groups, lesions were most common in the stomach, followed by the esophagus and the pharynx.

Neoplastic lesions in the pharynx, esophagus, or stomach – confirmed by histology – were detected in 60 patients (8%) with LCI versus 36 patients (4.8%) with WLI. This translated to a 1.67 times higher rate of detection.

First-pass WLI missed 26 lesions that were picked up by second-pass LCI. Five lesions were missed by LCI and were subsequently detected by WLI, which translated to a greater than 80% reduction in missed lesions with LCI.

Procedure time was longer with LCI than WLI, but mean differences were less than 20 seconds.

The investigators said that there is a possibility of overdiagnosis with both systems, but perhaps more so with LCI. Overall, WLI detected 121 lesions on first pass, 30.6% of which were neoplastic; first-pass LCI detected 185 lesions, 35.7% of which were neoplastic.

The trial was funded by Fujifilm. One investigator has received a grant and another has received research funding from Fujifilm. Dr. Ryou is a consultant for the company.

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

Use of linked-color imaging for upper gastrointestinal tract endoscopy improves the detection of neoplasms in comparison with conventional white-light imaging, according to results from a randomized trial involving more than 1,500 patients.

Linked-color imaging (LCI) is an advanced illumination technique that combines white light with narrow-band short-wavelength light to enhance the contrast of red and white hues during endoscopy, making it easier to recognize subtle differences in mucosal color.

At present, LCI is available only on systems manufactured by Fujifilm (that is, the Lasereo endoscopic system marketed in Japan and the Eluxeo system in the United States and Europe). The system includes the light source and a processor and can be used with various endoscopes.

“Combined with previous studies that show the efficacy of LCI in detecting large intestinal neoplasia, our findings make a strong case for wider adoption of this modality in surveillance of the entire endoscopically accessible digestive tract,” senior investigator and gastroenterologist Mototsugu Kato, MD, of the Hakodate National Hospital, Hokkaido, Japan, said in a press release.

The randomized trial was conducted at 19 Japanese hospitals by 58 expert endoscopists, all of whom were experienced with LCI.

“We need further research to confirm [LCI’s] efficacy in the hands of general clinicians for upper GI screening” of an average-risk population, Dr. Kato said.

Results from the trial were published in Annals of Internal Medicine.

Approached for comment, gastroenterologist Marvin Ryou, MD, director of endoscopic innovation at Brigham and Women’s Hospital, Boston, said that he has used Fujifilm’s LCI technology mostly for polyp detection on colonoscopy and has found it useful.

LCI “has been shown to be helpful for the detection of colonic neoplasia, and this Japanese multicenter study provides additional evidence of utility in foregut neoplasm detection. I would look forward to future studies of LCI in an average-risk population,” he said.
 

Details of the randomized trial

All of the trial participants had previous or current gastrointestinal cancer and were undergoing upper GI endoscopic surveillance. Patients were a little older than 70 years on average, and more than 75% were men.

The patients underwent two examinations during their endoscopy sessions, one performed with LCI, and the other with conventional white-light imaging (WLI). The endoscopy system used in the study allowed the scope to switch between the two modalities, as well as others.

Overall, 750 patients were randomly assigned to undergo LCI first and then WLI; 752 underwent WLI first and then LCI.

In both groups, lesions were most common in the stomach, followed by the esophagus and the pharynx.

Neoplastic lesions in the pharynx, esophagus, or stomach – confirmed by histology – were detected in 60 patients (8%) with LCI versus 36 patients (4.8%) with WLI. This translated to a 1.67 times higher rate of detection.

First-pass WLI missed 26 lesions that were picked up by second-pass LCI. Five lesions were missed by LCI and were subsequently detected by WLI, which translated to a greater than 80% reduction in missed lesions with LCI.

Procedure time was longer with LCI than WLI, but mean differences were less than 20 seconds.

The investigators said that there is a possibility of overdiagnosis with both systems, but perhaps more so with LCI. Overall, WLI detected 121 lesions on first pass, 30.6% of which were neoplastic; first-pass LCI detected 185 lesions, 35.7% of which were neoplastic.

The trial was funded by Fujifilm. One investigator has received a grant and another has received research funding from Fujifilm. Dr. Ryou is a consultant for the company.

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

Several updates in the strategy for prevention of and treatment of sexually transmitted infections were recently published in the United States.

Among these are the U.S. Department of Health and Human Services’ first “Sexually Transmitted Infections (STIs) National Strategic Plan for the United States,” which has a strong encompassing vision.

• Prevent New STIs.
• Improve the health of people by reducing adverse outcomes of STIs.
• Accelerate progress in STI research, technology, and innovation.
• Reduce STI-related health disparities and health inequities.
• Achieve integrated, coordinated efforts that address the STI epidemic.¹

In my opinion, family physicians have important roles to play in order for each of these goals to be achieved.Unfortunately, there are approximately 20 million new cases of STIs each year, and the U.S. has seen increases in the rates of STIs in the past decade.

“Sexually transmitted infections are frequently asymptomatic, which may delay diagnosis and treatment and lead persons to unknowingly transmit STIs to others,” according to a new recommendation statement from the USPSTF.² STIs may lead to serious health consequences for patients, cause harms to a mother and infant during pregnancy, and lead to cases of cancer among other concerning outcomes. As such, following the HHS new national strategic plan is critical for us to address the needs of our communities.
 

Preventing new STIs

Family physicians can be vital in achieving the first goal of the plan by helping to prevent new STIs. In August 2020, the USPSTF updated its guideline on behavioral counseling interventions to prevent STIs. In my opinion, the USPSTF offers some practical improvements from the earlier version of this guideline.

The task force provides a grade B recommendation that all sexually active adolescents and adults at increased risk for STIs be provided with behavioral counseling to prevent STIs. The guideline indicates that behavioral counseling interventions reduce the likelihood of those at increased risk for acquiring STIs.²

The 2014 guideline had recommended intensive interventions with a minimum of 30 minutes of counseling. Many family physicians may have found this previous recommendation impractical to implement. These updated recommendations now include a variety of interventions, such as those that take less than 30 minutes.

Although interventions with more than 120 minutes of contact time had the most effect, those with less than 30 minutes still demonstrated statistically significant fewer acquisitions of STIs during follow-up. These options include in-person counseling, and providing written materials, websites, videos, and telephone and text support to patients. These interventions can be delivered directly by the family physician, or patients may be referred to other settings or the media interventions.

The task force’s updated recommendation statement refers to a variety of resources that can be used to identify these interventions. Many of the studies reviewed for this guideline were conducted in STI clinics, and the guideline authors recommended further studies in primary care as opportunities for more generalizability.

In addition to behavioral counseling for STI prevention, family physicians can help prevent STIs in their patients through HPV vaccination and HIV pre-exposure prophylaxis (PrEP provision) within their practices. As the first contact for health care for many patients, we have an opportunity to significantly impact this first goal of prevention.
 

Treating STIs

Within the second goal of the national strategic plan is treatment of STIs, which family physicians should include in their practices as well as the diagnosis of STIs.

In December 2020, an update to the CDC’s treatment guideline for gonococcal infection was released. Prior to the publishing of this updated recommendation, the CDC recommended combination therapy of 250 mg intramuscular (IM) dose of ceftriaxone and either doxycycline or azithromycin. This recommendation has been changed to a single 500-mg IM dose of ceftriaxone for uncomplicated urogenital, anorectal, and pharyngeal gonorrhea. If chlamydia cannot be excluded, then the addition of oral doxycycline 100 mg twice daily for 7 days is recommended for nonpregnant persons, and 1 g oral azithromycin for pregnant persons. The previous treatment was recommended based on a concern for gonococcal resistance.

This updated guideline reflects increasing concerns for antimicrobial stewardship and emerging azithromycin resistance. It does not recommend a test-of-cure for urogenital or rectal gonorrhea, though did recommend a test-of-cure 7-14 days after treatment of pharyngeal gonorrhea. The guideline also recommends testing for reinfection 3-12 months after treatment as the rate of reinfection ranges from 7% to 12% among those previously treated.³

For some offices, the provision of the IM injection may be challenging, though having this medication in stock with the possibility of provision can greatly improve access and ease of treatment for patients. Family physicians can incorporate these updated recommendations along with those for other STIs such as chlamydia and syphilis with standing orders for treatment and testing within their offices.
 

Accelerating progress in STI research

Family physicians can also support the national strategic plan by participating in studies looking at the impact of behavioral counseling in the primary care office as opposed to in STI clinics. In addition, by following the STI treatment and screening guidelines, family physicians will contribute to the body of knowledge of prevalence, treatment failure, and reinfection rates of STIs. We can also help advance the research by providing feedback on interventions that have success within our practices.

Reducing STI-related health disparities and inequities

Family physicians are also in important places to support the strategic plan’s fourth goal of reducing health disparities and health inequities.

If we continue to ask the questions to identify those at high risk and ensure that we are offering appropriate STI prevention, care, and treatment services within our clinics, we can expand access to all who need services and improve equity. By offering these services within the primary care office, we may be able to decrease the stigma some may feel going to an STI clinic for services.

By incorporating additional screening and counseling in our practices we may identify some patients who were not aware that they were at risk for an STI and offer them preventive services.
 

Achieving integrated and coordinated efforts

Finally, as many family physicians have integrated practices, we are uniquely poised to support the fifth goal of the strategic plan of achieving integrated and coordinated efforts addressing the STI epidemic. In our practices we can participate in, lead, and refer to programs for substance use disorders, viral hepatitis, STIs, and HIV as part of full scope primary care.

Family physicians and other primary care providers should work to support the entire strategic plan to ensure that we are fully caring for our patients and communities and stopping the past decade’s increase in STIs. We have an opportunity to use this strategy and make a large impact in our communities.
 

Dr. Wheat is a family physician at Erie Family Health Center in Chicago. She is program director of Northwestern’s McGaw Family Medicine residency program at Humboldt Park, Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at [email protected].

References

1. U.S. Department of Health and Human Services. 2020. Sexually Transmitted Infections National Strategic Plan for the United States: 2021-2025. Washington.

2. U.S. Preventive Services Task Force. Behavioral counseling interventions to prevent sexually transmitted infections: U.S. Preventive Services Task Force Recommendation Statement. JAMA. 2020;324(7):674-81. doi: 10.1001/jama.2020.13095.

3. St. Cyr S et al. Update to CDC’s Treatment Guideline for Gonococcal Infection, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1911-6. doi: 10.15585/mmwr.mm6950a6external_icon.

Several updates in the strategy for prevention of and treatment of sexually transmitted infections were recently published in the United States.

Among these are the U.S. Department of Health and Human Services’ first “Sexually Transmitted Infections (STIs) National Strategic Plan for the United States,” which has a strong encompassing vision.

• Prevent New STIs.
• Improve the health of people by reducing adverse outcomes of STIs.
• Accelerate progress in STI research, technology, and innovation.
• Reduce STI-related health disparities and health inequities.
• Achieve integrated, coordinated efforts that address the STI epidemic.¹

In my opinion, family physicians have important roles to play in order for each of these goals to be achieved.Unfortunately, there are approximately 20 million new cases of STIs each year, and the U.S. has seen increases in the rates of STIs in the past decade.

“Sexually transmitted infections are frequently asymptomatic, which may delay diagnosis and treatment and lead persons to unknowingly transmit STIs to others,” according to a new recommendation statement from the USPSTF.² STIs may lead to serious health consequences for patients, cause harms to a mother and infant during pregnancy, and lead to cases of cancer among other concerning outcomes. As such, following the HHS new national strategic plan is critical for us to address the needs of our communities.
 

Preventing new STIs

Family physicians can be vital in achieving the first goal of the plan by helping to prevent new STIs. In August 2020, the USPSTF updated its guideline on behavioral counseling interventions to prevent STIs. In my opinion, the USPSTF offers some practical improvements from the earlier version of this guideline.

The task force provides a grade B recommendation that all sexually active adolescents and adults at increased risk for STIs be provided with behavioral counseling to prevent STIs. The guideline indicates that behavioral counseling interventions reduce the likelihood of those at increased risk for acquiring STIs.²

The 2014 guideline had recommended intensive interventions with a minimum of 30 minutes of counseling. Many family physicians may have found this previous recommendation impractical to implement. These updated recommendations now include a variety of interventions, such as those that take less than 30 minutes.

Although interventions with more than 120 minutes of contact time had the most effect, those with less than 30 minutes still demonstrated statistically significant fewer acquisitions of STIs during follow-up. These options include in-person counseling, and providing written materials, websites, videos, and telephone and text support to patients. These interventions can be delivered directly by the family physician, or patients may be referred to other settings or the media interventions.

The task force’s updated recommendation statement refers to a variety of resources that can be used to identify these interventions. Many of the studies reviewed for this guideline were conducted in STI clinics, and the guideline authors recommended further studies in primary care as opportunities for more generalizability.

In addition to behavioral counseling for STI prevention, family physicians can help prevent STIs in their patients through HPV vaccination and HIV pre-exposure prophylaxis (PrEP provision) within their practices. As the first contact for health care for many patients, we have an opportunity to significantly impact this first goal of prevention.
 

Treating STIs

Within the second goal of the national strategic plan is treatment of STIs, which family physicians should include in their practices as well as the diagnosis of STIs.

In December 2020, an update to the CDC’s treatment guideline for gonococcal infection was released. Prior to the publishing of this updated recommendation, the CDC recommended combination therapy of 250 mg intramuscular (IM) dose of ceftriaxone and either doxycycline or azithromycin. This recommendation has been changed to a single 500-mg IM dose of ceftriaxone for uncomplicated urogenital, anorectal, and pharyngeal gonorrhea. If chlamydia cannot be excluded, then the addition of oral doxycycline 100 mg twice daily for 7 days is recommended for nonpregnant persons, and 1 g oral azithromycin for pregnant persons. The previous treatment was recommended based on a concern for gonococcal resistance.

This updated guideline reflects increasing concerns for antimicrobial stewardship and emerging azithromycin resistance. It does not recommend a test-of-cure for urogenital or rectal gonorrhea, though did recommend a test-of-cure 7-14 days after treatment of pharyngeal gonorrhea. The guideline also recommends testing for reinfection 3-12 months after treatment as the rate of reinfection ranges from 7% to 12% among those previously treated.³

For some offices, the provision of the IM injection may be challenging, though having this medication in stock with the possibility of provision can greatly improve access and ease of treatment for patients. Family physicians can incorporate these updated recommendations along with those for other STIs such as chlamydia and syphilis with standing orders for treatment and testing within their offices.
 

Accelerating progress in STI research

Family physicians can also support the national strategic plan by participating in studies looking at the impact of behavioral counseling in the primary care office as opposed to in STI clinics. In addition, by following the STI treatment and screening guidelines, family physicians will contribute to the body of knowledge of prevalence, treatment failure, and reinfection rates of STIs. We can also help advance the research by providing feedback on interventions that have success within our practices.

Reducing STI-related health disparities and inequities

Family physicians are also in important places to support the strategic plan’s fourth goal of reducing health disparities and health inequities.

If we continue to ask the questions to identify those at high risk and ensure that we are offering appropriate STI prevention, care, and treatment services within our clinics, we can expand access to all who need services and improve equity. By offering these services within the primary care office, we may be able to decrease the stigma some may feel going to an STI clinic for services.

By incorporating additional screening and counseling in our practices we may identify some patients who were not aware that they were at risk for an STI and offer them preventive services.
 

Achieving integrated and coordinated efforts

Finally, as many family physicians have integrated practices, we are uniquely poised to support the fifth goal of the strategic plan of achieving integrated and coordinated efforts addressing the STI epidemic. In our practices we can participate in, lead, and refer to programs for substance use disorders, viral hepatitis, STIs, and HIV as part of full scope primary care.

Family physicians and other primary care providers should work to support the entire strategic plan to ensure that we are fully caring for our patients and communities and stopping the past decade’s increase in STIs. We have an opportunity to use this strategy and make a large impact in our communities.
 

Dr. Wheat is a family physician at Erie Family Health Center in Chicago. She is program director of Northwestern’s McGaw Family Medicine residency program at Humboldt Park, Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at [email protected].

References

1. U.S. Department of Health and Human Services. 2020. Sexually Transmitted Infections National Strategic Plan for the United States: 2021-2025. Washington.

2. U.S. Preventive Services Task Force. Behavioral counseling interventions to prevent sexually transmitted infections: U.S. Preventive Services Task Force Recommendation Statement. JAMA. 2020;324(7):674-81. doi: 10.1001/jama.2020.13095.

3. St. Cyr S et al. Update to CDC’s Treatment Guideline for Gonococcal Infection, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1911-6. doi: 10.15585/mmwr.mm6950a6external_icon.

Several updates in the strategy for prevention of and treatment of sexually transmitted infections were recently published in the United States.

Among these are the U.S. Department of Health and Human Services’ first “Sexually Transmitted Infections (STIs) National Strategic Plan for the United States,” which has a strong encompassing vision.

• Prevent New STIs.
• Improve the health of people by reducing adverse outcomes of STIs.
• Accelerate progress in STI research, technology, and innovation.
• Reduce STI-related health disparities and health inequities.
• Achieve integrated, coordinated efforts that address the STI epidemic.¹

In my opinion, family physicians have important roles to play in order for each of these goals to be achieved.Unfortunately, there are approximately 20 million new cases of STIs each year, and the U.S. has seen increases in the rates of STIs in the past decade.

“Sexually transmitted infections are frequently asymptomatic, which may delay diagnosis and treatment and lead persons to unknowingly transmit STIs to others,” according to a new recommendation statement from the USPSTF.² STIs may lead to serious health consequences for patients, cause harms to a mother and infant during pregnancy, and lead to cases of cancer among other concerning outcomes. As such, following the HHS new national strategic plan is critical for us to address the needs of our communities.
 

Preventing new STIs

Family physicians can be vital in achieving the first goal of the plan by helping to prevent new STIs. In August 2020, the USPSTF updated its guideline on behavioral counseling interventions to prevent STIs. In my opinion, the USPSTF offers some practical improvements from the earlier version of this guideline.

The task force provides a grade B recommendation that all sexually active adolescents and adults at increased risk for STIs be provided with behavioral counseling to prevent STIs. The guideline indicates that behavioral counseling interventions reduce the likelihood of those at increased risk for acquiring STIs.²

The 2014 guideline had recommended intensive interventions with a minimum of 30 minutes of counseling. Many family physicians may have found this previous recommendation impractical to implement. These updated recommendations now include a variety of interventions, such as those that take less than 30 minutes.

Although interventions with more than 120 minutes of contact time had the most effect, those with less than 30 minutes still demonstrated statistically significant fewer acquisitions of STIs during follow-up. These options include in-person counseling, and providing written materials, websites, videos, and telephone and text support to patients. These interventions can be delivered directly by the family physician, or patients may be referred to other settings or the media interventions.

The task force’s updated recommendation statement refers to a variety of resources that can be used to identify these interventions. Many of the studies reviewed for this guideline were conducted in STI clinics, and the guideline authors recommended further studies in primary care as opportunities for more generalizability.

In addition to behavioral counseling for STI prevention, family physicians can help prevent STIs in their patients through HPV vaccination and HIV pre-exposure prophylaxis (PrEP provision) within their practices. As the first contact for health care for many patients, we have an opportunity to significantly impact this first goal of prevention.
 

Treating STIs

Within the second goal of the national strategic plan is treatment of STIs, which family physicians should include in their practices as well as the diagnosis of STIs.

In December 2020, an update to the CDC’s treatment guideline for gonococcal infection was released. Prior to the publishing of this updated recommendation, the CDC recommended combination therapy of 250 mg intramuscular (IM) dose of ceftriaxone and either doxycycline or azithromycin. This recommendation has been changed to a single 500-mg IM dose of ceftriaxone for uncomplicated urogenital, anorectal, and pharyngeal gonorrhea. If chlamydia cannot be excluded, then the addition of oral doxycycline 100 mg twice daily for 7 days is recommended for nonpregnant persons, and 1 g oral azithromycin for pregnant persons. The previous treatment was recommended based on a concern for gonococcal resistance.

This updated guideline reflects increasing concerns for antimicrobial stewardship and emerging azithromycin resistance. It does not recommend a test-of-cure for urogenital or rectal gonorrhea, though did recommend a test-of-cure 7-14 days after treatment of pharyngeal gonorrhea. The guideline also recommends testing for reinfection 3-12 months after treatment as the rate of reinfection ranges from 7% to 12% among those previously treated.³

For some offices, the provision of the IM injection may be challenging, though having this medication in stock with the possibility of provision can greatly improve access and ease of treatment for patients. Family physicians can incorporate these updated recommendations along with those for other STIs such as chlamydia and syphilis with standing orders for treatment and testing within their offices.
 

Accelerating progress in STI research

Family physicians can also support the national strategic plan by participating in studies looking at the impact of behavioral counseling in the primary care office as opposed to in STI clinics. In addition, by following the STI treatment and screening guidelines, family physicians will contribute to the body of knowledge of prevalence, treatment failure, and reinfection rates of STIs. We can also help advance the research by providing feedback on interventions that have success within our practices.

Reducing STI-related health disparities and inequities

Family physicians are also in important places to support the strategic plan’s fourth goal of reducing health disparities and health inequities.

If we continue to ask the questions to identify those at high risk and ensure that we are offering appropriate STI prevention, care, and treatment services within our clinics, we can expand access to all who need services and improve equity. By offering these services within the primary care office, we may be able to decrease the stigma some may feel going to an STI clinic for services.

By incorporating additional screening and counseling in our practices we may identify some patients who were not aware that they were at risk for an STI and offer them preventive services.
 

Achieving integrated and coordinated efforts

Finally, as many family physicians have integrated practices, we are uniquely poised to support the fifth goal of the strategic plan of achieving integrated and coordinated efforts addressing the STI epidemic. In our practices we can participate in, lead, and refer to programs for substance use disorders, viral hepatitis, STIs, and HIV as part of full scope primary care.

Family physicians and other primary care providers should work to support the entire strategic plan to ensure that we are fully caring for our patients and communities and stopping the past decade’s increase in STIs. We have an opportunity to use this strategy and make a large impact in our communities.
 

Dr. Wheat is a family physician at Erie Family Health Center in Chicago. She is program director of Northwestern’s McGaw Family Medicine residency program at Humboldt Park, Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at [email protected].

References

1. U.S. Department of Health and Human Services. 2020. Sexually Transmitted Infections National Strategic Plan for the United States: 2021-2025. Washington.

2. U.S. Preventive Services Task Force. Behavioral counseling interventions to prevent sexually transmitted infections: U.S. Preventive Services Task Force Recommendation Statement. JAMA. 2020;324(7):674-81. doi: 10.1001/jama.2020.13095.

3. St. Cyr S et al. Update to CDC’s Treatment Guideline for Gonococcal Infection, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1911-6. doi: 10.15585/mmwr.mm6950a6external_icon.

We continue with a focus on circadian rhythms and implications for skin care this month, paying particular attention to research or insights pertaining to specific skin conditions, when possible, as well as clinical studies that may shed light on how to time skin care treatments.

Francesca Bellini/iStock/Getty Images

It is important to remember that several studies in the last 20 years have revealed cutaneous tendencies based on the time of day. For instance, sebum production is known to be highest around noon, and pH also peaks during the day and is at its lowest at night.^1-5
 

Skin aging

In 2019, Dong and associates showed that blue light at 410 nm reduces PER1 transcription in keratinocytes, indicating that epidermal cells have the capacity to directly sense light and regulate their own clock gene expression. With the introduction of blue light at night, circadian rhythm is disrupted as epidermal skin cells act as if it is daytime. The investigators also considered blue light–induced damage to skin cells at various doses and exposure times in comparison with cells that remained unexposed to light. The production of reactive oxygen species increased in the exposed cells, as did DNA impairment and the emergence of inflammatory mediators, all of which have the potential to hasten aging.6

Early this year, Dong and associates demonstrated that melatonin can dose-dependently stimulate PER1 clock gene expression in normal human dermal fibroblasts and normal human epidermal keratinocytes, and verified that the MT-1 melatonin receptor in such fibroblasts manifests a marked decline with age. The researchers concluded that the melatonin pathway contributes significantly in cutaneous aging and impairment, and that its relationship with skin circadian rhythm points to a possible role in slowing the rate of skin aging through the modulation of cutaneous melatonin receptors.⁷
 

Wound healing

In 2019, Walker and associates investigated the effects of dim artificial light at night on wound healing in female C57BL/6 mice, and found that those conditions prior to wounding reduced healing. They concluded that such information might warrant consideration in prescribing treatment.⁸

Atopic dermatitis

Vaughn and associates contended that alterations in circadian rhythm may contribute to the development of atopic dermatitis.⁹ A good example of the impact of circadian rhythms on cutaneous health is the nocturnal exacerbation of atopic dermatitis, particularly in children.¹⁰

Psoriasis

According to Plikus and associates, recent evidence has emerged showing that the circadian clock regulates UVB-induced DNA damage and cutaneous cancers, and it is also associated with the immune-mediated disorder psoriasis.¹¹

Clinical studies

In 2018, Deshayes and associates conducted a clinical study to evaluate the precursors and stem cell attributes of hHF (human hair follicle keratinocytes), hEpi (human interfollicular epidermal keratinocytes), and hHFDP (hair follicle dermal papilla stem cells) in response to clock pathway changes caused by long-term deregulation of circadian rhythms. A total of 20 women participated in the study, 10 in each group (day workers were the control group and compared with shift workers). Two 3-mm fresh punch biopsies were collected from the occipital region of each participant. The investigators reported that chronic circadian rhythm deregulation influenced clock pathway protein expression and correlated with changes in hHF, hEpi, and hHFDP. They concluded that their findings represented the first data in humans suggesting that deregulation of the clock pathway modulates regenerative activity in human cutaneous and hair precursor cells.¹²

Later that year, Wu and associates reported on the role of the circadian clock in the transcriptional regulation of human epidermis. Investigators sampled 20 human participants through a 24-hour period and a population of 219 people once, finding a potent circadian oscillator in human epidermis at the population level, hundreds of rhythmically expressed genes, as well as a biomarker set for human epidermis that can, with one sample, highlight circadian phase within a 3-hour time frame. The team concluded that rhythms in human epidermis persist at the population level, and that they were able to present an effective single-sample circadian biomarker.¹³ This is important, as Morris pointed out, because the standard practice for measuring an individual’s internal clock is to use a dim-light melatonin onset assay over the course of a day.¹⁴ In 2019, Jia and associates studied the skin surface lipid profiles of young women to evaluate and characterize circadian human facial surface lipid composition. The investigators identified significant markers of circadian rhythm, with glycerolipids most affected. They ascribed changes in skin barrier function, such as variable pH and transepidermal water loss, to alterations in triacylglycerol levels as well as free fatty acid chain lengths and content that were affected by variations in circadian rhythm.¹⁵
 

Sleep and the timing of topicals

Based on their recent review of the literature on circadian rhythm and skin, Lyons and associates argued that an understanding of circadian rhythm helps dermatologists in recommending the optimal times for patients to apply topical medications. They added that urging patients to get sufficient sleep is important because DNA repair of the skin occurs best at that time.¹⁶

Conclusions

Doctors have known for half a century that timing drug delivery to a patient’s circadian clock can enhance outcomes. Chronobiological research into how circadian rhythms work at the cellular level, and in cutaneous cells in particular, is a fascinating and expanding area of inquiry that could help dermatologists more accurately recommend timing for skin care regimens. Much more research, especially in clinical trials, is necessary to further elucidate how to best work with the skin’s natural rhythms.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions, a company that independently tests skin care products and makes recommendations to physicians on skin care technologies. Write to her at [email protected].

References

1. Mehling A et al. Skin Pharmacol Physiol. 2006;19(4):182-9.

2. Latreille J et al. Skin Pharmacol Physiol. 2004 May-Jun;17(3):133-40.

3. Le Fur I et al. J Invest Dermatol. 2001 Sep;117(3):718-24.

4. Verschoore M et al. Chronobiol Int. 1993 Oct;10(5):349-59.

5. Yosipovitch G et al. J Invest Dermatol. 1998 Jan;110(1):20-3.

6. Dong K et al. Int J Cosmet Sci. 2019 Dec;41(6):558-62.

7. Dong K et al. Int J Mol Sci. 2020 Jan 3;21(1):326.

8. Walker WH II et al. Arch Dermatol Res. 2019 Sep;311(7):573-6.

9. Vaughn AR et al. Pediatr Dermatol. 2018 Jan;35(1):152-7.

10. Fishbein AB et al. J Allergy Clin Immunol. 2015 Nov;136(5):1170-7.

11. Plikus MV et al. J Biol Rhythms. 2015 Jun;30(3):163-82.

12. Deshayes N et al. Eur J Dermatol. 2018 Aug 1;28(4):467-75.

13. Wu G et al. Proc Natl Acad Sci U S A. 2018 Nov 27;115(48):12313-8.

14. Morris A. Nat Rev Endocrinol. 2018 Dec;15(1):3.

15. Jia Y et al. Exp Dermatol. 2019 Jul;28(7):858-62.

16. Lyons AB et al. J Clin Aesthet Dermatol. 2019 Sep;12(9):42-5.
 

We continue with a focus on circadian rhythms and implications for skin care this month, paying particular attention to research or insights pertaining to specific skin conditions, when possible, as well as clinical studies that may shed light on how to time skin care treatments.

Francesca Bellini/iStock/Getty Images

It is important to remember that several studies in the last 20 years have revealed cutaneous tendencies based on the time of day. For instance, sebum production is known to be highest around noon, and pH also peaks during the day and is at its lowest at night.^1-5
 

Skin aging

In 2019, Dong and associates showed that blue light at 410 nm reduces PER1 transcription in keratinocytes, indicating that epidermal cells have the capacity to directly sense light and regulate their own clock gene expression. With the introduction of blue light at night, circadian rhythm is disrupted as epidermal skin cells act as if it is daytime. The investigators also considered blue light–induced damage to skin cells at various doses and exposure times in comparison with cells that remained unexposed to light. The production of reactive oxygen species increased in the exposed cells, as did DNA impairment and the emergence of inflammatory mediators, all of which have the potential to hasten aging.6

Early this year, Dong and associates demonstrated that melatonin can dose-dependently stimulate PER1 clock gene expression in normal human dermal fibroblasts and normal human epidermal keratinocytes, and verified that the MT-1 melatonin receptor in such fibroblasts manifests a marked decline with age. The researchers concluded that the melatonin pathway contributes significantly in cutaneous aging and impairment, and that its relationship with skin circadian rhythm points to a possible role in slowing the rate of skin aging through the modulation of cutaneous melatonin receptors.⁷
 

Wound healing

In 2019, Walker and associates investigated the effects of dim artificial light at night on wound healing in female C57BL/6 mice, and found that those conditions prior to wounding reduced healing. They concluded that such information might warrant consideration in prescribing treatment.⁸

Atopic dermatitis

Vaughn and associates contended that alterations in circadian rhythm may contribute to the development of atopic dermatitis.⁹ A good example of the impact of circadian rhythms on cutaneous health is the nocturnal exacerbation of atopic dermatitis, particularly in children.¹⁰

Psoriasis

According to Plikus and associates, recent evidence has emerged showing that the circadian clock regulates UVB-induced DNA damage and cutaneous cancers, and it is also associated with the immune-mediated disorder psoriasis.¹¹

Clinical studies

In 2018, Deshayes and associates conducted a clinical study to evaluate the precursors and stem cell attributes of hHF (human hair follicle keratinocytes), hEpi (human interfollicular epidermal keratinocytes), and hHFDP (hair follicle dermal papilla stem cells) in response to clock pathway changes caused by long-term deregulation of circadian rhythms. A total of 20 women participated in the study, 10 in each group (day workers were the control group and compared with shift workers). Two 3-mm fresh punch biopsies were collected from the occipital region of each participant. The investigators reported that chronic circadian rhythm deregulation influenced clock pathway protein expression and correlated with changes in hHF, hEpi, and hHFDP. They concluded that their findings represented the first data in humans suggesting that deregulation of the clock pathway modulates regenerative activity in human cutaneous and hair precursor cells.¹²

Later that year, Wu and associates reported on the role of the circadian clock in the transcriptional regulation of human epidermis. Investigators sampled 20 human participants through a 24-hour period and a population of 219 people once, finding a potent circadian oscillator in human epidermis at the population level, hundreds of rhythmically expressed genes, as well as a biomarker set for human epidermis that can, with one sample, highlight circadian phase within a 3-hour time frame. The team concluded that rhythms in human epidermis persist at the population level, and that they were able to present an effective single-sample circadian biomarker.¹³ This is important, as Morris pointed out, because the standard practice for measuring an individual’s internal clock is to use a dim-light melatonin onset assay over the course of a day.¹⁴ In 2019, Jia and associates studied the skin surface lipid profiles of young women to evaluate and characterize circadian human facial surface lipid composition. The investigators identified significant markers of circadian rhythm, with glycerolipids most affected. They ascribed changes in skin barrier function, such as variable pH and transepidermal water loss, to alterations in triacylglycerol levels as well as free fatty acid chain lengths and content that were affected by variations in circadian rhythm.¹⁵
 

Sleep and the timing of topicals

Based on their recent review of the literature on circadian rhythm and skin, Lyons and associates argued that an understanding of circadian rhythm helps dermatologists in recommending the optimal times for patients to apply topical medications. They added that urging patients to get sufficient sleep is important because DNA repair of the skin occurs best at that time.¹⁶

Conclusions

Doctors have known for half a century that timing drug delivery to a patient’s circadian clock can enhance outcomes. Chronobiological research into how circadian rhythms work at the cellular level, and in cutaneous cells in particular, is a fascinating and expanding area of inquiry that could help dermatologists more accurately recommend timing for skin care regimens. Much more research, especially in clinical trials, is necessary to further elucidate how to best work with the skin’s natural rhythms.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions, a company that independently tests skin care products and makes recommendations to physicians on skin care technologies. Write to her at [email protected].

References

1. Mehling A et al. Skin Pharmacol Physiol. 2006;19(4):182-9.

2. Latreille J et al. Skin Pharmacol Physiol. 2004 May-Jun;17(3):133-40.

3. Le Fur I et al. J Invest Dermatol. 2001 Sep;117(3):718-24.

4. Verschoore M et al. Chronobiol Int. 1993 Oct;10(5):349-59.

5. Yosipovitch G et al. J Invest Dermatol. 1998 Jan;110(1):20-3.

6. Dong K et al. Int J Cosmet Sci. 2019 Dec;41(6):558-62.

7. Dong K et al. Int J Mol Sci. 2020 Jan 3;21(1):326.

8. Walker WH II et al. Arch Dermatol Res. 2019 Sep;311(7):573-6.

9. Vaughn AR et al. Pediatr Dermatol. 2018 Jan;35(1):152-7.

10. Fishbein AB et al. J Allergy Clin Immunol. 2015 Nov;136(5):1170-7.

11. Plikus MV et al. J Biol Rhythms. 2015 Jun;30(3):163-82.

12. Deshayes N et al. Eur J Dermatol. 2018 Aug 1;28(4):467-75.

13. Wu G et al. Proc Natl Acad Sci U S A. 2018 Nov 27;115(48):12313-8.

14. Morris A. Nat Rev Endocrinol. 2018 Dec;15(1):3.

15. Jia Y et al. Exp Dermatol. 2019 Jul;28(7):858-62.

16. Lyons AB et al. J Clin Aesthet Dermatol. 2019 Sep;12(9):42-5.
 

We continue with a focus on circadian rhythms and implications for skin care this month, paying particular attention to research or insights pertaining to specific skin conditions, when possible, as well as clinical studies that may shed light on how to time skin care treatments.

Francesca Bellini/iStock/Getty Images

It is important to remember that several studies in the last 20 years have revealed cutaneous tendencies based on the time of day. For instance, sebum production is known to be highest around noon, and pH also peaks during the day and is at its lowest at night.^1-5
 

Skin aging

In 2019, Dong and associates showed that blue light at 410 nm reduces PER1 transcription in keratinocytes, indicating that epidermal cells have the capacity to directly sense light and regulate their own clock gene expression. With the introduction of blue light at night, circadian rhythm is disrupted as epidermal skin cells act as if it is daytime. The investigators also considered blue light–induced damage to skin cells at various doses and exposure times in comparison with cells that remained unexposed to light. The production of reactive oxygen species increased in the exposed cells, as did DNA impairment and the emergence of inflammatory mediators, all of which have the potential to hasten aging.6

Early this year, Dong and associates demonstrated that melatonin can dose-dependently stimulate PER1 clock gene expression in normal human dermal fibroblasts and normal human epidermal keratinocytes, and verified that the MT-1 melatonin receptor in such fibroblasts manifests a marked decline with age. The researchers concluded that the melatonin pathway contributes significantly in cutaneous aging and impairment, and that its relationship with skin circadian rhythm points to a possible role in slowing the rate of skin aging through the modulation of cutaneous melatonin receptors.⁷
 

Wound healing

In 2019, Walker and associates investigated the effects of dim artificial light at night on wound healing in female C57BL/6 mice, and found that those conditions prior to wounding reduced healing. They concluded that such information might warrant consideration in prescribing treatment.⁸

Atopic dermatitis

Vaughn and associates contended that alterations in circadian rhythm may contribute to the development of atopic dermatitis.⁹ A good example of the impact of circadian rhythms on cutaneous health is the nocturnal exacerbation of atopic dermatitis, particularly in children.¹⁰

Psoriasis

According to Plikus and associates, recent evidence has emerged showing that the circadian clock regulates UVB-induced DNA damage and cutaneous cancers, and it is also associated with the immune-mediated disorder psoriasis.¹¹

Clinical studies

In 2018, Deshayes and associates conducted a clinical study to evaluate the precursors and stem cell attributes of hHF (human hair follicle keratinocytes), hEpi (human interfollicular epidermal keratinocytes), and hHFDP (hair follicle dermal papilla stem cells) in response to clock pathway changes caused by long-term deregulation of circadian rhythms. A total of 20 women participated in the study, 10 in each group (day workers were the control group and compared with shift workers). Two 3-mm fresh punch biopsies were collected from the occipital region of each participant. The investigators reported that chronic circadian rhythm deregulation influenced clock pathway protein expression and correlated with changes in hHF, hEpi, and hHFDP. They concluded that their findings represented the first data in humans suggesting that deregulation of the clock pathway modulates regenerative activity in human cutaneous and hair precursor cells.¹²

Later that year, Wu and associates reported on the role of the circadian clock in the transcriptional regulation of human epidermis. Investigators sampled 20 human participants through a 24-hour period and a population of 219 people once, finding a potent circadian oscillator in human epidermis at the population level, hundreds of rhythmically expressed genes, as well as a biomarker set for human epidermis that can, with one sample, highlight circadian phase within a 3-hour time frame. The team concluded that rhythms in human epidermis persist at the population level, and that they were able to present an effective single-sample circadian biomarker.¹³ This is important, as Morris pointed out, because the standard practice for measuring an individual’s internal clock is to use a dim-light melatonin onset assay over the course of a day.¹⁴ In 2019, Jia and associates studied the skin surface lipid profiles of young women to evaluate and characterize circadian human facial surface lipid composition. The investigators identified significant markers of circadian rhythm, with glycerolipids most affected. They ascribed changes in skin barrier function, such as variable pH and transepidermal water loss, to alterations in triacylglycerol levels as well as free fatty acid chain lengths and content that were affected by variations in circadian rhythm.¹⁵
 

Sleep and the timing of topicals

Based on their recent review of the literature on circadian rhythm and skin, Lyons and associates argued that an understanding of circadian rhythm helps dermatologists in recommending the optimal times for patients to apply topical medications. They added that urging patients to get sufficient sleep is important because DNA repair of the skin occurs best at that time.¹⁶

Conclusions

Doctors have known for half a century that timing drug delivery to a patient’s circadian clock can enhance outcomes. Chronobiological research into how circadian rhythms work at the cellular level, and in cutaneous cells in particular, is a fascinating and expanding area of inquiry that could help dermatologists more accurately recommend timing for skin care regimens. Much more research, especially in clinical trials, is necessary to further elucidate how to best work with the skin’s natural rhythms.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions, a company that independently tests skin care products and makes recommendations to physicians on skin care technologies. Write to her at [email protected].

References

1. Mehling A et al. Skin Pharmacol Physiol. 2006;19(4):182-9.

2. Latreille J et al. Skin Pharmacol Physiol. 2004 May-Jun;17(3):133-40.

3. Le Fur I et al. J Invest Dermatol. 2001 Sep;117(3):718-24.

4. Verschoore M et al. Chronobiol Int. 1993 Oct;10(5):349-59.

5. Yosipovitch G et al. J Invest Dermatol. 1998 Jan;110(1):20-3.

6. Dong K et al. Int J Cosmet Sci. 2019 Dec;41(6):558-62.

7. Dong K et al. Int J Mol Sci. 2020 Jan 3;21(1):326.

8. Walker WH II et al. Arch Dermatol Res. 2019 Sep;311(7):573-6.

9. Vaughn AR et al. Pediatr Dermatol. 2018 Jan;35(1):152-7.

10. Fishbein AB et al. J Allergy Clin Immunol. 2015 Nov;136(5):1170-7.

11. Plikus MV et al. J Biol Rhythms. 2015 Jun;30(3):163-82.

12. Deshayes N et al. Eur J Dermatol. 2018 Aug 1;28(4):467-75.

13. Wu G et al. Proc Natl Acad Sci U S A. 2018 Nov 27;115(48):12313-8.

14. Morris A. Nat Rev Endocrinol. 2018 Dec;15(1):3.

15. Jia Y et al. Exp Dermatol. 2019 Jul;28(7):858-62.

16. Lyons AB et al. J Clin Aesthet Dermatol. 2019 Sep;12(9):42-5.