Outbreaks of coronavirus in a wide range of countries have officials at the Centers for Disease Control and Prevention believing it is now a matter of when, not if, there will be community spread in the United States.

Courtesy NIAID-RML

“We have for many weeks been saying that, while we hope this is not going to be severe, we are planning as if it is,” Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases at the CDC, said during a Feb. 25, 2020, telebriefing with reporters. “The data over the last week and the spread in other countries has certainly raised our level of concern and raised our level expectation that we are going to have community spread here.”

Dr. Messonnier noted that the coronavirus is now showing signs of community spread without a known source of exposure in a number of countries, including in Hong Kong, Iran, Italy, Japan, Singapore, South Korea, Taiwan, and Thailand. This has now raised the belief that there will be more widespread outbreaks in the United States.

“What we still don’t know is what that will look like,” she said. “As many of you know, we can have community spread in the United States and have it be reasonably mild. We can have community spread in the U.S. and have it be very severe. That is what we don’t completely know yet and we certainly also don’t exactly know when it is going to happen.”

She reiterated the number of actions being taken to slow the potential spread in the United States, including detecting, tracking, and isolating all cases, as well as restricting travel into the United States and issuing travel advisories for countries where coronavirus outbreaks are known.

“We are doing this with the goal of slowing the introduction of this new virus into the U.S. and buying us more time to prepare,” Dr. Messonnier said, noting the containment strategies have been largely successful, though it will be more difficult as more countries experience community spread of the virus.

Dr. Messonnier also reiterated that at this time there are no vaccines and no medicines to treat the coronavirus. She stressed the need to adhere to nonpharmaceutical interventions (NPIs), as they will be “the most important tools in our response to this virus.”

She said the NPIs will vary based on the severity of the outbreak in any given local community and include personal protective measures that individuals can take every day (many of which mirror the recommendations for preventing the spread of the seasonal flu virus), community NPIs that involve social distancing measures designed to keep people away from others, and environmental NPIs such as surface cleaning measures.

CDC’s latest warning comes as parent agency the Department of Health & Human Services is seeking $2.5 billion in funds from Congress to address the coronavirus outbreak.

During a separate press conference on the same day, HHS Secretary Alex Azar noted that there are five major priorities related to those funds, which would be used in the current year, including expansion of surveillance work within the influenza surveillance network; supporting public health preparedness and response for state and local governments; support the development of therapeutics and the development of vaccines; and the purchase of personal protective equipment for national stockpiles.

Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Disease at the National Institutes of Health, added during the press conference that vaccine work is in progress and could be ready for phase 1 testing within a month and a half. If all goes well, it would still be at least 12 - 18 months following the completion of a phase 2 trial before it could be produced for mass consumption.

“It is certainly conceivable that this issue with this coronavirus will go well beyond this season into next season,” Dr. Fauci said. “So a vaccine may not solve the problems of the next couple of months, but it certainly would be an important tool that we would have and we will keep you posted on that.”

He also mentioned that NIAID is looking at a number of candidates for therapeutic treatment of coronavirus. He highlighted Gilead’s remdesivir, a nucleotide analog, as one which undergoing two trials – a randomized controlled trial in China and a copy of that trial in Nebraska among patients with the coronavirus who were taken from the Diamond Princess cruise line in Japan.

“I am optimistic that we will at least get an answer if we do have do have a therapy that really is a gamechanger because then we could do something from the standpoint of intervention for those who are sick,” Dr. Fauci said.  

gtwachtman@mdedge.com

UPDATE: This story was updated 2/25 at 4:51 p.m. ET

Outbreaks of coronavirus in a wide range of countries have officials at the Centers for Disease Control and Prevention believing it is now a matter of when, not if, there will be community spread in the United States.

Courtesy NIAID-RML

“We have for many weeks been saying that, while we hope this is not going to be severe, we are planning as if it is,” Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases at the CDC, said during a Feb. 25, 2020, telebriefing with reporters. “The data over the last week and the spread in other countries has certainly raised our level of concern and raised our level expectation that we are going to have community spread here.”

Dr. Messonnier noted that the coronavirus is now showing signs of community spread without a known source of exposure in a number of countries, including in Hong Kong, Iran, Italy, Japan, Singapore, South Korea, Taiwan, and Thailand. This has now raised the belief that there will be more widespread outbreaks in the United States.

“What we still don’t know is what that will look like,” she said. “As many of you know, we can have community spread in the United States and have it be reasonably mild. We can have community spread in the U.S. and have it be very severe. That is what we don’t completely know yet and we certainly also don’t exactly know when it is going to happen.”

She reiterated the number of actions being taken to slow the potential spread in the United States, including detecting, tracking, and isolating all cases, as well as restricting travel into the United States and issuing travel advisories for countries where coronavirus outbreaks are known.

“We are doing this with the goal of slowing the introduction of this new virus into the U.S. and buying us more time to prepare,” Dr. Messonnier said, noting the containment strategies have been largely successful, though it will be more difficult as more countries experience community spread of the virus.

Dr. Messonnier also reiterated that at this time there are no vaccines and no medicines to treat the coronavirus. She stressed the need to adhere to nonpharmaceutical interventions (NPIs), as they will be “the most important tools in our response to this virus.”

She said the NPIs will vary based on the severity of the outbreak in any given local community and include personal protective measures that individuals can take every day (many of which mirror the recommendations for preventing the spread of the seasonal flu virus), community NPIs that involve social distancing measures designed to keep people away from others, and environmental NPIs such as surface cleaning measures.

CDC’s latest warning comes as parent agency the Department of Health & Human Services is seeking $2.5 billion in funds from Congress to address the coronavirus outbreak.

During a separate press conference on the same day, HHS Secretary Alex Azar noted that there are five major priorities related to those funds, which would be used in the current year, including expansion of surveillance work within the influenza surveillance network; supporting public health preparedness and response for state and local governments; support the development of therapeutics and the development of vaccines; and the purchase of personal protective equipment for national stockpiles.

Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Disease at the National Institutes of Health, added during the press conference that vaccine work is in progress and could be ready for phase 1 testing within a month and a half. If all goes well, it would still be at least 12 - 18 months following the completion of a phase 2 trial before it could be produced for mass consumption.

“It is certainly conceivable that this issue with this coronavirus will go well beyond this season into next season,” Dr. Fauci said. “So a vaccine may not solve the problems of the next couple of months, but it certainly would be an important tool that we would have and we will keep you posted on that.”

He also mentioned that NIAID is looking at a number of candidates for therapeutic treatment of coronavirus. He highlighted Gilead’s remdesivir, a nucleotide analog, as one which undergoing two trials – a randomized controlled trial in China and a copy of that trial in Nebraska among patients with the coronavirus who were taken from the Diamond Princess cruise line in Japan.

“I am optimistic that we will at least get an answer if we do have do have a therapy that really is a gamechanger because then we could do something from the standpoint of intervention for those who are sick,” Dr. Fauci said.  

gtwachtman@mdedge.com

UPDATE: This story was updated 2/25 at 4:51 p.m. ET

Outbreaks of coronavirus in a wide range of countries have officials at the Centers for Disease Control and Prevention believing it is now a matter of when, not if, there will be community spread in the United States.

Courtesy NIAID-RML

“We have for many weeks been saying that, while we hope this is not going to be severe, we are planning as if it is,” Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases at the CDC, said during a Feb. 25, 2020, telebriefing with reporters. “The data over the last week and the spread in other countries has certainly raised our level of concern and raised our level expectation that we are going to have community spread here.”

Dr. Messonnier noted that the coronavirus is now showing signs of community spread without a known source of exposure in a number of countries, including in Hong Kong, Iran, Italy, Japan, Singapore, South Korea, Taiwan, and Thailand. This has now raised the belief that there will be more widespread outbreaks in the United States.

“What we still don’t know is what that will look like,” she said. “As many of you know, we can have community spread in the United States and have it be reasonably mild. We can have community spread in the U.S. and have it be very severe. That is what we don’t completely know yet and we certainly also don’t exactly know when it is going to happen.”

She reiterated the number of actions being taken to slow the potential spread in the United States, including detecting, tracking, and isolating all cases, as well as restricting travel into the United States and issuing travel advisories for countries where coronavirus outbreaks are known.

“We are doing this with the goal of slowing the introduction of this new virus into the U.S. and buying us more time to prepare,” Dr. Messonnier said, noting the containment strategies have been largely successful, though it will be more difficult as more countries experience community spread of the virus.

Dr. Messonnier also reiterated that at this time there are no vaccines and no medicines to treat the coronavirus. She stressed the need to adhere to nonpharmaceutical interventions (NPIs), as they will be “the most important tools in our response to this virus.”

She said the NPIs will vary based on the severity of the outbreak in any given local community and include personal protective measures that individuals can take every day (many of which mirror the recommendations for preventing the spread of the seasonal flu virus), community NPIs that involve social distancing measures designed to keep people away from others, and environmental NPIs such as surface cleaning measures.

CDC’s latest warning comes as parent agency the Department of Health & Human Services is seeking $2.5 billion in funds from Congress to address the coronavirus outbreak.

During a separate press conference on the same day, HHS Secretary Alex Azar noted that there are five major priorities related to those funds, which would be used in the current year, including expansion of surveillance work within the influenza surveillance network; supporting public health preparedness and response for state and local governments; support the development of therapeutics and the development of vaccines; and the purchase of personal protective equipment for national stockpiles.

Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Disease at the National Institutes of Health, added during the press conference that vaccine work is in progress and could be ready for phase 1 testing within a month and a half. If all goes well, it would still be at least 12 - 18 months following the completion of a phase 2 trial before it could be produced for mass consumption.

“It is certainly conceivable that this issue with this coronavirus will go well beyond this season into next season,” Dr. Fauci said. “So a vaccine may not solve the problems of the next couple of months, but it certainly would be an important tool that we would have and we will keep you posted on that.”

He also mentioned that NIAID is looking at a number of candidates for therapeutic treatment of coronavirus. He highlighted Gilead’s remdesivir, a nucleotide analog, as one which undergoing two trials – a randomized controlled trial in China and a copy of that trial in Nebraska among patients with the coronavirus who were taken from the Diamond Princess cruise line in Japan.

“I am optimistic that we will at least get an answer if we do have do have a therapy that really is a gamechanger because then we could do something from the standpoint of intervention for those who are sick,” Dr. Fauci said.  

gtwachtman@mdedge.com

UPDATE: This story was updated 2/25 at 4:51 p.m. ET

Bullying happens to our patients and sometimes to the doctors in the medical community. As psychiatrists, we need to share information on how to spot it and deal with it in the workplace.

SDI Productions/iStock/Getty Images

We can view bullying as the endpoint in a continuum with authority at one end and harassment at the other extreme. Discipline maintains order but those in charge can be misguided or mean spirited.

Bullying is bad and prevalent, but is it inevitable in the workplace? There are three categories: those who get bullied, those who bully, and those who witness bullying. Any one, two, or even all three can apply in a work environment. Some escape the problem, and for them, bullying remains theoretical, a phenomenon to understand.

How do we define bullying? You know it when you see it; bullying interferes with functioning. It includes harsh language, threats, snubbing, screaming, and undermining.
 

Case is illustrative

Helen, a medical consultant on a surgical unit, was reading a chart when another internist arrived for the same purpose. He introduced himself as a new full-time assistant to the head of medical consultations. Helen greeted him and said: “Since I started with this case, I will continue. There was probably an error in the referral process.” Bill looked concerned. “But he has uncontrolled diabetes.” Taken aback, Helen said: “I think I can handle it. I’ve been on the hospital staff for 25 years.”

Then the bullying began. On occasion, Bill and a resident consulted on patients Helen was treating already, as though her input were nonexistent. When Helen inquired about this, rather than attribute it to an error in communication within a large hospital, Bill diminished the value of her input. She asked, “How many medical consultants does a patient need?” She decided to confront Bill and tell him that he had no reason to treat her with disrespect. After that, Bill’s disparaging remarks intensified and he threatened her saying, “I’m not someone you want to go up against.” Bill sent her an email, “You are demeaning and harsh to the staff; if you want to retain your hospital credentials you must change your behavior.” In her response, Helen agreed to meet with Bill and she emailed, “It is not in my nature to mistreat anyone, staff or patient.” The meeting never happened.

Helen sought me out for psychiatric consultation and psychotherapy because she felt demoralized. Confused by Bill’s assault on her reputation, she needed a strategy and confirmation of her worth. We conceived a plan. Helen decided to get busy and get better. She redoubled her efforts to be cordial, and she remained effective with her patients. I suggested that she confide in a trusted senior attending at the hospital, which she did. She aired her insights to him. Excellence mattered and the threats disappeared. Bill had no power over Helen after all. She was a voluntary attending. She never succumbed to despair; rather she converted her response to the threats into useful energy.

When does authority become harassment?

A pecking order exists in every organization because, from the CEO to the janitor, it is necessary to maintain productivity. But when does this hierarchy become abusive? Discipline gets learned early. Those who are familiar with the comic strip “Calvin and Hobbes” by Bill Watterson may remember the 6-year-old boy asserting his intention to stay home from school – only to be forced to the bus stop by his mother. Call that authority, discipline, or even bullying, but it represents a child’s first encounter with obedience despite protest. When authority interferes rather than enhances effectiveness, question the methods used to attain order.

The vulnerable

If you do your job and you do it well, there should be no bullying. It is hard to know why a target gets chosen for harassment. However, some questions may need answering by the target. Does he or she avoid conflict even when there is bad behavior? Does past trauma immobilize him into passivity? Such issues necessitate self examination. Psychotherapy helps to uncover and clear up these issues.

Is bullying a fact of life?

In “Lord of the Flies,” William Golding portrays a fictional group of unsupervised boys abandoned on an island. An initial hierarchy descends into threats and eventual violence. Consider the animal world. In the wild, a wolf pack isolates a caribou from the herd to kill and devour. On a farm, llamas raised for yarn establish which llama is in charge. Those cases illustrate the hierarchy that exists because there is the need for food or reproductive prowess.

In the workplace, isolation of the target is common when authority extends to bullying. According to Robert Sapolsky, PhD, a neuroscientist and author, there are biological underpinnings for group conformity. This implies that colleagues who stand apart feel distress and get relief when they join the ganging up on a target. Those who watch harassment may hide from confronting it or even from pointing it out to protect themselves. As psychiatrists, we need to notice bullying when it occurs so it can be eradicated for the sake of the workplace and the target.
 

How do bullies think?

Challenge the bully at your own peril, because expecting a bully to change is futile. Recall Helen’s confrontation with Bill. It provoked him. His power to harass her came from his perceived position. Bullies regard the pleasant person as weak. Bullies can fall into two categories: Sadists who get pleasure from seeing others suffer, and opportunists. The latter focus only on their goals and disregard concerns expressed by others. Outside of the workplace, they may be reasonable. If workplace morale deteriorates along with productivity, the bully gets ousted. Otherwise, companies usually protect high performers at the expense of targets.

Is bullying different in medicine?

It can happen in a training program. The ingredients for bullying exist, including imbalance of power. Often, there are no witnesses, and there can be lack of accountability because of changing authorities. Just as technology can help make harassment possible, it also enables the target to spot and document inappropriate communications by saving emails and texts. Whenever a need for advancement exists along with changing authority, bullying gets tolerated. Who wants to be derailed by reporting? Those in training have the goal of completing a program. If they report bullying, they fear antagonism and retribution, a personal expense that can deter advancement.

Remedies

Let truth and fairness be your guide. That is easy to say and hard to do, but there are helpful personal and legal resources.

Personal capability

Get busy; get better. That became Helen’s method of choice. She focused on her role and productivity, not on her hurt. Helen shunned victimhood. With the help of psychotherapy and by confiding in a mentor, she prevailed. What works is recalling challenges that were mastered and the qualities that made for success. Acquire skills, build a good reputation, be assertive, not defensive.

The group is powerful, and that means it is important to build alliances above and below in the organizational hierarchy; cultivate friendship with trustworthy people. Occasionally, there is unwarranted ganging up on a manager, bullying from below. It is more likely to happen to a newly appointed supervisor. A way to avert that is to communicate with staff throughout the institution and remain accessible.
 

Legal options

What are legal options to confront bullying? Of note, workplace bullying is not necessarily illegal. According to one employment attorney, “There is no law that prohibits uncivil behavior on the job.” However, under Title VII of the federal law enacted in 1964, there are protected characteristics such as race, color, national origin, sex, age, and disability. The Equal Employment Opportunity Commission enforces Title VII. In cases of assault or stalking, harassment is illegal and criminal.

Some employees report to Human Resources or seek out their company’s employee assistance program. As useful as those options may be, they are part of the company and potentially partial to the administration. There can be incentives to protect those with power against a complainant. For assistance, it is preferable to enlist an outside attorney and a therapist in the community.

Advocacy exists. The Workplace Bullying Institute maintains a website, holds workshops, promotes literature, and offers information. The National Employment Lawyers Association can provide referrals or recommendations that come from other legal sources. Cases rarely reach court because of the expense of a trial; rather, the parties reach a financial settlement. When there is cause, an employment attorney can best pursue justice for the worker.
 

Conclusion

Get busy; get better is the solution to bullying. Avoid victimhood. That means prepare: Update the resume, seek opportunities, and identify allies. Bullies get beaten; as Abraham Lincoln said, “You can fool some of the people some of the time but you can’t fool all of the people all of the time.”

According to the Workplace Bullying Institute, 7 out of 10 bullied workers either resign or get fired. You should leave only when the leaving is better than the staying. Bullying brings out the worst in the workplace. Those who bully isolate the target. Coworkers often shun the target, fearing for their own position; they may even participate in the harassment. Psychiatrists need to remain sensitive to harassment in their own environment and for their patients. We have tools to address bullying in the workplace and a moral responsibility to combat it.
 

References

Workplace Bullying Institute (WBI)

National Employment Lawyers Association (NELA)

“Ozymandias” by Percy Bysshe Shelley

BY BEN HINDELL, PSY.D.

Cyberbullying is willful, repeated harm inflicted with the use of computers, cell phones, and other electronic devices. In some cases, a single message may be viewed by multiple people because the text and pictures are posted elsewhere.

Courtesy Dr. Hindell

Technology makes is possible to harass at any hour. The concept of willful harm is essential. Without interaction between sender and recipient, nuances are lost. Face to face might make a communication benign instead of malevolent or threatening. This has implications for the workplace, where colleagues increasingly communicate by email rather than discuss matters in person or by telephone.
 

Steps for survivors of cyberbullying

• Do not respond immediately to an inflammatory message, post, or email. Gather your thoughts and avoid responding in anger.
• Keep calm and rational, not emotional.
• Try to respond in person and work to avoid a conflict.
• Remember, your interpretation may differ from what was intended.
• Communicate openly and honestly and not defensively.
• Calmly indicate you were offended and you want the comments to stop.
• Move up the chain of command, if comments don’t cease.
• Save all messages and posts as evidence.
• Report the cyberbullying to your employer. Human resources may get involved.
• Detach from the cyberbully, if it continues. Block social media, cell phone messaging, and emails.
• Find support from friends, family, and a psychotherapist, if needed. As a last resort, it may become necessary to enlist an attorney.
• Take the high road; remain calm and professional at work. The bully may be seeking a reaction from the behavior. Prevent it.

All of the elements of workplace bullying apply to cyberbullying, but the latter can be more insidious. Psychiatrists and psychologists are able to support patients who deal with cyberbullying and help them cope successfully.
 

Dr. Cohen is in private practice and is a clinical assistant professor of psychiatry at Weill Cornell Medical Center of New York-Presbyterian Hospital, and psychiatric consultant at the Hospital for Special Surgery, also in New York. She made changes to the patient’s story to protect confidentiality.

Dr. Hindell is a psychologist with the Mental Health Service of Colorado College, Colorado Springs. He also practices psychotherapy in Denver. Dr. Hindell is the son of Dr. Cohen.

Bullying happens to our patients and sometimes to the doctors in the medical community. As psychiatrists, we need to share information on how to spot it and deal with it in the workplace.

SDI Productions/iStock/Getty Images

We can view bullying as the endpoint in a continuum with authority at one end and harassment at the other extreme. Discipline maintains order but those in charge can be misguided or mean spirited.

Bullying is bad and prevalent, but is it inevitable in the workplace? There are three categories: those who get bullied, those who bully, and those who witness bullying. Any one, two, or even all three can apply in a work environment. Some escape the problem, and for them, bullying remains theoretical, a phenomenon to understand.

How do we define bullying? You know it when you see it; bullying interferes with functioning. It includes harsh language, threats, snubbing, screaming, and undermining.
 

Case is illustrative

Helen, a medical consultant on a surgical unit, was reading a chart when another internist arrived for the same purpose. He introduced himself as a new full-time assistant to the head of medical consultations. Helen greeted him and said: “Since I started with this case, I will continue. There was probably an error in the referral process.” Bill looked concerned. “But he has uncontrolled diabetes.” Taken aback, Helen said: “I think I can handle it. I’ve been on the hospital staff for 25 years.”

Then the bullying began. On occasion, Bill and a resident consulted on patients Helen was treating already, as though her input were nonexistent. When Helen inquired about this, rather than attribute it to an error in communication within a large hospital, Bill diminished the value of her input. She asked, “How many medical consultants does a patient need?” She decided to confront Bill and tell him that he had no reason to treat her with disrespect. After that, Bill’s disparaging remarks intensified and he threatened her saying, “I’m not someone you want to go up against.” Bill sent her an email, “You are demeaning and harsh to the staff; if you want to retain your hospital credentials you must change your behavior.” In her response, Helen agreed to meet with Bill and she emailed, “It is not in my nature to mistreat anyone, staff or patient.” The meeting never happened.

Helen sought me out for psychiatric consultation and psychotherapy because she felt demoralized. Confused by Bill’s assault on her reputation, she needed a strategy and confirmation of her worth. We conceived a plan. Helen decided to get busy and get better. She redoubled her efforts to be cordial, and she remained effective with her patients. I suggested that she confide in a trusted senior attending at the hospital, which she did. She aired her insights to him. Excellence mattered and the threats disappeared. Bill had no power over Helen after all. She was a voluntary attending. She never succumbed to despair; rather she converted her response to the threats into useful energy.

When does authority become harassment?

A pecking order exists in every organization because, from the CEO to the janitor, it is necessary to maintain productivity. But when does this hierarchy become abusive? Discipline gets learned early. Those who are familiar with the comic strip “Calvin and Hobbes” by Bill Watterson may remember the 6-year-old boy asserting his intention to stay home from school – only to be forced to the bus stop by his mother. Call that authority, discipline, or even bullying, but it represents a child’s first encounter with obedience despite protest. When authority interferes rather than enhances effectiveness, question the methods used to attain order.

The vulnerable

If you do your job and you do it well, there should be no bullying. It is hard to know why a target gets chosen for harassment. However, some questions may need answering by the target. Does he or she avoid conflict even when there is bad behavior? Does past trauma immobilize him into passivity? Such issues necessitate self examination. Psychotherapy helps to uncover and clear up these issues.

Is bullying a fact of life?

In “Lord of the Flies,” William Golding portrays a fictional group of unsupervised boys abandoned on an island. An initial hierarchy descends into threats and eventual violence. Consider the animal world. In the wild, a wolf pack isolates a caribou from the herd to kill and devour. On a farm, llamas raised for yarn establish which llama is in charge. Those cases illustrate the hierarchy that exists because there is the need for food or reproductive prowess.

In the workplace, isolation of the target is common when authority extends to bullying. According to Robert Sapolsky, PhD, a neuroscientist and author, there are biological underpinnings for group conformity. This implies that colleagues who stand apart feel distress and get relief when they join the ganging up on a target. Those who watch harassment may hide from confronting it or even from pointing it out to protect themselves. As psychiatrists, we need to notice bullying when it occurs so it can be eradicated for the sake of the workplace and the target.
 

How do bullies think?

Challenge the bully at your own peril, because expecting a bully to change is futile. Recall Helen’s confrontation with Bill. It provoked him. His power to harass her came from his perceived position. Bullies regard the pleasant person as weak. Bullies can fall into two categories: Sadists who get pleasure from seeing others suffer, and opportunists. The latter focus only on their goals and disregard concerns expressed by others. Outside of the workplace, they may be reasonable. If workplace morale deteriorates along with productivity, the bully gets ousted. Otherwise, companies usually protect high performers at the expense of targets.

Is bullying different in medicine?

It can happen in a training program. The ingredients for bullying exist, including imbalance of power. Often, there are no witnesses, and there can be lack of accountability because of changing authorities. Just as technology can help make harassment possible, it also enables the target to spot and document inappropriate communications by saving emails and texts. Whenever a need for advancement exists along with changing authority, bullying gets tolerated. Who wants to be derailed by reporting? Those in training have the goal of completing a program. If they report bullying, they fear antagonism and retribution, a personal expense that can deter advancement.

Remedies

Let truth and fairness be your guide. That is easy to say and hard to do, but there are helpful personal and legal resources.

Personal capability

Get busy; get better. That became Helen’s method of choice. She focused on her role and productivity, not on her hurt. Helen shunned victimhood. With the help of psychotherapy and by confiding in a mentor, she prevailed. What works is recalling challenges that were mastered and the qualities that made for success. Acquire skills, build a good reputation, be assertive, not defensive.

The group is powerful, and that means it is important to build alliances above and below in the organizational hierarchy; cultivate friendship with trustworthy people. Occasionally, there is unwarranted ganging up on a manager, bullying from below. It is more likely to happen to a newly appointed supervisor. A way to avert that is to communicate with staff throughout the institution and remain accessible.
 

Legal options

What are legal options to confront bullying? Of note, workplace bullying is not necessarily illegal. According to one employment attorney, “There is no law that prohibits uncivil behavior on the job.” However, under Title VII of the federal law enacted in 1964, there are protected characteristics such as race, color, national origin, sex, age, and disability. The Equal Employment Opportunity Commission enforces Title VII. In cases of assault or stalking, harassment is illegal and criminal.

Some employees report to Human Resources or seek out their company’s employee assistance program. As useful as those options may be, they are part of the company and potentially partial to the administration. There can be incentives to protect those with power against a complainant. For assistance, it is preferable to enlist an outside attorney and a therapist in the community.

Advocacy exists. The Workplace Bullying Institute maintains a website, holds workshops, promotes literature, and offers information. The National Employment Lawyers Association can provide referrals or recommendations that come from other legal sources. Cases rarely reach court because of the expense of a trial; rather, the parties reach a financial settlement. When there is cause, an employment attorney can best pursue justice for the worker.
 

Conclusion

Get busy; get better is the solution to bullying. Avoid victimhood. That means prepare: Update the resume, seek opportunities, and identify allies. Bullies get beaten; as Abraham Lincoln said, “You can fool some of the people some of the time but you can’t fool all of the people all of the time.”

According to the Workplace Bullying Institute, 7 out of 10 bullied workers either resign or get fired. You should leave only when the leaving is better than the staying. Bullying brings out the worst in the workplace. Those who bully isolate the target. Coworkers often shun the target, fearing for their own position; they may even participate in the harassment. Psychiatrists need to remain sensitive to harassment in their own environment and for their patients. We have tools to address bullying in the workplace and a moral responsibility to combat it.
 

References

Workplace Bullying Institute (WBI)

National Employment Lawyers Association (NELA)

“Ozymandias” by Percy Bysshe Shelley

BY BEN HINDELL, PSY.D.

Cyberbullying is willful, repeated harm inflicted with the use of computers, cell phones, and other electronic devices. In some cases, a single message may be viewed by multiple people because the text and pictures are posted elsewhere.

Courtesy Dr. Hindell

Technology makes is possible to harass at any hour. The concept of willful harm is essential. Without interaction between sender and recipient, nuances are lost. Face to face might make a communication benign instead of malevolent or threatening. This has implications for the workplace, where colleagues increasingly communicate by email rather than discuss matters in person or by telephone.
 

Steps for survivors of cyberbullying

• Do not respond immediately to an inflammatory message, post, or email. Gather your thoughts and avoid responding in anger.
• Keep calm and rational, not emotional.
• Try to respond in person and work to avoid a conflict.
• Remember, your interpretation may differ from what was intended.
• Communicate openly and honestly and not defensively.
• Calmly indicate you were offended and you want the comments to stop.
• Move up the chain of command, if comments don’t cease.
• Save all messages and posts as evidence.
• Report the cyberbullying to your employer. Human resources may get involved.
• Detach from the cyberbully, if it continues. Block social media, cell phone messaging, and emails.
• Find support from friends, family, and a psychotherapist, if needed. As a last resort, it may become necessary to enlist an attorney.
• Take the high road; remain calm and professional at work. The bully may be seeking a reaction from the behavior. Prevent it.

All of the elements of workplace bullying apply to cyberbullying, but the latter can be more insidious. Psychiatrists and psychologists are able to support patients who deal with cyberbullying and help them cope successfully.
 

Dr. Cohen is in private practice and is a clinical assistant professor of psychiatry at Weill Cornell Medical Center of New York-Presbyterian Hospital, and psychiatric consultant at the Hospital for Special Surgery, also in New York. She made changes to the patient’s story to protect confidentiality.

Dr. Hindell is a psychologist with the Mental Health Service of Colorado College, Colorado Springs. He also practices psychotherapy in Denver. Dr. Hindell is the son of Dr. Cohen.

Bullying happens to our patients and sometimes to the doctors in the medical community. As psychiatrists, we need to share information on how to spot it and deal with it in the workplace.

SDI Productions/iStock/Getty Images

We can view bullying as the endpoint in a continuum with authority at one end and harassment at the other extreme. Discipline maintains order but those in charge can be misguided or mean spirited.

Bullying is bad and prevalent, but is it inevitable in the workplace? There are three categories: those who get bullied, those who bully, and those who witness bullying. Any one, two, or even all three can apply in a work environment. Some escape the problem, and for them, bullying remains theoretical, a phenomenon to understand.

How do we define bullying? You know it when you see it; bullying interferes with functioning. It includes harsh language, threats, snubbing, screaming, and undermining.
 

Case is illustrative

Helen, a medical consultant on a surgical unit, was reading a chart when another internist arrived for the same purpose. He introduced himself as a new full-time assistant to the head of medical consultations. Helen greeted him and said: “Since I started with this case, I will continue. There was probably an error in the referral process.” Bill looked concerned. “But he has uncontrolled diabetes.” Taken aback, Helen said: “I think I can handle it. I’ve been on the hospital staff for 25 years.”

Then the bullying began. On occasion, Bill and a resident consulted on patients Helen was treating already, as though her input were nonexistent. When Helen inquired about this, rather than attribute it to an error in communication within a large hospital, Bill diminished the value of her input. She asked, “How many medical consultants does a patient need?” She decided to confront Bill and tell him that he had no reason to treat her with disrespect. After that, Bill’s disparaging remarks intensified and he threatened her saying, “I’m not someone you want to go up against.” Bill sent her an email, “You are demeaning and harsh to the staff; if you want to retain your hospital credentials you must change your behavior.” In her response, Helen agreed to meet with Bill and she emailed, “It is not in my nature to mistreat anyone, staff or patient.” The meeting never happened.

Helen sought me out for psychiatric consultation and psychotherapy because she felt demoralized. Confused by Bill’s assault on her reputation, she needed a strategy and confirmation of her worth. We conceived a plan. Helen decided to get busy and get better. She redoubled her efforts to be cordial, and she remained effective with her patients. I suggested that she confide in a trusted senior attending at the hospital, which she did. She aired her insights to him. Excellence mattered and the threats disappeared. Bill had no power over Helen after all. She was a voluntary attending. She never succumbed to despair; rather she converted her response to the threats into useful energy.

When does authority become harassment?

A pecking order exists in every organization because, from the CEO to the janitor, it is necessary to maintain productivity. But when does this hierarchy become abusive? Discipline gets learned early. Those who are familiar with the comic strip “Calvin and Hobbes” by Bill Watterson may remember the 6-year-old boy asserting his intention to stay home from school – only to be forced to the bus stop by his mother. Call that authority, discipline, or even bullying, but it represents a child’s first encounter with obedience despite protest. When authority interferes rather than enhances effectiveness, question the methods used to attain order.

The vulnerable

If you do your job and you do it well, there should be no bullying. It is hard to know why a target gets chosen for harassment. However, some questions may need answering by the target. Does he or she avoid conflict even when there is bad behavior? Does past trauma immobilize him into passivity? Such issues necessitate self examination. Psychotherapy helps to uncover and clear up these issues.

Is bullying a fact of life?

In “Lord of the Flies,” William Golding portrays a fictional group of unsupervised boys abandoned on an island. An initial hierarchy descends into threats and eventual violence. Consider the animal world. In the wild, a wolf pack isolates a caribou from the herd to kill and devour. On a farm, llamas raised for yarn establish which llama is in charge. Those cases illustrate the hierarchy that exists because there is the need for food or reproductive prowess.

In the workplace, isolation of the target is common when authority extends to bullying. According to Robert Sapolsky, PhD, a neuroscientist and author, there are biological underpinnings for group conformity. This implies that colleagues who stand apart feel distress and get relief when they join the ganging up on a target. Those who watch harassment may hide from confronting it or even from pointing it out to protect themselves. As psychiatrists, we need to notice bullying when it occurs so it can be eradicated for the sake of the workplace and the target.
 

How do bullies think?

Challenge the bully at your own peril, because expecting a bully to change is futile. Recall Helen’s confrontation with Bill. It provoked him. His power to harass her came from his perceived position. Bullies regard the pleasant person as weak. Bullies can fall into two categories: Sadists who get pleasure from seeing others suffer, and opportunists. The latter focus only on their goals and disregard concerns expressed by others. Outside of the workplace, they may be reasonable. If workplace morale deteriorates along with productivity, the bully gets ousted. Otherwise, companies usually protect high performers at the expense of targets.

Is bullying different in medicine?

It can happen in a training program. The ingredients for bullying exist, including imbalance of power. Often, there are no witnesses, and there can be lack of accountability because of changing authorities. Just as technology can help make harassment possible, it also enables the target to spot and document inappropriate communications by saving emails and texts. Whenever a need for advancement exists along with changing authority, bullying gets tolerated. Who wants to be derailed by reporting? Those in training have the goal of completing a program. If they report bullying, they fear antagonism and retribution, a personal expense that can deter advancement.

Remedies

Let truth and fairness be your guide. That is easy to say and hard to do, but there are helpful personal and legal resources.

Personal capability

Get busy; get better. That became Helen’s method of choice. She focused on her role and productivity, not on her hurt. Helen shunned victimhood. With the help of psychotherapy and by confiding in a mentor, she prevailed. What works is recalling challenges that were mastered and the qualities that made for success. Acquire skills, build a good reputation, be assertive, not defensive.

The group is powerful, and that means it is important to build alliances above and below in the organizational hierarchy; cultivate friendship with trustworthy people. Occasionally, there is unwarranted ganging up on a manager, bullying from below. It is more likely to happen to a newly appointed supervisor. A way to avert that is to communicate with staff throughout the institution and remain accessible.
 

Legal options

What are legal options to confront bullying? Of note, workplace bullying is not necessarily illegal. According to one employment attorney, “There is no law that prohibits uncivil behavior on the job.” However, under Title VII of the federal law enacted in 1964, there are protected characteristics such as race, color, national origin, sex, age, and disability. The Equal Employment Opportunity Commission enforces Title VII. In cases of assault or stalking, harassment is illegal and criminal.

Some employees report to Human Resources or seek out their company’s employee assistance program. As useful as those options may be, they are part of the company and potentially partial to the administration. There can be incentives to protect those with power against a complainant. For assistance, it is preferable to enlist an outside attorney and a therapist in the community.

Advocacy exists. The Workplace Bullying Institute maintains a website, holds workshops, promotes literature, and offers information. The National Employment Lawyers Association can provide referrals or recommendations that come from other legal sources. Cases rarely reach court because of the expense of a trial; rather, the parties reach a financial settlement. When there is cause, an employment attorney can best pursue justice for the worker.
 

Conclusion

Get busy; get better is the solution to bullying. Avoid victimhood. That means prepare: Update the resume, seek opportunities, and identify allies. Bullies get beaten; as Abraham Lincoln said, “You can fool some of the people some of the time but you can’t fool all of the people all of the time.”

According to the Workplace Bullying Institute, 7 out of 10 bullied workers either resign or get fired. You should leave only when the leaving is better than the staying. Bullying brings out the worst in the workplace. Those who bully isolate the target. Coworkers often shun the target, fearing for their own position; they may even participate in the harassment. Psychiatrists need to remain sensitive to harassment in their own environment and for their patients. We have tools to address bullying in the workplace and a moral responsibility to combat it.
 

References

Workplace Bullying Institute (WBI)

National Employment Lawyers Association (NELA)

“Ozymandias” by Percy Bysshe Shelley

BY BEN HINDELL, PSY.D.

Cyberbullying is willful, repeated harm inflicted with the use of computers, cell phones, and other electronic devices. In some cases, a single message may be viewed by multiple people because the text and pictures are posted elsewhere.

Courtesy Dr. Hindell

Technology makes is possible to harass at any hour. The concept of willful harm is essential. Without interaction between sender and recipient, nuances are lost. Face to face might make a communication benign instead of malevolent or threatening. This has implications for the workplace, where colleagues increasingly communicate by email rather than discuss matters in person or by telephone.
 

Steps for survivors of cyberbullying

• Do not respond immediately to an inflammatory message, post, or email. Gather your thoughts and avoid responding in anger.
• Keep calm and rational, not emotional.
• Try to respond in person and work to avoid a conflict.
• Remember, your interpretation may differ from what was intended.
• Communicate openly and honestly and not defensively.
• Calmly indicate you were offended and you want the comments to stop.
• Move up the chain of command, if comments don’t cease.
• Save all messages and posts as evidence.
• Report the cyberbullying to your employer. Human resources may get involved.
• Detach from the cyberbully, if it continues. Block social media, cell phone messaging, and emails.
• Find support from friends, family, and a psychotherapist, if needed. As a last resort, it may become necessary to enlist an attorney.
• Take the high road; remain calm and professional at work. The bully may be seeking a reaction from the behavior. Prevent it.

All of the elements of workplace bullying apply to cyberbullying, but the latter can be more insidious. Psychiatrists and psychologists are able to support patients who deal with cyberbullying and help them cope successfully.
 

Dr. Cohen is in private practice and is a clinical assistant professor of psychiatry at Weill Cornell Medical Center of New York-Presbyterian Hospital, and psychiatric consultant at the Hospital for Special Surgery, also in New York. She made changes to the patient’s story to protect confidentiality.

Dr. Hindell is a psychologist with the Mental Health Service of Colorado College, Colorado Springs. He also practices psychotherapy in Denver. Dr. Hindell is the son of Dr. Cohen.

There is no Baby Book of Names or hurricane alphabet to readily name diseases and their causal entities. Throughout history and even in the modern era, a host of considerations have intruded on the decision as to what to call these blights upon humanity. Names have varied from inflammatory to misleading, from colloquial to scientific. And when it concerns a new epidemiological entity such as the latest coronavirus outbreak originating in China, health organizations, media, politicians, scientific taxonomy commissions, and the public at large all have a stake in the naming.

Courtesy NIAID-RML

From “Wuhan virus” to “novel coronavirus-2019” to “COVID-19 virus,” the name of the new coronavirus that first appeared in China has been evolving to its now official designation: SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). But where did the final name come from, how does such a name become official, and who makes it so?
 

Virus taxonomy

The Coronavirus Study Group (CSG) of the International Committee on Taxonomy of Viruses (ICTV) named the new coronavirus SARS-CoV-2 based upon its genetic relationship to the original SARS-CoV that caused an outbreak of disease in 2002–2003.

According to the ICTV website, the first internationally organized attempts to introduce order into the bewildering variety of viruses took place at the International Congress of Microbiology held in Moscow in 1966 where a committee was created that later became the ICTV and was given the task of developing a single, universal taxonomic scheme for all the viruses infecting animals, plants, fungi, bacteria, and archaea. The ICTV was created as a committee of the virology division of the International Union of Microbiological Societies and is governed by statutes approved by the virology division. Virus classification and nomenclature are subject to rules set out in an International Code.

These designate that: “The universal virus classification system shall employ the hierarchical levels of realm, subrealm, kingdom, subkingdom, phylum, subphylum, class, subclass, order, suborder, family, subfamily, genus, subgenus and species.”

Many of the topmost areas of classification are based on whether the viruses are DNA or RNA, single or double stranded, and have a simple protein shell or a complex lipoprotein envelope. Other levels of classification include host species, type of replication, and type of diseases they cause, the later exemplified in the SARS designation for this virus.

There are 98 international study groups (SGs) covering all major virus orders, families, and genera that are part of the ICTV, and it was the one dedicated to the single-stranded RNA coronaviruses, the CSG, that came up with the SARS-CoV-2 name and first referenced it in their Feb 11 publication in the Cold Springs Harbor preprint journal bioRxiv.

“Based on phylogeny, taxonomy and established practice, the CSG formally recognizes this virus as a sister to severe acute respiratory syndrome coronaviruses (SARS-CoVs) of the species severe acute respiratory syndrome–related coronavirus and designates it as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),” they wrote.

According to the National Center for Biotechnology Information Taxonomy Browser, with respect to the original SARS CoV virus, of which this is a relative, the full taxonomic designation is: Viruses, Riboviria, Nidovirales, Cornidovirineae, Coronaviridae, Orthocoronavirinae, Betacoronavirus, Sarbecovirus.
 

The problem with naming names

The World Health Organization currently is not using the official scientific name of the virus, but rather is merely labeling it with regard to the disease: COVID-19, which simply refers to coronavirus disease 2019.

They are following a modern standard by which disease names avoid inflammatory connotations with people and places. Too often in the past from syphilis as the “French pox,” the 1918 influenza as the “Spanish flu,” AIDS as the “gay plague,” Middle East Respiratory Syndrome (MERS), and the currently named “WuFlu,” which made an appearance early in the new outbreak and which is symbolic of a sudden wave of anti-Asian, and specifically Chinese, prejudice.

Chinatown districts even in the United States are being affected economically through unwarranted fear associated with the virus. And there have been equivalently virulent outbreaks of hate speech against Asian individuals in places untouched by the new virus.

However, although SARS-CoV-2 as a name avoids such problems, different considerations led the WHO to reject it in its discussions, determining that its use ties it to tightly to the much more deadly SARS-CoV-1 virus in the public mind, risking greater fear and panic, especially in Asia, where SARS-CoV-1 had the biggest impact.

Back in 1896, William Sykes, MD, writing in the first flush of the triumph of germ theory in modern medicine, attempted to give some guidance to how medical science should best come up with new names of diseases by merging the demands of common parlance with those of taxonomic legitimacy. His “On the Origin and History of Disease-Names,” published in the Lancet, had clearcut advice: “It is vain to attempt to replace a folk name or one widely adopted by the people by a new one deliberately coined by scholars, and this for the following reasons: first, whatever names may be accepted by medical men must be translated by them into the vernacular of their patients, and by a resulting reaction the vernacular name comes to be the commoner one with themselves; and, secondly, there is no continuity or unchangeableness in the terms invented by savants, which are amended, improved upon, and displaced by the next writer on the subject, or, even more absurdly still, by the very inventors themselves in a subsequent publication.”

This is the reason that virus taxonomy provides names based upon unchangeable scientific descriptors of the actual disease causing entity, as illustrated by the decisions of the ICTV. In addition, the genomic sequences being provided by the scientific community are all being organized under the SARS-CoV-2 name and thus are cementing that moniker as the only acceptable scientific one.

Whether the rest of the world universally adopts SARS-CoV-2 as a name is still in question. If the outbreak spreads significantly beyond its current limits, fear and confusion – and simply the need for a more familiar-sounding label – may lead the general public to adopt more colloquial designations than those that science attempts to impose, as Dr. Sykes suggested back in 1896. That remains to be seen.

mlesney@mdedge.com

Mark Lesney is the managing editor of MDedge.com/IDPractioner. He has a PhD in plant virology and a PhD in the history of science, with a focus on the history of biotechnology and medicine. He has served as an adjunct assistant professor of the department of biochemistry and molecular & cellular biology at Georgetown University, Washington.

There is no Baby Book of Names or hurricane alphabet to readily name diseases and their causal entities. Throughout history and even in the modern era, a host of considerations have intruded on the decision as to what to call these blights upon humanity. Names have varied from inflammatory to misleading, from colloquial to scientific. And when it concerns a new epidemiological entity such as the latest coronavirus outbreak originating in China, health organizations, media, politicians, scientific taxonomy commissions, and the public at large all have a stake in the naming.

Courtesy NIAID-RML

From “Wuhan virus” to “novel coronavirus-2019” to “COVID-19 virus,” the name of the new coronavirus that first appeared in China has been evolving to its now official designation: SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). But where did the final name come from, how does such a name become official, and who makes it so?
 

Virus taxonomy

The Coronavirus Study Group (CSG) of the International Committee on Taxonomy of Viruses (ICTV) named the new coronavirus SARS-CoV-2 based upon its genetic relationship to the original SARS-CoV that caused an outbreak of disease in 2002–2003.

According to the ICTV website, the first internationally organized attempts to introduce order into the bewildering variety of viruses took place at the International Congress of Microbiology held in Moscow in 1966 where a committee was created that later became the ICTV and was given the task of developing a single, universal taxonomic scheme for all the viruses infecting animals, plants, fungi, bacteria, and archaea. The ICTV was created as a committee of the virology division of the International Union of Microbiological Societies and is governed by statutes approved by the virology division. Virus classification and nomenclature are subject to rules set out in an International Code.

These designate that: “The universal virus classification system shall employ the hierarchical levels of realm, subrealm, kingdom, subkingdom, phylum, subphylum, class, subclass, order, suborder, family, subfamily, genus, subgenus and species.”

Many of the topmost areas of classification are based on whether the viruses are DNA or RNA, single or double stranded, and have a simple protein shell or a complex lipoprotein envelope. Other levels of classification include host species, type of replication, and type of diseases they cause, the later exemplified in the SARS designation for this virus.

There are 98 international study groups (SGs) covering all major virus orders, families, and genera that are part of the ICTV, and it was the one dedicated to the single-stranded RNA coronaviruses, the CSG, that came up with the SARS-CoV-2 name and first referenced it in their Feb 11 publication in the Cold Springs Harbor preprint journal bioRxiv.

“Based on phylogeny, taxonomy and established practice, the CSG formally recognizes this virus as a sister to severe acute respiratory syndrome coronaviruses (SARS-CoVs) of the species severe acute respiratory syndrome–related coronavirus and designates it as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),” they wrote.

According to the National Center for Biotechnology Information Taxonomy Browser, with respect to the original SARS CoV virus, of which this is a relative, the full taxonomic designation is: Viruses, Riboviria, Nidovirales, Cornidovirineae, Coronaviridae, Orthocoronavirinae, Betacoronavirus, Sarbecovirus.
 

The problem with naming names

The World Health Organization currently is not using the official scientific name of the virus, but rather is merely labeling it with regard to the disease: COVID-19, which simply refers to coronavirus disease 2019.

They are following a modern standard by which disease names avoid inflammatory connotations with people and places. Too often in the past from syphilis as the “French pox,” the 1918 influenza as the “Spanish flu,” AIDS as the “gay plague,” Middle East Respiratory Syndrome (MERS), and the currently named “WuFlu,” which made an appearance early in the new outbreak and which is symbolic of a sudden wave of anti-Asian, and specifically Chinese, prejudice.

Chinatown districts even in the United States are being affected economically through unwarranted fear associated with the virus. And there have been equivalently virulent outbreaks of hate speech against Asian individuals in places untouched by the new virus.

However, although SARS-CoV-2 as a name avoids such problems, different considerations led the WHO to reject it in its discussions, determining that its use ties it to tightly to the much more deadly SARS-CoV-1 virus in the public mind, risking greater fear and panic, especially in Asia, where SARS-CoV-1 had the biggest impact.

Back in 1896, William Sykes, MD, writing in the first flush of the triumph of germ theory in modern medicine, attempted to give some guidance to how medical science should best come up with new names of diseases by merging the demands of common parlance with those of taxonomic legitimacy. His “On the Origin and History of Disease-Names,” published in the Lancet, had clearcut advice: “It is vain to attempt to replace a folk name or one widely adopted by the people by a new one deliberately coined by scholars, and this for the following reasons: first, whatever names may be accepted by medical men must be translated by them into the vernacular of their patients, and by a resulting reaction the vernacular name comes to be the commoner one with themselves; and, secondly, there is no continuity or unchangeableness in the terms invented by savants, which are amended, improved upon, and displaced by the next writer on the subject, or, even more absurdly still, by the very inventors themselves in a subsequent publication.”

This is the reason that virus taxonomy provides names based upon unchangeable scientific descriptors of the actual disease causing entity, as illustrated by the decisions of the ICTV. In addition, the genomic sequences being provided by the scientific community are all being organized under the SARS-CoV-2 name and thus are cementing that moniker as the only acceptable scientific one.

Whether the rest of the world universally adopts SARS-CoV-2 as a name is still in question. If the outbreak spreads significantly beyond its current limits, fear and confusion – and simply the need for a more familiar-sounding label – may lead the general public to adopt more colloquial designations than those that science attempts to impose, as Dr. Sykes suggested back in 1896. That remains to be seen.

mlesney@mdedge.com

Mark Lesney is the managing editor of MDedge.com/IDPractioner. He has a PhD in plant virology and a PhD in the history of science, with a focus on the history of biotechnology and medicine. He has served as an adjunct assistant professor of the department of biochemistry and molecular & cellular biology at Georgetown University, Washington.

There is no Baby Book of Names or hurricane alphabet to readily name diseases and their causal entities. Throughout history and even in the modern era, a host of considerations have intruded on the decision as to what to call these blights upon humanity. Names have varied from inflammatory to misleading, from colloquial to scientific. And when it concerns a new epidemiological entity such as the latest coronavirus outbreak originating in China, health organizations, media, politicians, scientific taxonomy commissions, and the public at large all have a stake in the naming.

Courtesy NIAID-RML

From “Wuhan virus” to “novel coronavirus-2019” to “COVID-19 virus,” the name of the new coronavirus that first appeared in China has been evolving to its now official designation: SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). But where did the final name come from, how does such a name become official, and who makes it so?
 

Virus taxonomy

The Coronavirus Study Group (CSG) of the International Committee on Taxonomy of Viruses (ICTV) named the new coronavirus SARS-CoV-2 based upon its genetic relationship to the original SARS-CoV that caused an outbreak of disease in 2002–2003.

According to the ICTV website, the first internationally organized attempts to introduce order into the bewildering variety of viruses took place at the International Congress of Microbiology held in Moscow in 1966 where a committee was created that later became the ICTV and was given the task of developing a single, universal taxonomic scheme for all the viruses infecting animals, plants, fungi, bacteria, and archaea. The ICTV was created as a committee of the virology division of the International Union of Microbiological Societies and is governed by statutes approved by the virology division. Virus classification and nomenclature are subject to rules set out in an International Code.

These designate that: “The universal virus classification system shall employ the hierarchical levels of realm, subrealm, kingdom, subkingdom, phylum, subphylum, class, subclass, order, suborder, family, subfamily, genus, subgenus and species.”

Many of the topmost areas of classification are based on whether the viruses are DNA or RNA, single or double stranded, and have a simple protein shell or a complex lipoprotein envelope. Other levels of classification include host species, type of replication, and type of diseases they cause, the later exemplified in the SARS designation for this virus.

There are 98 international study groups (SGs) covering all major virus orders, families, and genera that are part of the ICTV, and it was the one dedicated to the single-stranded RNA coronaviruses, the CSG, that came up with the SARS-CoV-2 name and first referenced it in their Feb 11 publication in the Cold Springs Harbor preprint journal bioRxiv.

“Based on phylogeny, taxonomy and established practice, the CSG formally recognizes this virus as a sister to severe acute respiratory syndrome coronaviruses (SARS-CoVs) of the species severe acute respiratory syndrome–related coronavirus and designates it as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),” they wrote.

According to the National Center for Biotechnology Information Taxonomy Browser, with respect to the original SARS CoV virus, of which this is a relative, the full taxonomic designation is: Viruses, Riboviria, Nidovirales, Cornidovirineae, Coronaviridae, Orthocoronavirinae, Betacoronavirus, Sarbecovirus.
 

The problem with naming names

The World Health Organization currently is not using the official scientific name of the virus, but rather is merely labeling it with regard to the disease: COVID-19, which simply refers to coronavirus disease 2019.

They are following a modern standard by which disease names avoid inflammatory connotations with people and places. Too often in the past from syphilis as the “French pox,” the 1918 influenza as the “Spanish flu,” AIDS as the “gay plague,” Middle East Respiratory Syndrome (MERS), and the currently named “WuFlu,” which made an appearance early in the new outbreak and which is symbolic of a sudden wave of anti-Asian, and specifically Chinese, prejudice.

Chinatown districts even in the United States are being affected economically through unwarranted fear associated with the virus. And there have been equivalently virulent outbreaks of hate speech against Asian individuals in places untouched by the new virus.

However, although SARS-CoV-2 as a name avoids such problems, different considerations led the WHO to reject it in its discussions, determining that its use ties it to tightly to the much more deadly SARS-CoV-1 virus in the public mind, risking greater fear and panic, especially in Asia, where SARS-CoV-1 had the biggest impact.

Back in 1896, William Sykes, MD, writing in the first flush of the triumph of germ theory in modern medicine, attempted to give some guidance to how medical science should best come up with new names of diseases by merging the demands of common parlance with those of taxonomic legitimacy. His “On the Origin and History of Disease-Names,” published in the Lancet, had clearcut advice: “It is vain to attempt to replace a folk name or one widely adopted by the people by a new one deliberately coined by scholars, and this for the following reasons: first, whatever names may be accepted by medical men must be translated by them into the vernacular of their patients, and by a resulting reaction the vernacular name comes to be the commoner one with themselves; and, secondly, there is no continuity or unchangeableness in the terms invented by savants, which are amended, improved upon, and displaced by the next writer on the subject, or, even more absurdly still, by the very inventors themselves in a subsequent publication.”

This is the reason that virus taxonomy provides names based upon unchangeable scientific descriptors of the actual disease causing entity, as illustrated by the decisions of the ICTV. In addition, the genomic sequences being provided by the scientific community are all being organized under the SARS-CoV-2 name and thus are cementing that moniker as the only acceptable scientific one.

Whether the rest of the world universally adopts SARS-CoV-2 as a name is still in question. If the outbreak spreads significantly beyond its current limits, fear and confusion – and simply the need for a more familiar-sounding label – may lead the general public to adopt more colloquial designations than those that science attempts to impose, as Dr. Sykes suggested back in 1896. That remains to be seen.

mlesney@mdedge.com

Mark Lesney is the managing editor of MDedge.com/IDPractioner. He has a PhD in plant virology and a PhD in the history of science, with a focus on the history of biotechnology and medicine. He has served as an adjunct assistant professor of the department of biochemistry and molecular & cellular biology at Georgetown University, Washington.

The Chinese Center for Disease Control and Prevention has released the largest case series to date for novel coronavirus 2019 (COVID-19), and a summary of key findings appears in JAMA.

• The virus, which spread from a single city to a whole country in only 30 days, has so far has caused over 72,314 cases as of Feb. 11, 2020, and 1,023 fatalities (2.3%) overall.
• The age distribution shows that most of the cases (87%) occurred in patients aged 30-79 years, while 10% were in patients 29 years and younger and 3% at 80 years and older.
• Following the SARS outbreak in 2002-2003, the Chinese government adjusted its epidemic response protocol. For example, according to the summary, while there were 300 cases and 5 deaths with SARS before the Chinese government reported it to the World Health Organization, there were only 27 cases and no deaths with COVID-19 before it was reported to that agency.
• A major goal, the authors wrote, is to buy enough time for scientific research, hopefully before the disease has become too widespread.

The summary argues that, while some measures the Chinese government has taken could be seen as extreme, the overall benefits and lives saved outweigh the potential infringement on civil liberties. It also suggests that countries need to work together in situations like this because disease pathogens do not respect geopolitical borders.

cpalmer@mdedge.com

SOURCE: Wu Z, McGoogan JM. JAMA. 2020 Feb 24. doi: 10.1001/jama.2020.2648.

The Chinese Center for Disease Control and Prevention has released the largest case series to date for novel coronavirus 2019 (COVID-19), and a summary of key findings appears in JAMA.

• The virus, which spread from a single city to a whole country in only 30 days, has so far has caused over 72,314 cases as of Feb. 11, 2020, and 1,023 fatalities (2.3%) overall.
• The age distribution shows that most of the cases (87%) occurred in patients aged 30-79 years, while 10% were in patients 29 years and younger and 3% at 80 years and older.
• Following the SARS outbreak in 2002-2003, the Chinese government adjusted its epidemic response protocol. For example, according to the summary, while there were 300 cases and 5 deaths with SARS before the Chinese government reported it to the World Health Organization, there were only 27 cases and no deaths with COVID-19 before it was reported to that agency.
• A major goal, the authors wrote, is to buy enough time for scientific research, hopefully before the disease has become too widespread.

The summary argues that, while some measures the Chinese government has taken could be seen as extreme, the overall benefits and lives saved outweigh the potential infringement on civil liberties. It also suggests that countries need to work together in situations like this because disease pathogens do not respect geopolitical borders.

cpalmer@mdedge.com

SOURCE: Wu Z, McGoogan JM. JAMA. 2020 Feb 24. doi: 10.1001/jama.2020.2648.

The Chinese Center for Disease Control and Prevention has released the largest case series to date for novel coronavirus 2019 (COVID-19), and a summary of key findings appears in JAMA.

• The virus, which spread from a single city to a whole country in only 30 days, has so far has caused over 72,314 cases as of Feb. 11, 2020, and 1,023 fatalities (2.3%) overall.
• The age distribution shows that most of the cases (87%) occurred in patients aged 30-79 years, while 10% were in patients 29 years and younger and 3% at 80 years and older.
• Following the SARS outbreak in 2002-2003, the Chinese government adjusted its epidemic response protocol. For example, according to the summary, while there were 300 cases and 5 deaths with SARS before the Chinese government reported it to the World Health Organization, there were only 27 cases and no deaths with COVID-19 before it was reported to that agency.
• A major goal, the authors wrote, is to buy enough time for scientific research, hopefully before the disease has become too widespread.

The summary argues that, while some measures the Chinese government has taken could be seen as extreme, the overall benefits and lives saved outweigh the potential infringement on civil liberties. It also suggests that countries need to work together in situations like this because disease pathogens do not respect geopolitical borders.

cpalmer@mdedge.com

SOURCE: Wu Z, McGoogan JM. JAMA. 2020 Feb 24. doi: 10.1001/jama.2020.2648.

Bempedoic acid, the first agent in a new class of drugs that reduce LDL cholesterol, received Food and Drug Administration approval on Feb. 21 for treating selected hypercholesterolemic patients and is a welcome addition to the medicine cabinet, say lipid experts.

MDedge News

However, it is a tertiary option at least until results from a 14,000 patient clinical-outcome trial of bempedoic acid come out, likely in 2022, they agreed.

“I’m excited to have a new tool in the toolkit for treating high-risk patients, but I will always reach first for the drugs proven to reduce clinical outcomes,” said Erin D. Michos, MD, director of Women’s Cardiovascular Health and associate director of Preventive Cardiology at Johns Hopkins Medicine in Baltimore. That sentiment, shared by other experts, should for the time being relegate bempedoic acid (Nexletol) to a backup role behind statins, ezetimibe, and the PCSK9 inhibitor antibodies that are all now on the U.S. market and all buttressed with evidence of their ability to cut cardiovascular disease death and other CVD outcomes from large outcome studies.

The existing evidence base for bempedoic acid rests primarily two multicenter, randomized, placebo-controlled clinical trials of bempedoic acid in patients with LDL levels above 70 mg/dL while on maximally tolerated lipid-lowering therapy. In CLEAR Harmony, results showed that treatment with bempedoic acid cut LDL-cholesterol levels by an average of 18% more compared with placebo (N Engl J Med 2019;380:1022-32). In CLEAR Wisdom, bempedoic acid reduced LDL cholesterol levels by 17% (JAMA. 2019;322[18]:1780-8).

While those two trials proved the drug’s ability to lower levels of LDL cholesterol, they lacked the power to address whether this effect cut the incidence of CVD events, a question that the CLEAR Outcomes trial aims to answer.

“I believe in the lipid hypothesis, but the main thing we need to see is whether bempedoic acid leads to a meaningful reduction in CVD events. The window for bempedoic acid will remain narrow until we see the outcomes results,” Dr. Michos said in an interview.

Bempedoic acid is a prodrug that’s activated in liver and targets the same cholesterol synthesis pathway as statins by inhibition of ATP-citrate lyase, an enzyme that’s upstream of HMG-CoA reductase, thereby enhancing LDL cholesterol clearance via up-regulation of LDL receptors

.

Combined treatment with bempedoic acid and ezetimibe “may be successful in avoiding [using] a PCSK9 inhibitor in some patients, and in particular patients with HeFH or those who are statin intolerant.” But like his colleagues, Dr. Eckel agreed that, for the moment, ezetimibe has an edge over bempedoic acid because of its more extensive evidence base. “If the combination of bempedoic acid and ezetimibe is not needed, the decision [of which one of these to use] needs to depend on the outcome trial results for ezetimibe,” he said. Other factors clinicians could apply if faced with choosing between these two agents include the significant reduction in high-sensitivity C-reactive protein that bempedoic acid produces; the downside that bempedoic acid can cause in some patients an early and persistent rise in serum uric acid levels that can trigger gout flares in patients with a history of gout or at risk for gout; and cost, he said.

Cost is the room-dwelling elephant that colors many decisions about which lipid-lowering drug to use for patients, with options running the price gamut from the generic and uniformly affordable statins and ezetimibe, to the notoriously pricey PCSK9 inhibitors that remain for many patients either prohibitively expensive or hard to get covered by some insurers. Bempedoic acid seems on track to fall somewhere between these two poles, although staff members from Esperion, the company that developed and will market bempedoic acid as Nexletol starting on March 30, declared in a conference call on Feb. 24 that “cost will not be an issue,” for indicated patients prescribed the drug. Company representatives cited a program of coupons, discounts, and rebates they have planned that they anticipate will allow patients who meet the labeled indications to have an out-of-pocket cost for bempedoic acid of “as low as” $10 for a 90-pill supply. They also noted their goal of getting bempedoic acid onto the lowest tier of the Medicare formulary.

How these steps actually play out in the fun house of U.S. prescription drug pricing and preauthorizations remains to be seen. “Out-of-pocket costs are not the real drivers” of drug access, noted Dr. Robinson. “Insurers will likely start with restricted access and prior authorization requirements, just as they did with ezetimibe when it was on patent and prior to having the results from a CVD outcomes trial.” For the time being, bempedoic acid can generally be seen as “expensive ezetimibe,” summed up Dr. Robinson.

Despite that somewhat dismissive characterization, experts are intrigued by the possibility of combining two moderately potent, oral, and safe lipid-lowering drugs in selected patients as a potential alternative to the still financially challenging PCSK9 inhibitors. Combining bempedoic acid and ezetimibe “has a lot of appeal,” said Dr. Michos. “Even though preauthorization has gotten better, it’s still a challenge to get a PCSK9 inhibitor approved.”

Much of her enthusiasm stems from a study reported last year that randomized 301 patients to treatment with bempedoic acid, ezetimibe, or both. The results showed that combined treatment has a similar safety profile to treatment with either drug alone, and produced a cut in LDL cholesterol that was roughly additive for the reductions produced by each drug by itself: Ezetimibe alone cut LDL by about 23%, bempedoic acid alone by about 17%, and the two dosed together once daily resulted in an average 36% drop (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864671). The results showed that, “in patients requiring intensive LDL cholesterol lowering, who cannot afford PCSK9 inhibitors, or have statin intolerance, bempedoic acid and ezetimibe are stronger together and can serve as an alternative approach for lipid management in ASCVD prevention,” wrote Dr. Michos and a coauthor in a commentary that appeared with the study results (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864672).

The concept of combined bempedoic acid and ezetimibe treatment is so appealing that the bempedoic acid manufacturer, Esperion, has already developed a single-pill formulation of the two drugs that received FDA marketing approval on February 26. A company statement said that marketing of this combined formulation, Nexlizet, will start in July 2020.

Although interest in bempedoic acid seems running high for patients included in the new FDA indication, Dr. Michos and others see possibly greater potential for what would now be off-label use for primary prevention in high-risk patients without HeFH, patients who generally don’t qualify for insurance coverage of a PCSK9 inhibitor.

“Use in primary prevention in [non-HeFH] patients with insufficient lowering of LDL cholesterol wouldn’t surprise me,” but a big concern will be out-of-pocket cost when off-label use precludes insurance coverage or discount eligibility, noted Dr. Eckel. An Esperion spokesperson said that the undiscounted, wholesale acquisition cost for bempedoic acid is expected to be roughly $10/pill, or about $300 for a 30-day supply, positioning it more or less midway between generic statins and ezetimibe and the list price for a PCSk9 inhibitor of roughly $500/month.

“I’m most excited about bempedoic acid in the off-label space, for patients who can’t get approved for a PCSK9 inhibitor, for treating patients with subclinical ASCVD, or really high-risk patients with multiple risk factors including diabetes,” especially when these patients are intolerant of a high-intensity statin regimen, said Dr. Michos. “I have a clinic full of patients” who can’t take their full, indicated dosage of a high-intensity statin, and when those patients also can’t get on treatment with a PCSK9 inhibitor then bempedoic acid will be an important part of their alternative regimen, she explained.

Dr. Michos had no disclosures. Dr. Robinson has received research funding from Esperion and from several other companies, and she has been a consultant to Amgen, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi. Dr. Eckel has received honoraria from Kowa, Merck, Novo Nordisk, and Sanofi/Regeneron.

This article was updated 2/27/20.

mzoler@mdedge.com

Bempedoic acid, the first agent in a new class of drugs that reduce LDL cholesterol, received Food and Drug Administration approval on Feb. 21 for treating selected hypercholesterolemic patients and is a welcome addition to the medicine cabinet, say lipid experts.

MDedge News

However, it is a tertiary option at least until results from a 14,000 patient clinical-outcome trial of bempedoic acid come out, likely in 2022, they agreed.

“I’m excited to have a new tool in the toolkit for treating high-risk patients, but I will always reach first for the drugs proven to reduce clinical outcomes,” said Erin D. Michos, MD, director of Women’s Cardiovascular Health and associate director of Preventive Cardiology at Johns Hopkins Medicine in Baltimore. That sentiment, shared by other experts, should for the time being relegate bempedoic acid (Nexletol) to a backup role behind statins, ezetimibe, and the PCSK9 inhibitor antibodies that are all now on the U.S. market and all buttressed with evidence of their ability to cut cardiovascular disease death and other CVD outcomes from large outcome studies.

The existing evidence base for bempedoic acid rests primarily two multicenter, randomized, placebo-controlled clinical trials of bempedoic acid in patients with LDL levels above 70 mg/dL while on maximally tolerated lipid-lowering therapy. In CLEAR Harmony, results showed that treatment with bempedoic acid cut LDL-cholesterol levels by an average of 18% more compared with placebo (N Engl J Med 2019;380:1022-32). In CLEAR Wisdom, bempedoic acid reduced LDL cholesterol levels by 17% (JAMA. 2019;322[18]:1780-8).

While those two trials proved the drug’s ability to lower levels of LDL cholesterol, they lacked the power to address whether this effect cut the incidence of CVD events, a question that the CLEAR Outcomes trial aims to answer.

“I believe in the lipid hypothesis, but the main thing we need to see is whether bempedoic acid leads to a meaningful reduction in CVD events. The window for bempedoic acid will remain narrow until we see the outcomes results,” Dr. Michos said in an interview.

Bempedoic acid is a prodrug that’s activated in liver and targets the same cholesterol synthesis pathway as statins by inhibition of ATP-citrate lyase, an enzyme that’s upstream of HMG-CoA reductase, thereby enhancing LDL cholesterol clearance via up-regulation of LDL receptors

.

Combined treatment with bempedoic acid and ezetimibe “may be successful in avoiding [using] a PCSK9 inhibitor in some patients, and in particular patients with HeFH or those who are statin intolerant.” But like his colleagues, Dr. Eckel agreed that, for the moment, ezetimibe has an edge over bempedoic acid because of its more extensive evidence base. “If the combination of bempedoic acid and ezetimibe is not needed, the decision [of which one of these to use] needs to depend on the outcome trial results for ezetimibe,” he said. Other factors clinicians could apply if faced with choosing between these two agents include the significant reduction in high-sensitivity C-reactive protein that bempedoic acid produces; the downside that bempedoic acid can cause in some patients an early and persistent rise in serum uric acid levels that can trigger gout flares in patients with a history of gout or at risk for gout; and cost, he said.

Cost is the room-dwelling elephant that colors many decisions about which lipid-lowering drug to use for patients, with options running the price gamut from the generic and uniformly affordable statins and ezetimibe, to the notoriously pricey PCSK9 inhibitors that remain for many patients either prohibitively expensive or hard to get covered by some insurers. Bempedoic acid seems on track to fall somewhere between these two poles, although staff members from Esperion, the company that developed and will market bempedoic acid as Nexletol starting on March 30, declared in a conference call on Feb. 24 that “cost will not be an issue,” for indicated patients prescribed the drug. Company representatives cited a program of coupons, discounts, and rebates they have planned that they anticipate will allow patients who meet the labeled indications to have an out-of-pocket cost for bempedoic acid of “as low as” $10 for a 90-pill supply. They also noted their goal of getting bempedoic acid onto the lowest tier of the Medicare formulary.

How these steps actually play out in the fun house of U.S. prescription drug pricing and preauthorizations remains to be seen. “Out-of-pocket costs are not the real drivers” of drug access, noted Dr. Robinson. “Insurers will likely start with restricted access and prior authorization requirements, just as they did with ezetimibe when it was on patent and prior to having the results from a CVD outcomes trial.” For the time being, bempedoic acid can generally be seen as “expensive ezetimibe,” summed up Dr. Robinson.

Despite that somewhat dismissive characterization, experts are intrigued by the possibility of combining two moderately potent, oral, and safe lipid-lowering drugs in selected patients as a potential alternative to the still financially challenging PCSK9 inhibitors. Combining bempedoic acid and ezetimibe “has a lot of appeal,” said Dr. Michos. “Even though preauthorization has gotten better, it’s still a challenge to get a PCSK9 inhibitor approved.”

Much of her enthusiasm stems from a study reported last year that randomized 301 patients to treatment with bempedoic acid, ezetimibe, or both. The results showed that combined treatment has a similar safety profile to treatment with either drug alone, and produced a cut in LDL cholesterol that was roughly additive for the reductions produced by each drug by itself: Ezetimibe alone cut LDL by about 23%, bempedoic acid alone by about 17%, and the two dosed together once daily resulted in an average 36% drop (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864671). The results showed that, “in patients requiring intensive LDL cholesterol lowering, who cannot afford PCSK9 inhibitors, or have statin intolerance, bempedoic acid and ezetimibe are stronger together and can serve as an alternative approach for lipid management in ASCVD prevention,” wrote Dr. Michos and a coauthor in a commentary that appeared with the study results (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864672).

The concept of combined bempedoic acid and ezetimibe treatment is so appealing that the bempedoic acid manufacturer, Esperion, has already developed a single-pill formulation of the two drugs that received FDA marketing approval on February 26. A company statement said that marketing of this combined formulation, Nexlizet, will start in July 2020.

Although interest in bempedoic acid seems running high for patients included in the new FDA indication, Dr. Michos and others see possibly greater potential for what would now be off-label use for primary prevention in high-risk patients without HeFH, patients who generally don’t qualify for insurance coverage of a PCSK9 inhibitor.

“Use in primary prevention in [non-HeFH] patients with insufficient lowering of LDL cholesterol wouldn’t surprise me,” but a big concern will be out-of-pocket cost when off-label use precludes insurance coverage or discount eligibility, noted Dr. Eckel. An Esperion spokesperson said that the undiscounted, wholesale acquisition cost for bempedoic acid is expected to be roughly $10/pill, or about $300 for a 30-day supply, positioning it more or less midway between generic statins and ezetimibe and the list price for a PCSk9 inhibitor of roughly $500/month.

“I’m most excited about bempedoic acid in the off-label space, for patients who can’t get approved for a PCSK9 inhibitor, for treating patients with subclinical ASCVD, or really high-risk patients with multiple risk factors including diabetes,” especially when these patients are intolerant of a high-intensity statin regimen, said Dr. Michos. “I have a clinic full of patients” who can’t take their full, indicated dosage of a high-intensity statin, and when those patients also can’t get on treatment with a PCSK9 inhibitor then bempedoic acid will be an important part of their alternative regimen, she explained.

Dr. Michos had no disclosures. Dr. Robinson has received research funding from Esperion and from several other companies, and she has been a consultant to Amgen, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi. Dr. Eckel has received honoraria from Kowa, Merck, Novo Nordisk, and Sanofi/Regeneron.

This article was updated 2/27/20.

mzoler@mdedge.com

Bempedoic acid, the first agent in a new class of drugs that reduce LDL cholesterol, received Food and Drug Administration approval on Feb. 21 for treating selected hypercholesterolemic patients and is a welcome addition to the medicine cabinet, say lipid experts.

MDedge News

However, it is a tertiary option at least until results from a 14,000 patient clinical-outcome trial of bempedoic acid come out, likely in 2022, they agreed.

“I’m excited to have a new tool in the toolkit for treating high-risk patients, but I will always reach first for the drugs proven to reduce clinical outcomes,” said Erin D. Michos, MD, director of Women’s Cardiovascular Health and associate director of Preventive Cardiology at Johns Hopkins Medicine in Baltimore. That sentiment, shared by other experts, should for the time being relegate bempedoic acid (Nexletol) to a backup role behind statins, ezetimibe, and the PCSK9 inhibitor antibodies that are all now on the U.S. market and all buttressed with evidence of their ability to cut cardiovascular disease death and other CVD outcomes from large outcome studies.

The existing evidence base for bempedoic acid rests primarily two multicenter, randomized, placebo-controlled clinical trials of bempedoic acid in patients with LDL levels above 70 mg/dL while on maximally tolerated lipid-lowering therapy. In CLEAR Harmony, results showed that treatment with bempedoic acid cut LDL-cholesterol levels by an average of 18% more compared with placebo (N Engl J Med 2019;380:1022-32). In CLEAR Wisdom, bempedoic acid reduced LDL cholesterol levels by 17% (JAMA. 2019;322[18]:1780-8).

While those two trials proved the drug’s ability to lower levels of LDL cholesterol, they lacked the power to address whether this effect cut the incidence of CVD events, a question that the CLEAR Outcomes trial aims to answer.

“I believe in the lipid hypothesis, but the main thing we need to see is whether bempedoic acid leads to a meaningful reduction in CVD events. The window for bempedoic acid will remain narrow until we see the outcomes results,” Dr. Michos said in an interview.

Bempedoic acid is a prodrug that’s activated in liver and targets the same cholesterol synthesis pathway as statins by inhibition of ATP-citrate lyase, an enzyme that’s upstream of HMG-CoA reductase, thereby enhancing LDL cholesterol clearance via up-regulation of LDL receptors

.

Combined treatment with bempedoic acid and ezetimibe “may be successful in avoiding [using] a PCSK9 inhibitor in some patients, and in particular patients with HeFH or those who are statin intolerant.” But like his colleagues, Dr. Eckel agreed that, for the moment, ezetimibe has an edge over bempedoic acid because of its more extensive evidence base. “If the combination of bempedoic acid and ezetimibe is not needed, the decision [of which one of these to use] needs to depend on the outcome trial results for ezetimibe,” he said. Other factors clinicians could apply if faced with choosing between these two agents include the significant reduction in high-sensitivity C-reactive protein that bempedoic acid produces; the downside that bempedoic acid can cause in some patients an early and persistent rise in serum uric acid levels that can trigger gout flares in patients with a history of gout or at risk for gout; and cost, he said.

Cost is the room-dwelling elephant that colors many decisions about which lipid-lowering drug to use for patients, with options running the price gamut from the generic and uniformly affordable statins and ezetimibe, to the notoriously pricey PCSK9 inhibitors that remain for many patients either prohibitively expensive or hard to get covered by some insurers. Bempedoic acid seems on track to fall somewhere between these two poles, although staff members from Esperion, the company that developed and will market bempedoic acid as Nexletol starting on March 30, declared in a conference call on Feb. 24 that “cost will not be an issue,” for indicated patients prescribed the drug. Company representatives cited a program of coupons, discounts, and rebates they have planned that they anticipate will allow patients who meet the labeled indications to have an out-of-pocket cost for bempedoic acid of “as low as” $10 for a 90-pill supply. They also noted their goal of getting bempedoic acid onto the lowest tier of the Medicare formulary.

How these steps actually play out in the fun house of U.S. prescription drug pricing and preauthorizations remains to be seen. “Out-of-pocket costs are not the real drivers” of drug access, noted Dr. Robinson. “Insurers will likely start with restricted access and prior authorization requirements, just as they did with ezetimibe when it was on patent and prior to having the results from a CVD outcomes trial.” For the time being, bempedoic acid can generally be seen as “expensive ezetimibe,” summed up Dr. Robinson.

Despite that somewhat dismissive characterization, experts are intrigued by the possibility of combining two moderately potent, oral, and safe lipid-lowering drugs in selected patients as a potential alternative to the still financially challenging PCSK9 inhibitors. Combining bempedoic acid and ezetimibe “has a lot of appeal,” said Dr. Michos. “Even though preauthorization has gotten better, it’s still a challenge to get a PCSK9 inhibitor approved.”

Much of her enthusiasm stems from a study reported last year that randomized 301 patients to treatment with bempedoic acid, ezetimibe, or both. The results showed that combined treatment has a similar safety profile to treatment with either drug alone, and produced a cut in LDL cholesterol that was roughly additive for the reductions produced by each drug by itself: Ezetimibe alone cut LDL by about 23%, bempedoic acid alone by about 17%, and the two dosed together once daily resulted in an average 36% drop (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864671). The results showed that, “in patients requiring intensive LDL cholesterol lowering, who cannot afford PCSK9 inhibitors, or have statin intolerance, bempedoic acid and ezetimibe are stronger together and can serve as an alternative approach for lipid management in ASCVD prevention,” wrote Dr. Michos and a coauthor in a commentary that appeared with the study results (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864672).

The concept of combined bempedoic acid and ezetimibe treatment is so appealing that the bempedoic acid manufacturer, Esperion, has already developed a single-pill formulation of the two drugs that received FDA marketing approval on February 26. A company statement said that marketing of this combined formulation, Nexlizet, will start in July 2020.

Although interest in bempedoic acid seems running high for patients included in the new FDA indication, Dr. Michos and others see possibly greater potential for what would now be off-label use for primary prevention in high-risk patients without HeFH, patients who generally don’t qualify for insurance coverage of a PCSK9 inhibitor.

“Use in primary prevention in [non-HeFH] patients with insufficient lowering of LDL cholesterol wouldn’t surprise me,” but a big concern will be out-of-pocket cost when off-label use precludes insurance coverage or discount eligibility, noted Dr. Eckel. An Esperion spokesperson said that the undiscounted, wholesale acquisition cost for bempedoic acid is expected to be roughly $10/pill, or about $300 for a 30-day supply, positioning it more or less midway between generic statins and ezetimibe and the list price for a PCSk9 inhibitor of roughly $500/month.

“I’m most excited about bempedoic acid in the off-label space, for patients who can’t get approved for a PCSK9 inhibitor, for treating patients with subclinical ASCVD, or really high-risk patients with multiple risk factors including diabetes,” especially when these patients are intolerant of a high-intensity statin regimen, said Dr. Michos. “I have a clinic full of patients” who can’t take their full, indicated dosage of a high-intensity statin, and when those patients also can’t get on treatment with a PCSK9 inhibitor then bempedoic acid will be an important part of their alternative regimen, she explained.

Dr. Michos had no disclosures. Dr. Robinson has received research funding from Esperion and from several other companies, and she has been a consultant to Amgen, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi. Dr. Eckel has received honoraria from Kowa, Merck, Novo Nordisk, and Sanofi/Regeneron.

This article was updated 2/27/20.

mzoler@mdedge.com

To the Editor:

Acanthosis nigricans (AN) is characterized by asymptomatic, hyperpigmented, velvety plaques that can occur anywhere on the body but most often present on the skin of the neck, axillae, groin, and other body folds.^1-12 Although there are 5 subtypes, benign AN is the most common and is related to insulin resistance.^1-4 Insulin can bind to insulinlike growth factor 1 (IGF-1) on keratinocytes, stimulating their proliferation. In type 2 diabetes mellitus, endogenous insulin levels are high enough to bind IGF-1 and activate keratinocytes, leading to the development of AN. Insulin injections have been associated with cutaneous side effects including lipoatrophy, lipohypertrophy, and postinflammatory hyperpigmentation.³ Acanthosis nigricans at insulin injection sites is a rare clinical condition.

A 64-year-old man presented for evaluation of a growing asymptomatic lesion on the abdomen of 6 years’ duration. He had a 17-year history of type 2 diabetes mellitus treated with insulin injections for 14 years after failing oral hypoglycemic agents. The patient reported injecting at the same site on the abdomen for the last 14 years. Physical examination revealed a lichenified, hyperpigmented, verrucous plaque on the lower abdomen under the umbilicus (Figure 1). No similar skin lesions were observed elsewhere on the body. A punch biopsy of the plaque showed hyperkeratosis, papillomatosis, acanthosis, and hyperpigmentation, which was consistent with AN (Figure 2). The patient was instructed to rotate injection sites and avoid the affected area. Over-the-counter ammonium lactate cream applied twice daily to the affected site also was recommended. After 2 months of treatment with this regimen, the patient reported softening and lightening of the lesion on the abdomen.

A PubMed search of articles indexed for MEDLINE for all English-language studies with human participants using the terms acanthosis nigricans and insulin injections yielded 20 results. Of them, 13 discussed localized AN at insulin injection sites: 12 case reports (Table)^1-12 and 1 observational study in a group of diabetic patients.¹³

It has been suggested that localized AN at insulin injection sites develops through similar mechanisms as benign AN. Contributing factors to the development of benign AN may be IGF-1, fibroblast growth factor, and epidermal growth factor.^1-3 Insulin is similar in structure to IGF-1 and can bind to IGF-1 receptors at high enough concentrations. Insulinlike growth factor 1 receptors are present on keratinocytes and fibroblasts, which proliferate upon activation, leading to the development of AN.^1-3 Localized AN is thought to occur when repetitive insulin at the injection site saturates IGF-1 receptors on local keratinocytes.

Based on our patient and prior reports in the literature, localized AN is an uncommon cutaneous complication of insulin injections. Physicians should ask about repetitive insulin injections in the same site when localized AN occurs in patients with diabetes mellitus on insulin therapy. They also should discuss the importance of rotating sites for insulin adminstration to prevent the development of cutaneous complications including AN.

To the Editor:

Acanthosis nigricans (AN) is characterized by asymptomatic, hyperpigmented, velvety plaques that can occur anywhere on the body but most often present on the skin of the neck, axillae, groin, and other body folds.^1-12 Although there are 5 subtypes, benign AN is the most common and is related to insulin resistance.^1-4 Insulin can bind to insulinlike growth factor 1 (IGF-1) on keratinocytes, stimulating their proliferation. In type 2 diabetes mellitus, endogenous insulin levels are high enough to bind IGF-1 and activate keratinocytes, leading to the development of AN. Insulin injections have been associated with cutaneous side effects including lipoatrophy, lipohypertrophy, and postinflammatory hyperpigmentation.³ Acanthosis nigricans at insulin injection sites is a rare clinical condition.

A 64-year-old man presented for evaluation of a growing asymptomatic lesion on the abdomen of 6 years’ duration. He had a 17-year history of type 2 diabetes mellitus treated with insulin injections for 14 years after failing oral hypoglycemic agents. The patient reported injecting at the same site on the abdomen for the last 14 years. Physical examination revealed a lichenified, hyperpigmented, verrucous plaque on the lower abdomen under the umbilicus (Figure 1). No similar skin lesions were observed elsewhere on the body. A punch biopsy of the plaque showed hyperkeratosis, papillomatosis, acanthosis, and hyperpigmentation, which was consistent with AN (Figure 2). The patient was instructed to rotate injection sites and avoid the affected area. Over-the-counter ammonium lactate cream applied twice daily to the affected site also was recommended. After 2 months of treatment with this regimen, the patient reported softening and lightening of the lesion on the abdomen.

A PubMed search of articles indexed for MEDLINE for all English-language studies with human participants using the terms acanthosis nigricans and insulin injections yielded 20 results. Of them, 13 discussed localized AN at insulin injection sites: 12 case reports (Table)^1-12 and 1 observational study in a group of diabetic patients.¹³

It has been suggested that localized AN at insulin injection sites develops through similar mechanisms as benign AN. Contributing factors to the development of benign AN may be IGF-1, fibroblast growth factor, and epidermal growth factor.^1-3 Insulin is similar in structure to IGF-1 and can bind to IGF-1 receptors at high enough concentrations. Insulinlike growth factor 1 receptors are present on keratinocytes and fibroblasts, which proliferate upon activation, leading to the development of AN.^1-3 Localized AN is thought to occur when repetitive insulin at the injection site saturates IGF-1 receptors on local keratinocytes.

Based on our patient and prior reports in the literature, localized AN is an uncommon cutaneous complication of insulin injections. Physicians should ask about repetitive insulin injections in the same site when localized AN occurs in patients with diabetes mellitus on insulin therapy. They also should discuss the importance of rotating sites for insulin adminstration to prevent the development of cutaneous complications including AN.

To the Editor:

Acanthosis nigricans (AN) is characterized by asymptomatic, hyperpigmented, velvety plaques that can occur anywhere on the body but most often present on the skin of the neck, axillae, groin, and other body folds.^1-12 Although there are 5 subtypes, benign AN is the most common and is related to insulin resistance.^1-4 Insulin can bind to insulinlike growth factor 1 (IGF-1) on keratinocytes, stimulating their proliferation. In type 2 diabetes mellitus, endogenous insulin levels are high enough to bind IGF-1 and activate keratinocytes, leading to the development of AN. Insulin injections have been associated with cutaneous side effects including lipoatrophy, lipohypertrophy, and postinflammatory hyperpigmentation.³ Acanthosis nigricans at insulin injection sites is a rare clinical condition.

A 64-year-old man presented for evaluation of a growing asymptomatic lesion on the abdomen of 6 years’ duration. He had a 17-year history of type 2 diabetes mellitus treated with insulin injections for 14 years after failing oral hypoglycemic agents. The patient reported injecting at the same site on the abdomen for the last 14 years. Physical examination revealed a lichenified, hyperpigmented, verrucous plaque on the lower abdomen under the umbilicus (Figure 1). No similar skin lesions were observed elsewhere on the body. A punch biopsy of the plaque showed hyperkeratosis, papillomatosis, acanthosis, and hyperpigmentation, which was consistent with AN (Figure 2). The patient was instructed to rotate injection sites and avoid the affected area. Over-the-counter ammonium lactate cream applied twice daily to the affected site also was recommended. After 2 months of treatment with this regimen, the patient reported softening and lightening of the lesion on the abdomen.

A PubMed search of articles indexed for MEDLINE for all English-language studies with human participants using the terms acanthosis nigricans and insulin injections yielded 20 results. Of them, 13 discussed localized AN at insulin injection sites: 12 case reports (Table)^1-12 and 1 observational study in a group of diabetic patients.¹³

It has been suggested that localized AN at insulin injection sites develops through similar mechanisms as benign AN. Contributing factors to the development of benign AN may be IGF-1, fibroblast growth factor, and epidermal growth factor.^1-3 Insulin is similar in structure to IGF-1 and can bind to IGF-1 receptors at high enough concentrations. Insulinlike growth factor 1 receptors are present on keratinocytes and fibroblasts, which proliferate upon activation, leading to the development of AN.^1-3 Localized AN is thought to occur when repetitive insulin at the injection site saturates IGF-1 receptors on local keratinocytes.

Based on our patient and prior reports in the literature, localized AN is an uncommon cutaneous complication of insulin injections. Physicians should ask about repetitive insulin injections in the same site when localized AN occurs in patients with diabetes mellitus on insulin therapy. They also should discuss the importance of rotating sites for insulin adminstration to prevent the development of cutaneous complications including AN.

Neurologists reported being the least happy specialty at work in the Medscape Neurologist Lifestyle, Happiness, and Burnout Report 2020. Most reported they did not plan to seek help for their depression and/or burnout, and nearly half said they wouldn’t even participate in a workplace program.

The report found that only 18% of neurologists were very happy at work, and 41% overall identified themselves as burned out. Among reasons for burnout, 61% reported mounting bureaucratic tasks as their top reason, with 40% listing spending too many hours at work.

Coping strategies varied, with isolation from others topping the list at 46%, followed by talking with close friends and family and exercise tied at 40%.

Less than half (46%) claimed there was no impact on patients, but most (65%) don’t intend to seek professional help for depression and/or burnout and haven’t done so in the past. Similarly, 48% reported it’s unlikely they’d participate in a workplace program – in fact, only 33% said they would.

A slideshow laying out the findings in the report is available on Medscape.
 

A closer look at the numbers

Over 15,000 physicians across 29 specialties completed the 10-minute survey in the summer of 2019; 62% were men and most of the group were Baby Boomers (ages 55-73), then Generation X (ages 40-54), and lastly Millennials (ages 25-39). Of the specialties surveyed, neurologists scored lowest in the happiness-at-work category, with only 18% saying they were happy. Neurologists also scored lowest in happiness outside of work (44%). Half the neurologists surveyed said they were burned out, which was slightly more than the surveyed group of physicians in general. The biggest contributors to burnout were bureaucratic tasks, too many hours at work, and lack of control. Most coped by isolating themselves, talking with family members or friends, exercising and sleep. About 65% did not seek help for burnout or depression. The main reasons were being too busy, preferring to deal with it themselves, or feeling that the problem was not significant enough to warrant intervention.

A majority of the neurologists surveyed (70%-80%) are married and 85% say they have a good marriage. Almost half of neurologists take 3-4 weeks of vacation and a third take 1-2 weeks. Neurologists surveyed drive mostly Hondas and Toyotas; 4% drive Teslas and 3% drive Porsches. One third of neurologists exercise two to three times per week and 10% exercise daily. Only 20% have a drink more than four times per week.
 

Looking for solutions

“It is a bit distressing to see how many neurologists are unhappy at work and unhappy even outside of work,” said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles. Many neurologists claim to be burned out and a small percent report depression. Most do not seek help, do not take care of themselves well enough, and do not vacation or exercise enough, added Dr. Rapoport, who also is a past president of the International Headache Society and is editor in chief of Neurology Reviews.

Dr. Rapoport believes that some studies about this situation should be done by the American Academy of Neurology and other subspecialty organizations (for example, the American Headache Society), and results should be published in the neurology and subspecialty journals. Further work in this area should include suggestions for rectifying the situation and encouraging neurologists to seek help and improve their lifestyle. “I think that one of the ways that headache specialists have avoided burnout and depression is by focusing on one subspecialty area and engaging in different types of activities, such as seeing patients in the office and hospital, giving lectures, traveling to meetings, writing papers, and balancing their professional and personal lives. It appears that we need help as a profession, and we had better help ourselves to get it.”

cpalmer@mdedge.com

Neurologists reported being the least happy specialty at work in the Medscape Neurologist Lifestyle, Happiness, and Burnout Report 2020. Most reported they did not plan to seek help for their depression and/or burnout, and nearly half said they wouldn’t even participate in a workplace program.

The report found that only 18% of neurologists were very happy at work, and 41% overall identified themselves as burned out. Among reasons for burnout, 61% reported mounting bureaucratic tasks as their top reason, with 40% listing spending too many hours at work.

Coping strategies varied, with isolation from others topping the list at 46%, followed by talking with close friends and family and exercise tied at 40%.

Less than half (46%) claimed there was no impact on patients, but most (65%) don’t intend to seek professional help for depression and/or burnout and haven’t done so in the past. Similarly, 48% reported it’s unlikely they’d participate in a workplace program – in fact, only 33% said they would.

A slideshow laying out the findings in the report is available on Medscape.
 

A closer look at the numbers

Over 15,000 physicians across 29 specialties completed the 10-minute survey in the summer of 2019; 62% were men and most of the group were Baby Boomers (ages 55-73), then Generation X (ages 40-54), and lastly Millennials (ages 25-39). Of the specialties surveyed, neurologists scored lowest in the happiness-at-work category, with only 18% saying they were happy. Neurologists also scored lowest in happiness outside of work (44%). Half the neurologists surveyed said they were burned out, which was slightly more than the surveyed group of physicians in general. The biggest contributors to burnout were bureaucratic tasks, too many hours at work, and lack of control. Most coped by isolating themselves, talking with family members or friends, exercising and sleep. About 65% did not seek help for burnout or depression. The main reasons were being too busy, preferring to deal with it themselves, or feeling that the problem was not significant enough to warrant intervention.

A majority of the neurologists surveyed (70%-80%) are married and 85% say they have a good marriage. Almost half of neurologists take 3-4 weeks of vacation and a third take 1-2 weeks. Neurologists surveyed drive mostly Hondas and Toyotas; 4% drive Teslas and 3% drive Porsches. One third of neurologists exercise two to three times per week and 10% exercise daily. Only 20% have a drink more than four times per week.
 

Looking for solutions

“It is a bit distressing to see how many neurologists are unhappy at work and unhappy even outside of work,” said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles. Many neurologists claim to be burned out and a small percent report depression. Most do not seek help, do not take care of themselves well enough, and do not vacation or exercise enough, added Dr. Rapoport, who also is a past president of the International Headache Society and is editor in chief of Neurology Reviews.

Dr. Rapoport believes that some studies about this situation should be done by the American Academy of Neurology and other subspecialty organizations (for example, the American Headache Society), and results should be published in the neurology and subspecialty journals. Further work in this area should include suggestions for rectifying the situation and encouraging neurologists to seek help and improve their lifestyle. “I think that one of the ways that headache specialists have avoided burnout and depression is by focusing on one subspecialty area and engaging in different types of activities, such as seeing patients in the office and hospital, giving lectures, traveling to meetings, writing papers, and balancing their professional and personal lives. It appears that we need help as a profession, and we had better help ourselves to get it.”

cpalmer@mdedge.com

Neurologists reported being the least happy specialty at work in the Medscape Neurologist Lifestyle, Happiness, and Burnout Report 2020. Most reported they did not plan to seek help for their depression and/or burnout, and nearly half said they wouldn’t even participate in a workplace program.

The report found that only 18% of neurologists were very happy at work, and 41% overall identified themselves as burned out. Among reasons for burnout, 61% reported mounting bureaucratic tasks as their top reason, with 40% listing spending too many hours at work.

Coping strategies varied, with isolation from others topping the list at 46%, followed by talking with close friends and family and exercise tied at 40%.

Less than half (46%) claimed there was no impact on patients, but most (65%) don’t intend to seek professional help for depression and/or burnout and haven’t done so in the past. Similarly, 48% reported it’s unlikely they’d participate in a workplace program – in fact, only 33% said they would.

A slideshow laying out the findings in the report is available on Medscape.
 

A closer look at the numbers

Over 15,000 physicians across 29 specialties completed the 10-minute survey in the summer of 2019; 62% were men and most of the group were Baby Boomers (ages 55-73), then Generation X (ages 40-54), and lastly Millennials (ages 25-39). Of the specialties surveyed, neurologists scored lowest in the happiness-at-work category, with only 18% saying they were happy. Neurologists also scored lowest in happiness outside of work (44%). Half the neurologists surveyed said they were burned out, which was slightly more than the surveyed group of physicians in general. The biggest contributors to burnout were bureaucratic tasks, too many hours at work, and lack of control. Most coped by isolating themselves, talking with family members or friends, exercising and sleep. About 65% did not seek help for burnout or depression. The main reasons were being too busy, preferring to deal with it themselves, or feeling that the problem was not significant enough to warrant intervention.

A majority of the neurologists surveyed (70%-80%) are married and 85% say they have a good marriage. Almost half of neurologists take 3-4 weeks of vacation and a third take 1-2 weeks. Neurologists surveyed drive mostly Hondas and Toyotas; 4% drive Teslas and 3% drive Porsches. One third of neurologists exercise two to three times per week and 10% exercise daily. Only 20% have a drink more than four times per week.
 

Looking for solutions

“It is a bit distressing to see how many neurologists are unhappy at work and unhappy even outside of work,” said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles. Many neurologists claim to be burned out and a small percent report depression. Most do not seek help, do not take care of themselves well enough, and do not vacation or exercise enough, added Dr. Rapoport, who also is a past president of the International Headache Society and is editor in chief of Neurology Reviews.

Dr. Rapoport believes that some studies about this situation should be done by the American Academy of Neurology and other subspecialty organizations (for example, the American Headache Society), and results should be published in the neurology and subspecialty journals. Further work in this area should include suggestions for rectifying the situation and encouraging neurologists to seek help and improve their lifestyle. “I think that one of the ways that headache specialists have avoided burnout and depression is by focusing on one subspecialty area and engaging in different types of activities, such as seeing patients in the office and hospital, giving lectures, traveling to meetings, writing papers, and balancing their professional and personal lives. It appears that we need help as a profession, and we had better help ourselves to get it.”

cpalmer@mdedge.com

MAUI, HAWAII – There might well be a cure for hepatitis B in coming years, just like there is now for hepatitis C, according to Norah Terrault, MD, chief of the division of GI and liver at the University of Southern California, Los Angeles.

M. Alexander Otto/MDedge News

“We are going to have a laundry list of new drugs” that are in the pipeline now. Phase 2 results “look encouraging. You will hear much more about this in the years ahead,” said Dr. Terrault, lead author of the 2018 American Association for the Study of Liver Diseases (AASLD) hepatitis B guidance.

For now, though, the field is largely limited to the nucleoside analogues tenofovir and entecavir. Treatment is often indefinite because, although hepatitis B virus (HBV) e-antigen is cleared, it usually doesn’t clear the HBV surface antigen, which is linked to liver cancer. “Even with e-antigen–negative patients, we feel that indefinite therapy is really the way to go,” Dr. Terrault said at the Gastroenterology Updates, IBD, Liver Disease Conference.

One of the biggest problems with that strategy is what to do when HBV does not seem to be much of a problem for carriers. Such patients are referred to as immune tolerant.
 

A newly recognized cancer risk

Immune tolerant patients tend to be young and have extremely high viral loads but no apparent ill effects, with normal ALT levels, normal histology, and no sign of cirrhosis. Although the AASLD recommends not treating these patients until they are 40 years old, waiting makes people nervous. “You have a hammer, you want to hit a nail,” Dr. Terrault said.

A recent review (Gut. 2018 May;67[5]:945-52) suggests that hitting the nail might be the way to go. South Korean investigators found that 413 untreated immune tolerate patients with a mean age of 38 years had more than twice the risk of liver cancer over 10 years than did almost 1,500 treated patients with active disease.

The study investigators concluded that “unnecessary deaths could be prevented through earlier antiviral intervention in select [immune tolerate] patients.”

This finding is one reason “we [AASLD] are rethinking the mantra of not treating the immune tolerant. There is a group that is transitioning” to active disease. “I’m thinking we should really [lower] the age cutoff” to 30 years, as some other groups [European Association for the Study of the Liver and Asian Pacific Association for the Study of the Liver] have done, plus “patients feel really good when they know the virus is controlled, and so do physicians,” Dr. Terrault said.
 

Entecavir versus tenofovir

Meanwhile, recent studies have raised the question of whether tenofovir is better than entecavir at preventing liver cancer.

A JAMA Oncology (JAMA Oncol. 2019 Jan 1;5[1]:30-6) study of some 25,000 patients in South Korea found a 32% lower risk of liver cancer when they were treated with tenofovir instead of entecavir. “This led to a lot of concern that maybe we should be moving all our patients to tenofovir,” she said.

Another study, a meta-analysis published earlier this year (Hepatol Int. 2020 Jan;14[1]:105-14), confirmed the difference in cancer risk when it combined those findings with other research. After adjustment for potential confounders, including disease stage and length of follow-up, “the difference disappeared” (hazard ration, 0.87; 95% confidence interval, 0.73-1.04), authors of the meta-analysis reported.

Study patients who received entecavir tended to be “treated many years ago and tended to have more severe [baseline] disease,” Dr. Terrault said.

So “while we see this difference, there’s not enough data yet for us to make a recommendation for our patients to switch from” entecavir to tenofovir. “Until a randomized controlled trial is done, this may remain an issue,” she said.
 

A drug holiday?

Dr. Terrault also reviewed research that suggests nucleoside analogue treatment can be stopped in e-antigen–negative patients after at least 3 years.

“The evidence is increasing that a finite NA [nucleoside analogue] treatment approach leads to higher HBsAg [hepatitis B surface antigen] loss rates, compared with the current long-term NA strategy, and can be considered a rational strategy to induce a functional cure in selected HBeAg-negative patients without cirrhosis who are willing to comply with close follow-up monitoring. ... The current observed functional cure rates” – perhaps about 40% – “would be well worth the effort,” editorialists commenting on the research concluded (Hepatology. 2018 Aug;68[2]:397-400).

It’s an interesting idea, Dr. Terrault said, but the virus will flare 8-12 weeks after treatment withdrawal, which is why it shouldn’t be considered in patients with cirrhosis.

Dr. Terrault is a consultant for AbbVie, Merck, Gilead, and other companies and disclosed grants from those companies and others.

aotto@mdedge.com

MAUI, HAWAII – There might well be a cure for hepatitis B in coming years, just like there is now for hepatitis C, according to Norah Terrault, MD, chief of the division of GI and liver at the University of Southern California, Los Angeles.

M. Alexander Otto/MDedge News

“We are going to have a laundry list of new drugs” that are in the pipeline now. Phase 2 results “look encouraging. You will hear much more about this in the years ahead,” said Dr. Terrault, lead author of the 2018 American Association for the Study of Liver Diseases (AASLD) hepatitis B guidance.

For now, though, the field is largely limited to the nucleoside analogues tenofovir and entecavir. Treatment is often indefinite because, although hepatitis B virus (HBV) e-antigen is cleared, it usually doesn’t clear the HBV surface antigen, which is linked to liver cancer. “Even with e-antigen–negative patients, we feel that indefinite therapy is really the way to go,” Dr. Terrault said at the Gastroenterology Updates, IBD, Liver Disease Conference.

One of the biggest problems with that strategy is what to do when HBV does not seem to be much of a problem for carriers. Such patients are referred to as immune tolerant.
 

A newly recognized cancer risk

Immune tolerant patients tend to be young and have extremely high viral loads but no apparent ill effects, with normal ALT levels, normal histology, and no sign of cirrhosis. Although the AASLD recommends not treating these patients until they are 40 years old, waiting makes people nervous. “You have a hammer, you want to hit a nail,” Dr. Terrault said.

A recent review (Gut. 2018 May;67[5]:945-52) suggests that hitting the nail might be the way to go. South Korean investigators found that 413 untreated immune tolerate patients with a mean age of 38 years had more than twice the risk of liver cancer over 10 years than did almost 1,500 treated patients with active disease.

The study investigators concluded that “unnecessary deaths could be prevented through earlier antiviral intervention in select [immune tolerate] patients.”

This finding is one reason “we [AASLD] are rethinking the mantra of not treating the immune tolerant. There is a group that is transitioning” to active disease. “I’m thinking we should really [lower] the age cutoff” to 30 years, as some other groups [European Association for the Study of the Liver and Asian Pacific Association for the Study of the Liver] have done, plus “patients feel really good when they know the virus is controlled, and so do physicians,” Dr. Terrault said.
 

Entecavir versus tenofovir

Meanwhile, recent studies have raised the question of whether tenofovir is better than entecavir at preventing liver cancer.

A JAMA Oncology (JAMA Oncol. 2019 Jan 1;5[1]:30-6) study of some 25,000 patients in South Korea found a 32% lower risk of liver cancer when they were treated with tenofovir instead of entecavir. “This led to a lot of concern that maybe we should be moving all our patients to tenofovir,” she said.

Another study, a meta-analysis published earlier this year (Hepatol Int. 2020 Jan;14[1]:105-14), confirmed the difference in cancer risk when it combined those findings with other research. After adjustment for potential confounders, including disease stage and length of follow-up, “the difference disappeared” (hazard ration, 0.87; 95% confidence interval, 0.73-1.04), authors of the meta-analysis reported.

Study patients who received entecavir tended to be “treated many years ago and tended to have more severe [baseline] disease,” Dr. Terrault said.

So “while we see this difference, there’s not enough data yet for us to make a recommendation for our patients to switch from” entecavir to tenofovir. “Until a randomized controlled trial is done, this may remain an issue,” she said.
 

A drug holiday?

Dr. Terrault also reviewed research that suggests nucleoside analogue treatment can be stopped in e-antigen–negative patients after at least 3 years.

“The evidence is increasing that a finite NA [nucleoside analogue] treatment approach leads to higher HBsAg [hepatitis B surface antigen] loss rates, compared with the current long-term NA strategy, and can be considered a rational strategy to induce a functional cure in selected HBeAg-negative patients without cirrhosis who are willing to comply with close follow-up monitoring. ... The current observed functional cure rates” – perhaps about 40% – “would be well worth the effort,” editorialists commenting on the research concluded (Hepatology. 2018 Aug;68[2]:397-400).

It’s an interesting idea, Dr. Terrault said, but the virus will flare 8-12 weeks after treatment withdrawal, which is why it shouldn’t be considered in patients with cirrhosis.

Dr. Terrault is a consultant for AbbVie, Merck, Gilead, and other companies and disclosed grants from those companies and others.

aotto@mdedge.com

MAUI, HAWAII – There might well be a cure for hepatitis B in coming years, just like there is now for hepatitis C, according to Norah Terrault, MD, chief of the division of GI and liver at the University of Southern California, Los Angeles.

M. Alexander Otto/MDedge News

“We are going to have a laundry list of new drugs” that are in the pipeline now. Phase 2 results “look encouraging. You will hear much more about this in the years ahead,” said Dr. Terrault, lead author of the 2018 American Association for the Study of Liver Diseases (AASLD) hepatitis B guidance.

For now, though, the field is largely limited to the nucleoside analogues tenofovir and entecavir. Treatment is often indefinite because, although hepatitis B virus (HBV) e-antigen is cleared, it usually doesn’t clear the HBV surface antigen, which is linked to liver cancer. “Even with e-antigen–negative patients, we feel that indefinite therapy is really the way to go,” Dr. Terrault said at the Gastroenterology Updates, IBD, Liver Disease Conference.

One of the biggest problems with that strategy is what to do when HBV does not seem to be much of a problem for carriers. Such patients are referred to as immune tolerant.
 

A newly recognized cancer risk

Immune tolerant patients tend to be young and have extremely high viral loads but no apparent ill effects, with normal ALT levels, normal histology, and no sign of cirrhosis. Although the AASLD recommends not treating these patients until they are 40 years old, waiting makes people nervous. “You have a hammer, you want to hit a nail,” Dr. Terrault said.

A recent review (Gut. 2018 May;67[5]:945-52) suggests that hitting the nail might be the way to go. South Korean investigators found that 413 untreated immune tolerate patients with a mean age of 38 years had more than twice the risk of liver cancer over 10 years than did almost 1,500 treated patients with active disease.

The study investigators concluded that “unnecessary deaths could be prevented through earlier antiviral intervention in select [immune tolerate] patients.”

This finding is one reason “we [AASLD] are rethinking the mantra of not treating the immune tolerant. There is a group that is transitioning” to active disease. “I’m thinking we should really [lower] the age cutoff” to 30 years, as some other groups [European Association for the Study of the Liver and Asian Pacific Association for the Study of the Liver] have done, plus “patients feel really good when they know the virus is controlled, and so do physicians,” Dr. Terrault said.
 

Entecavir versus tenofovir

Meanwhile, recent studies have raised the question of whether tenofovir is better than entecavir at preventing liver cancer.

A JAMA Oncology (JAMA Oncol. 2019 Jan 1;5[1]:30-6) study of some 25,000 patients in South Korea found a 32% lower risk of liver cancer when they were treated with tenofovir instead of entecavir. “This led to a lot of concern that maybe we should be moving all our patients to tenofovir,” she said.

Another study, a meta-analysis published earlier this year (Hepatol Int. 2020 Jan;14[1]:105-14), confirmed the difference in cancer risk when it combined those findings with other research. After adjustment for potential confounders, including disease stage and length of follow-up, “the difference disappeared” (hazard ration, 0.87; 95% confidence interval, 0.73-1.04), authors of the meta-analysis reported.

Study patients who received entecavir tended to be “treated many years ago and tended to have more severe [baseline] disease,” Dr. Terrault said.

So “while we see this difference, there’s not enough data yet for us to make a recommendation for our patients to switch from” entecavir to tenofovir. “Until a randomized controlled trial is done, this may remain an issue,” she said.
 

A drug holiday?

Dr. Terrault also reviewed research that suggests nucleoside analogue treatment can be stopped in e-antigen–negative patients after at least 3 years.

“The evidence is increasing that a finite NA [nucleoside analogue] treatment approach leads to higher HBsAg [hepatitis B surface antigen] loss rates, compared with the current long-term NA strategy, and can be considered a rational strategy to induce a functional cure in selected HBeAg-negative patients without cirrhosis who are willing to comply with close follow-up monitoring. ... The current observed functional cure rates” – perhaps about 40% – “would be well worth the effort,” editorialists commenting on the research concluded (Hepatology. 2018 Aug;68[2]:397-400).

It’s an interesting idea, Dr. Terrault said, but the virus will flare 8-12 weeks after treatment withdrawal, which is why it shouldn’t be considered in patients with cirrhosis.

Dr. Terrault is a consultant for AbbVie, Merck, Gilead, and other companies and disclosed grants from those companies and others.

aotto@mdedge.com

Children exposed to macrolides during the first trimester of pregnancy had an increased risk of major malformations, compared with first-trimester penicillin exposure, according to an observational study.

Creatas Images

Use of antibiotics is common in pregnancy, and macrolides commonly are used if a penicillin allergy is reported.

Hypospadias and other genital malformations also were more likely with exposure during any trimester to macrolides, although this association lost significance when limited to the first trimester. The researchers did not identify any associations with macrolides exposure and neurodevelopmental disorders.

The observational study could not establish causality, but the researchers calculated an estimate of likely excess malformations if the association were found to be causal: “For every 1,000 mothers prescribed macrolides instead of penicillins during the first trimester, an additional 4.1 children would have cardiovascular malformations,” Heng Fan, a PhD student at the University College London, and colleagues wrote in the BMJ. “The corresponding figures for prescriptions during any trimester and genital malformations would be 1.7.”

The researchers used records from the U.K. Clinical Practice Research Datalink to analyze outcomes in 104,605 children born between 1990 and 2016 to mothers who received at least one prescription of erythromycin, clarithromycin, azithromycin, or penicillin monotherapy between their fourth week of pregnancy and delivery. Women prescribed any known teratogenic medications were excluded.

The majority of the mothers (92%) had been prescribed penicillin once, and 8% were prescribed a macrolide antibiotic once during pregnancy.

The researchers tallied and calculated the children’s risk of major malformations; cerebral palsy; epilepsy; ADHD; autism spectrum disorder; and any nervous, cardiovascular, gastrointestinal, genital, or urinary malformations. The children were tracked through a median 6 years of age.

In comparing risk of malformations or neurodevelopmental disorders among children, the researchers chose to compare exposure to macrolides and penicillin to reduce the likelihood of confounding by indication for infections. (They also included two negative control groups: unexposed siblings and women prescribed antibiotics before conception.) The authors acknowledged, however, that residual confounding still may occur “if macrolides were prescribed for specific indications (e.g., chlamydia), or when potential risk factors for malformations or neurodevelopmental outcomes differed between treatment groups.”

The overall rate of malformations was 22 per 1,000 children prenatally exposed to macrolides (28 in first trimester and 20 in second or third trimester) and 17 per 1,000 children prenatally exposed to penicillin. The risk and type of malformations varied, however, according to the trimester.

The researchers made adjustments to account for differences in a wide range of maternal factors: age at delivery, calendar year of delivery, alcohol misuse, illegal drug use, tobacco use, obesity, hypertension, diabetes, anxiety, depression, and epilepsy. They also adjusted for parity, multiples, and chronic medical treatments, as well as genitourinary tract infections or STIs during pregnancy, both of which are linked to preterm labor.

Compared with children exposed to penicillin during the first trimester of pregnancy, risk of malformations was 1.6 times greater in those exposed to macrolides in the first trimester (risk ratio, 1.55; 28 vs. 18 per 1,000). Erythromycin exposure in the first trimester also was linked to a 50% greater likelihood of any major malformation compared with penicillin (RR, 1.5; 27 vs. 18 per 1,000).

Cardiovascular malformations in particular were more likely in those exposed to macrolides (11 per 1,000), compared with penicillin (7 per 1,000) in the first trimester (RR, 1.62). Meanwhile, genital malformations, primarily hypospadias, occurred more frequently in children whose mothers were prescribed macrolides (5 per 1,000), compared with penicillin (3 per 1,000) in any trimester (RR, 1.58).

No increased risk of major malformations was associated with macrolides prescribed only in the second or third trimester, although a borderline significant association existed with gastrointestinal malformations. The authors also found no links between macrolides exposure and increased risk of cerebral palsy, epilepsy, ADHD, or autism spectrum disorder.

The findings did not change in several sensitivity analyses, including one that restricted analysis to antibiotics prescribed only for respiratory tract infections.

Dr. Fan and associates discussed several potential biological mechanisms for causation, including the arrhythmic effect of macrolides that may relate to cardiovascular malformations or contribute to fetal hypoxia. They noted that “macrolide prescribing during pregnancy warrants caution,” and recommend including on drug safety labels “that there is uncertainty about the safety of macrolides, including erythromycin” and alternative antibiotics should be used when possible.

Iris Krishna, MD, MPH, assistant professor of maternal-fetal medicine at Emory University, Atlanta, agreed with the study authors that use of macrolides in the first trimester warrants further investigation, and if an appropriate alternative antibiotic is available, then it should be preferentially considered when treating infections in the first trimester.

“However, if macrolides are the only treatment option, pregnant women can be reassured that the absolute risk of a birth defect is low, and this should not discourage them from taking a macrolide when needed as untreated infections pose a greater risk in pregnancy,” she said in an interview.

“This study does not establish that macrolide antibiotics cause birth defects, but it suggests a potential association. Previous studies examining the use of macrolides, such as erythromycin, have not demonstrated a consistent pattern of birth defects, and heart defects identified were classified as mostly mild. The authors suggest that the potential biologic mechanism based on rat models may be that macrolides might induce fetal cardiac arrhythmias and short-term fetal hypoxia. This study was underpowered to examine macrolide exposure for specific malformations. To avoid underpowered comparisons, the authors’ categorized malformations by organ systems, so the spectrum of cardiac defects is unclear,” commented Dr. Krishna, who also is a member of the Ob.Gyn. News editorial advisory board.

“Current recommendations for macrolide antibiotic use in pregnancy in the second and third trimester of pregnancy, and in particular when used for obstetric indications, such as prelabor rupture of membranes to prolong the latency period to delivery, should not be altered based on the findings of this study,” she concluded.

The research was funded by Child Health Research CIO Trust, the China Scholarship Council, Health Data Research UK, and the National Institute for Health Research. Dr. Fan and associates had no industry disclosures. Dr. Krishna had no relevant financial disclosures.

SOURCE: Fan H et al. BMJ. 2020;368:m331.

Children exposed to macrolides during the first trimester of pregnancy had an increased risk of major malformations, compared with first-trimester penicillin exposure, according to an observational study.

Creatas Images

Use of antibiotics is common in pregnancy, and macrolides commonly are used if a penicillin allergy is reported.

Hypospadias and other genital malformations also were more likely with exposure during any trimester to macrolides, although this association lost significance when limited to the first trimester. The researchers did not identify any associations with macrolides exposure and neurodevelopmental disorders.

The observational study could not establish causality, but the researchers calculated an estimate of likely excess malformations if the association were found to be causal: “For every 1,000 mothers prescribed macrolides instead of penicillins during the first trimester, an additional 4.1 children would have cardiovascular malformations,” Heng Fan, a PhD student at the University College London, and colleagues wrote in the BMJ. “The corresponding figures for prescriptions during any trimester and genital malformations would be 1.7.”

The researchers used records from the U.K. Clinical Practice Research Datalink to analyze outcomes in 104,605 children born between 1990 and 2016 to mothers who received at least one prescription of erythromycin, clarithromycin, azithromycin, or penicillin monotherapy between their fourth week of pregnancy and delivery. Women prescribed any known teratogenic medications were excluded.

The majority of the mothers (92%) had been prescribed penicillin once, and 8% were prescribed a macrolide antibiotic once during pregnancy.

The researchers tallied and calculated the children’s risk of major malformations; cerebral palsy; epilepsy; ADHD; autism spectrum disorder; and any nervous, cardiovascular, gastrointestinal, genital, or urinary malformations. The children were tracked through a median 6 years of age.

In comparing risk of malformations or neurodevelopmental disorders among children, the researchers chose to compare exposure to macrolides and penicillin to reduce the likelihood of confounding by indication for infections. (They also included two negative control groups: unexposed siblings and women prescribed antibiotics before conception.) The authors acknowledged, however, that residual confounding still may occur “if macrolides were prescribed for specific indications (e.g., chlamydia), or when potential risk factors for malformations or neurodevelopmental outcomes differed between treatment groups.”

The overall rate of malformations was 22 per 1,000 children prenatally exposed to macrolides (28 in first trimester and 20 in second or third trimester) and 17 per 1,000 children prenatally exposed to penicillin. The risk and type of malformations varied, however, according to the trimester.

The researchers made adjustments to account for differences in a wide range of maternal factors: age at delivery, calendar year of delivery, alcohol misuse, illegal drug use, tobacco use, obesity, hypertension, diabetes, anxiety, depression, and epilepsy. They also adjusted for parity, multiples, and chronic medical treatments, as well as genitourinary tract infections or STIs during pregnancy, both of which are linked to preterm labor.

Compared with children exposed to penicillin during the first trimester of pregnancy, risk of malformations was 1.6 times greater in those exposed to macrolides in the first trimester (risk ratio, 1.55; 28 vs. 18 per 1,000). Erythromycin exposure in the first trimester also was linked to a 50% greater likelihood of any major malformation compared with penicillin (RR, 1.5; 27 vs. 18 per 1,000).

Cardiovascular malformations in particular were more likely in those exposed to macrolides (11 per 1,000), compared with penicillin (7 per 1,000) in the first trimester (RR, 1.62). Meanwhile, genital malformations, primarily hypospadias, occurred more frequently in children whose mothers were prescribed macrolides (5 per 1,000), compared with penicillin (3 per 1,000) in any trimester (RR, 1.58).

No increased risk of major malformations was associated with macrolides prescribed only in the second or third trimester, although a borderline significant association existed with gastrointestinal malformations. The authors also found no links between macrolides exposure and increased risk of cerebral palsy, epilepsy, ADHD, or autism spectrum disorder.

The findings did not change in several sensitivity analyses, including one that restricted analysis to antibiotics prescribed only for respiratory tract infections.

Dr. Fan and associates discussed several potential biological mechanisms for causation, including the arrhythmic effect of macrolides that may relate to cardiovascular malformations or contribute to fetal hypoxia. They noted that “macrolide prescribing during pregnancy warrants caution,” and recommend including on drug safety labels “that there is uncertainty about the safety of macrolides, including erythromycin” and alternative antibiotics should be used when possible.

Iris Krishna, MD, MPH, assistant professor of maternal-fetal medicine at Emory University, Atlanta, agreed with the study authors that use of macrolides in the first trimester warrants further investigation, and if an appropriate alternative antibiotic is available, then it should be preferentially considered when treating infections in the first trimester.

“However, if macrolides are the only treatment option, pregnant women can be reassured that the absolute risk of a birth defect is low, and this should not discourage them from taking a macrolide when needed as untreated infections pose a greater risk in pregnancy,” she said in an interview.

“This study does not establish that macrolide antibiotics cause birth defects, but it suggests a potential association. Previous studies examining the use of macrolides, such as erythromycin, have not demonstrated a consistent pattern of birth defects, and heart defects identified were classified as mostly mild. The authors suggest that the potential biologic mechanism based on rat models may be that macrolides might induce fetal cardiac arrhythmias and short-term fetal hypoxia. This study was underpowered to examine macrolide exposure for specific malformations. To avoid underpowered comparisons, the authors’ categorized malformations by organ systems, so the spectrum of cardiac defects is unclear,” commented Dr. Krishna, who also is a member of the Ob.Gyn. News editorial advisory board.

“Current recommendations for macrolide antibiotic use in pregnancy in the second and third trimester of pregnancy, and in particular when used for obstetric indications, such as prelabor rupture of membranes to prolong the latency period to delivery, should not be altered based on the findings of this study,” she concluded.

The research was funded by Child Health Research CIO Trust, the China Scholarship Council, Health Data Research UK, and the National Institute for Health Research. Dr. Fan and associates had no industry disclosures. Dr. Krishna had no relevant financial disclosures.

SOURCE: Fan H et al. BMJ. 2020;368:m331.

Children exposed to macrolides during the first trimester of pregnancy had an increased risk of major malformations, compared with first-trimester penicillin exposure, according to an observational study.

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Use of antibiotics is common in pregnancy, and macrolides commonly are used if a penicillin allergy is reported.

Hypospadias and other genital malformations also were more likely with exposure during any trimester to macrolides, although this association lost significance when limited to the first trimester. The researchers did not identify any associations with macrolides exposure and neurodevelopmental disorders.

The observational study could not establish causality, but the researchers calculated an estimate of likely excess malformations if the association were found to be causal: “For every 1,000 mothers prescribed macrolides instead of penicillins during the first trimester, an additional 4.1 children would have cardiovascular malformations,” Heng Fan, a PhD student at the University College London, and colleagues wrote in the BMJ. “The corresponding figures for prescriptions during any trimester and genital malformations would be 1.7.”

The researchers used records from the U.K. Clinical Practice Research Datalink to analyze outcomes in 104,605 children born between 1990 and 2016 to mothers who received at least one prescription of erythromycin, clarithromycin, azithromycin, or penicillin monotherapy between their fourth week of pregnancy and delivery. Women prescribed any known teratogenic medications were excluded.

The majority of the mothers (92%) had been prescribed penicillin once, and 8% were prescribed a macrolide antibiotic once during pregnancy.

The researchers tallied and calculated the children’s risk of major malformations; cerebral palsy; epilepsy; ADHD; autism spectrum disorder; and any nervous, cardiovascular, gastrointestinal, genital, or urinary malformations. The children were tracked through a median 6 years of age.

In comparing risk of malformations or neurodevelopmental disorders among children, the researchers chose to compare exposure to macrolides and penicillin to reduce the likelihood of confounding by indication for infections. (They also included two negative control groups: unexposed siblings and women prescribed antibiotics before conception.) The authors acknowledged, however, that residual confounding still may occur “if macrolides were prescribed for specific indications (e.g., chlamydia), or when potential risk factors for malformations or neurodevelopmental outcomes differed between treatment groups.”

The overall rate of malformations was 22 per 1,000 children prenatally exposed to macrolides (28 in first trimester and 20 in second or third trimester) and 17 per 1,000 children prenatally exposed to penicillin. The risk and type of malformations varied, however, according to the trimester.

The researchers made adjustments to account for differences in a wide range of maternal factors: age at delivery, calendar year of delivery, alcohol misuse, illegal drug use, tobacco use, obesity, hypertension, diabetes, anxiety, depression, and epilepsy. They also adjusted for parity, multiples, and chronic medical treatments, as well as genitourinary tract infections or STIs during pregnancy, both of which are linked to preterm labor.

Compared with children exposed to penicillin during the first trimester of pregnancy, risk of malformations was 1.6 times greater in those exposed to macrolides in the first trimester (risk ratio, 1.55; 28 vs. 18 per 1,000). Erythromycin exposure in the first trimester also was linked to a 50% greater likelihood of any major malformation compared with penicillin (RR, 1.5; 27 vs. 18 per 1,000).

Cardiovascular malformations in particular were more likely in those exposed to macrolides (11 per 1,000), compared with penicillin (7 per 1,000) in the first trimester (RR, 1.62). Meanwhile, genital malformations, primarily hypospadias, occurred more frequently in children whose mothers were prescribed macrolides (5 per 1,000), compared with penicillin (3 per 1,000) in any trimester (RR, 1.58).

No increased risk of major malformations was associated with macrolides prescribed only in the second or third trimester, although a borderline significant association existed with gastrointestinal malformations. The authors also found no links between macrolides exposure and increased risk of cerebral palsy, epilepsy, ADHD, or autism spectrum disorder.

The findings did not change in several sensitivity analyses, including one that restricted analysis to antibiotics prescribed only for respiratory tract infections.

Dr. Fan and associates discussed several potential biological mechanisms for causation, including the arrhythmic effect of macrolides that may relate to cardiovascular malformations or contribute to fetal hypoxia. They noted that “macrolide prescribing during pregnancy warrants caution,” and recommend including on drug safety labels “that there is uncertainty about the safety of macrolides, including erythromycin” and alternative antibiotics should be used when possible.

Iris Krishna, MD, MPH, assistant professor of maternal-fetal medicine at Emory University, Atlanta, agreed with the study authors that use of macrolides in the first trimester warrants further investigation, and if an appropriate alternative antibiotic is available, then it should be preferentially considered when treating infections in the first trimester.

“However, if macrolides are the only treatment option, pregnant women can be reassured that the absolute risk of a birth defect is low, and this should not discourage them from taking a macrolide when needed as untreated infections pose a greater risk in pregnancy,” she said in an interview.

“This study does not establish that macrolide antibiotics cause birth defects, but it suggests a potential association. Previous studies examining the use of macrolides, such as erythromycin, have not demonstrated a consistent pattern of birth defects, and heart defects identified were classified as mostly mild. The authors suggest that the potential biologic mechanism based on rat models may be that macrolides might induce fetal cardiac arrhythmias and short-term fetal hypoxia. This study was underpowered to examine macrolide exposure for specific malformations. To avoid underpowered comparisons, the authors’ categorized malformations by organ systems, so the spectrum of cardiac defects is unclear,” commented Dr. Krishna, who also is a member of the Ob.Gyn. News editorial advisory board.

“Current recommendations for macrolide antibiotic use in pregnancy in the second and third trimester of pregnancy, and in particular when used for obstetric indications, such as prelabor rupture of membranes to prolong the latency period to delivery, should not be altered based on the findings of this study,” she concluded.

The research was funded by Child Health Research CIO Trust, the China Scholarship Council, Health Data Research UK, and the National Institute for Health Research. Dr. Fan and associates had no industry disclosures. Dr. Krishna had no relevant financial disclosures.

SOURCE: Fan H et al. BMJ. 2020;368:m331.

The U.S. Preventive Services Task Force has deemed the current evidence “insufficient” to make a recommendation in regard to screening for cognitive impairment in adults aged 65 years or older.

“More research is needed on the effect of screening and early detection of cognitive impairment on important patient, caregiver, and societal outcomes, including decision making, advance planning, and caregiver outcomes,” wrote lead author Douglas K. Owens, MD, of Stanford (Calif.) University and fellow members of the task force. The statement was published in JAMA.

To update a 2014 recommendation from the USPSTF, which also found insufficient evidence to properly assess cognitive screening’s benefits and harms, the task force commissioned a systematic review of studies applicable to community-dwelling older adults who are not exhibiting signs or symptoms of cognitive impairment. For their statement, “cognitive impairment” is defined as mild cognitive impairment and mild to moderate dementia.

Ultimately, they determined several factors that limited the overall evidence, including the short duration of most trials and the heterogenous nature of interventions and inconsistencies in outcomes reported. Any evidence that suggested improvements was mostly applicable to patients with moderate dementia, meaning “its applicability to a screen-detected population is uncertain.”
 

Updating 2014 recommendations

Their statement was based on an evidence report, also published in JAMA, in which a team of researchers reviewed 287 studies that included more than 285,000 older adults; 92 of the studies were newly identified, while the other 195 were carried forward from the 2014 recommendation’s review. The researchers sought the answers to five key questions, carrying over the framework from the previous review.

“Despite the accumulation of new data, the conclusions for these key questions are essentially unchanged from the prior review,” wrote lead author Carrie D. Patnode, PhD, of the Kaiser Permanente Center for Health Research in Portland, Ore., and coauthors.

Of the questions – which concerned the accuracy of screening instruments; the harms of screening; the harms of interventions; and if screening or interventions improved decision making or outcomes for the patient, family/caregiver, or society – moderate evidence was found to support the accuracy of the instruments, treatment with acetylcholinesterase inhibitors and memantine for patients with moderate dementia, and psychoeducation interventions for caregivers of patients with moderate dementia. At the same time, there was moderate evidence of adverse effects from acetylcholinesterase inhibitors and memantine in patients with moderate dementia.

“I think, eventually, there will be sufficient evidence to justify screening, once we have what I call a tiered approach,” Marwan Sabbagh, MD, of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, said in an interview. “The very near future will include blood tests for Alzheimer’s, or PET scans, or genetics, or something else. Right now, the cognitive screens lack the specificity and sensitivity, and the secondary screening infrastructure that would improve the accuracy doesn’t exist yet.

“I think this is a ‘not now,’ ” he added, “but I wouldn’t say ‘not ever.’ ”

Dr. Patnode and coauthors noted specific limitations in the evidence, including a lack of studies on how screening for and treating cognitive impairment affects decision making. In addition, details like quality of life and institutionalization were inconsistently reported, and “consistent and standardized reporting of results according to meaningful thresholds of clinical significance” would have been valuable across all measures.
 

Clinical implications

The implications of this report’s conclusions are substantial, especially as the rising prevalence of mild cognitive impairment and dementia becomes a worldwide concern, wrote Ronald C. Petersen, PhD, MD, of the Mayo Clinic in Rochester, Minn., and Kristine Yaffe, MD, of the University of California, San Francisco, in an accompanying editorial.

Though the data does not explicitly support screening, Dr. Petersen and Dr. Yaffe noted that it still may have benefits. An estimated 10% of cognitive impairment is caused by at least somewhat reversible causes, and screening could also be used to improve care in medical problems that are worsened by cognitive impairment. To find the true value of these efforts, they wrote, researchers need to design and execute additional clinical trials that “answer many of the important questions surrounding screening and treatment of cognitive impairment.”

“The absence of evidence for benefit may lead to inaction,” they added, noting that clinicians screening should still consider the value of screening on a case-by-case basis in order to keep up with the impact of new disease-modifying therapies for certain neurodegenerative diseases.

All members of the USPSTF received travel reimbursement and an honorarium for participating in meetings. One member reported receiving grants and personal fees from Healthwise. The study was funded by the Department of Health & Human Services. One of the authors reported receiving grants from the National Institutes of Health and the Food and Drug Administration. Dr. Petersen and Dr. Yaffe reported consulting for, and receiving funding from, various pharmaceutical companies, foundations, and government organizations.

SOURCES: Owens DK et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2020.0435; Patnode CD et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2019.22258.

The U.S. Preventive Services Task Force has deemed the current evidence “insufficient” to make a recommendation in regard to screening for cognitive impairment in adults aged 65 years or older.

“More research is needed on the effect of screening and early detection of cognitive impairment on important patient, caregiver, and societal outcomes, including decision making, advance planning, and caregiver outcomes,” wrote lead author Douglas K. Owens, MD, of Stanford (Calif.) University and fellow members of the task force. The statement was published in JAMA.

To update a 2014 recommendation from the USPSTF, which also found insufficient evidence to properly assess cognitive screening’s benefits and harms, the task force commissioned a systematic review of studies applicable to community-dwelling older adults who are not exhibiting signs or symptoms of cognitive impairment. For their statement, “cognitive impairment” is defined as mild cognitive impairment and mild to moderate dementia.

Ultimately, they determined several factors that limited the overall evidence, including the short duration of most trials and the heterogenous nature of interventions and inconsistencies in outcomes reported. Any evidence that suggested improvements was mostly applicable to patients with moderate dementia, meaning “its applicability to a screen-detected population is uncertain.”
 

Updating 2014 recommendations

Their statement was based on an evidence report, also published in JAMA, in which a team of researchers reviewed 287 studies that included more than 285,000 older adults; 92 of the studies were newly identified, while the other 195 were carried forward from the 2014 recommendation’s review. The researchers sought the answers to five key questions, carrying over the framework from the previous review.

“Despite the accumulation of new data, the conclusions for these key questions are essentially unchanged from the prior review,” wrote lead author Carrie D. Patnode, PhD, of the Kaiser Permanente Center for Health Research in Portland, Ore., and coauthors.

Of the questions – which concerned the accuracy of screening instruments; the harms of screening; the harms of interventions; and if screening or interventions improved decision making or outcomes for the patient, family/caregiver, or society – moderate evidence was found to support the accuracy of the instruments, treatment with acetylcholinesterase inhibitors and memantine for patients with moderate dementia, and psychoeducation interventions for caregivers of patients with moderate dementia. At the same time, there was moderate evidence of adverse effects from acetylcholinesterase inhibitors and memantine in patients with moderate dementia.

“I think, eventually, there will be sufficient evidence to justify screening, once we have what I call a tiered approach,” Marwan Sabbagh, MD, of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, said in an interview. “The very near future will include blood tests for Alzheimer’s, or PET scans, or genetics, or something else. Right now, the cognitive screens lack the specificity and sensitivity, and the secondary screening infrastructure that would improve the accuracy doesn’t exist yet.

“I think this is a ‘not now,’ ” he added, “but I wouldn’t say ‘not ever.’ ”

Dr. Patnode and coauthors noted specific limitations in the evidence, including a lack of studies on how screening for and treating cognitive impairment affects decision making. In addition, details like quality of life and institutionalization were inconsistently reported, and “consistent and standardized reporting of results according to meaningful thresholds of clinical significance” would have been valuable across all measures.
 

Clinical implications

The implications of this report’s conclusions are substantial, especially as the rising prevalence of mild cognitive impairment and dementia becomes a worldwide concern, wrote Ronald C. Petersen, PhD, MD, of the Mayo Clinic in Rochester, Minn., and Kristine Yaffe, MD, of the University of California, San Francisco, in an accompanying editorial.

Though the data does not explicitly support screening, Dr. Petersen and Dr. Yaffe noted that it still may have benefits. An estimated 10% of cognitive impairment is caused by at least somewhat reversible causes, and screening could also be used to improve care in medical problems that are worsened by cognitive impairment. To find the true value of these efforts, they wrote, researchers need to design and execute additional clinical trials that “answer many of the important questions surrounding screening and treatment of cognitive impairment.”

“The absence of evidence for benefit may lead to inaction,” they added, noting that clinicians screening should still consider the value of screening on a case-by-case basis in order to keep up with the impact of new disease-modifying therapies for certain neurodegenerative diseases.

All members of the USPSTF received travel reimbursement and an honorarium for participating in meetings. One member reported receiving grants and personal fees from Healthwise. The study was funded by the Department of Health & Human Services. One of the authors reported receiving grants from the National Institutes of Health and the Food and Drug Administration. Dr. Petersen and Dr. Yaffe reported consulting for, and receiving funding from, various pharmaceutical companies, foundations, and government organizations.

SOURCES: Owens DK et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2020.0435; Patnode CD et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2019.22258.

The U.S. Preventive Services Task Force has deemed the current evidence “insufficient” to make a recommendation in regard to screening for cognitive impairment in adults aged 65 years or older.

“More research is needed on the effect of screening and early detection of cognitive impairment on important patient, caregiver, and societal outcomes, including decision making, advance planning, and caregiver outcomes,” wrote lead author Douglas K. Owens, MD, of Stanford (Calif.) University and fellow members of the task force. The statement was published in JAMA.

To update a 2014 recommendation from the USPSTF, which also found insufficient evidence to properly assess cognitive screening’s benefits and harms, the task force commissioned a systematic review of studies applicable to community-dwelling older adults who are not exhibiting signs or symptoms of cognitive impairment. For their statement, “cognitive impairment” is defined as mild cognitive impairment and mild to moderate dementia.

Ultimately, they determined several factors that limited the overall evidence, including the short duration of most trials and the heterogenous nature of interventions and inconsistencies in outcomes reported. Any evidence that suggested improvements was mostly applicable to patients with moderate dementia, meaning “its applicability to a screen-detected population is uncertain.”
 

Updating 2014 recommendations

Their statement was based on an evidence report, also published in JAMA, in which a team of researchers reviewed 287 studies that included more than 285,000 older adults; 92 of the studies were newly identified, while the other 195 were carried forward from the 2014 recommendation’s review. The researchers sought the answers to five key questions, carrying over the framework from the previous review.

“Despite the accumulation of new data, the conclusions for these key questions are essentially unchanged from the prior review,” wrote lead author Carrie D. Patnode, PhD, of the Kaiser Permanente Center for Health Research in Portland, Ore., and coauthors.

Of the questions – which concerned the accuracy of screening instruments; the harms of screening; the harms of interventions; and if screening or interventions improved decision making or outcomes for the patient, family/caregiver, or society – moderate evidence was found to support the accuracy of the instruments, treatment with acetylcholinesterase inhibitors and memantine for patients with moderate dementia, and psychoeducation interventions for caregivers of patients with moderate dementia. At the same time, there was moderate evidence of adverse effects from acetylcholinesterase inhibitors and memantine in patients with moderate dementia.

“I think, eventually, there will be sufficient evidence to justify screening, once we have what I call a tiered approach,” Marwan Sabbagh, MD, of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, said in an interview. “The very near future will include blood tests for Alzheimer’s, or PET scans, or genetics, or something else. Right now, the cognitive screens lack the specificity and sensitivity, and the secondary screening infrastructure that would improve the accuracy doesn’t exist yet.

“I think this is a ‘not now,’ ” he added, “but I wouldn’t say ‘not ever.’ ”

Dr. Patnode and coauthors noted specific limitations in the evidence, including a lack of studies on how screening for and treating cognitive impairment affects decision making. In addition, details like quality of life and institutionalization were inconsistently reported, and “consistent and standardized reporting of results according to meaningful thresholds of clinical significance” would have been valuable across all measures.
 

Clinical implications

The implications of this report’s conclusions are substantial, especially as the rising prevalence of mild cognitive impairment and dementia becomes a worldwide concern, wrote Ronald C. Petersen, PhD, MD, of the Mayo Clinic in Rochester, Minn., and Kristine Yaffe, MD, of the University of California, San Francisco, in an accompanying editorial.

Though the data does not explicitly support screening, Dr. Petersen and Dr. Yaffe noted that it still may have benefits. An estimated 10% of cognitive impairment is caused by at least somewhat reversible causes, and screening could also be used to improve care in medical problems that are worsened by cognitive impairment. To find the true value of these efforts, they wrote, researchers need to design and execute additional clinical trials that “answer many of the important questions surrounding screening and treatment of cognitive impairment.”

“The absence of evidence for benefit may lead to inaction,” they added, noting that clinicians screening should still consider the value of screening on a case-by-case basis in order to keep up with the impact of new disease-modifying therapies for certain neurodegenerative diseases.

All members of the USPSTF received travel reimbursement and an honorarium for participating in meetings. One member reported receiving grants and personal fees from Healthwise. The study was funded by the Department of Health & Human Services. One of the authors reported receiving grants from the National Institutes of Health and the Food and Drug Administration. Dr. Petersen and Dr. Yaffe reported consulting for, and receiving funding from, various pharmaceutical companies, foundations, and government organizations.

SOURCES: Owens DK et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2020.0435; Patnode CD et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2019.22258.