The COVID-19 pandemic has, like it or not, made experimental labs rats out of us all.

Since the U.S. “shutdown” began in March, we have all had to adjust to a situation in which we are home more, stuck seeing less of our friends, exercising less, often eating and drinking more, or using recreational substances more – in part because of the severe stress. We have been ripped away from many of the social “anchors” of our weeks; that is, the spiritual, social and physical, and tactile supports that sustain and motivate us in our lives.

And yet, many of us, of all ages, stripes, and colors are thriving. Why is that so? Without necessarily being fully fledged, card carrying misanthropes, many of us are actually not bereft when forced to spend some alone time.

CANCER CIFTCI/Getty Images

We may be self-starters and have hobbies and interests that we may have neglected but can fall back on with alacrity. Activities such as gardening, cooking, reading, working at our day jobs, listening to music, streaming TV, and so on are now more available to us.

The pandemic has produced unforeseen side effects, such as decreased pollution, less seismic “noise” on our planet, increasingly bold activity by wild life, and we can actually hear bird songs in our yards. Likewise, the social isolation has enabled us to focus more on “back burner” projects and to motivate us toward accessing and achieving other internally driven goals.

Also, to many, it has provided a surprising and unexpected privilege to meaningfully connect while in close quarters with spouses, children, and other loved ones, which has improved and cemented relationships under some level of duress, perhaps.

Similarly, and perhaps surprisingly, in addition to the above reasons, many of our patients with chronic mental illness may be functioning reasonably well, too, even better than their “walking wounded” loved ones and peers. They may be reaping the rewards of many years of consistent biopsychosocial support in strong mental health programs.

But another reason might be the lowered expectations. As one stable patient with schizophrenia said, “No one is hassling me now; no one is aggravating me to go to this group or that, to leave the house to volunteer, to get a job. I’m just so much more relaxed; I’ve got this.” And certainly the Freudian “schadenfreude” defense has something to do with this as well. Seeing family members lose their jobs, become financially vulnerable, being unable to or stymied from demonstrating mastery in many different situations and skill sets elicit the empathy and galvanizes the support of well-managed patients with mental illness – already used to existential threats – for their generally higher functioning loved ones.

As one of my struggling patients said, “Welcome to my world!” Years of hardship, lack of intimate relationships because of social anxiety, and psychotic level obsessive-compulsive disorder have trained, indeed, inured her to the daily pain, constriction, and misery of social isolation. Her life, despite working full time, has remained static, while younger siblings have married, started a family, moved away. She is still living at home with her elderly parents. They now worry about catching COVID-19, while she is now their protector with roles reversed, doing their shopping, and providing moral support and encouragement for the whole family.

Many of us have lost jobs, been furloughed, seen our dreams disappear, and are unable to pay rent or mortgages. Those with chronic mental illness, especially those living in states with a strong social safety net, are continuing to receive their Social Security disability checks, and maintain their in-home health and family supports. They also have continued their adherence with the mental health system structure by continuing with telemedicine therapy and regular medications or monthly intramuscular shots. Their families are especially cognizant of the need for ongoing structure and stability, which is now easier to provide. And what of those patients who endured severe anxiety and panic disorders in their prepandemic states? It is true that many do require higher doses of their anxiolytics, especially benzodiazepines. They do know how to “roll with the punches” with their lifetime experience, as opposed to the “newbies” whose incipient anxiety is brought to the forefront and who might not even recognize these debilitating symptoms and are not keen, for reasons of stigma, to be seen by a mental health expert unless compelled to.

It is up to us as psychiatrists and other mental health clinicians to minimize dependence on those medications by using alternative non–dependence-forming anxiolytics and encouraging our patients to hone and develop the skills from cognitive-behavioral therapy. COVID-19 is just one more stressor, superimposed on many others, and unlikely to precipitate any “tipping point” in functioning, even if there are significant losses among loved ones to the virus.

How about our child and adolescent patients? As a rule of thumb, those with anxiety disorders, social anxiety, selective mutism – and those experiencing challenges and bullying in the rough and tumble world of schools – are doing significantly better. Those with ADHD and impulse control disorders, however, might be struggling with school, especially with Zoom calls and very high distractibility, boredom, and motivational challenges. They may need their doses of medications adjusted up, and their parents are struggling. The risk for unwitnessed and unmonitored abuse in home situations is higher.

Those with chronic mental illness often do have increased risk factors for COVID-19 that might be compounded by their psychopharmacologic treatment for conditions/behaviors such as diabetes, obesity, cardiovascular disease, and substance use. By proactively monitoring those comorbid disorders in a multimodal treatment program, we can help mitigate those baseline challenges.

This aspect of the COVID-19 pandemic is, alas, likely to prove to be an illusory positive “blip” on the radar screen for many with chronic mental illness. Nevertheless, the self-knowledge and awareness of hidden strengths rather than weakness, resilience rather than shrinking from challenges, is not insignificant. This “flight into normality” may be a change that can be internalized and nurtured once vaccines are available and life on planet Earth returns to a new normal.
 

Dr. Tofler is affiliated with Kaiser Permanente Psychiatry in Los Angeles. He also is a visiting faculty member in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles. Dr. Tofler has no conflicts of interest.

The COVID-19 pandemic has, like it or not, made experimental labs rats out of us all.

Since the U.S. “shutdown” began in March, we have all had to adjust to a situation in which we are home more, stuck seeing less of our friends, exercising less, often eating and drinking more, or using recreational substances more – in part because of the severe stress. We have been ripped away from many of the social “anchors” of our weeks; that is, the spiritual, social and physical, and tactile supports that sustain and motivate us in our lives.

And yet, many of us, of all ages, stripes, and colors are thriving. Why is that so? Without necessarily being fully fledged, card carrying misanthropes, many of us are actually not bereft when forced to spend some alone time.

CANCER CIFTCI/Getty Images

We may be self-starters and have hobbies and interests that we may have neglected but can fall back on with alacrity. Activities such as gardening, cooking, reading, working at our day jobs, listening to music, streaming TV, and so on are now more available to us.

The pandemic has produced unforeseen side effects, such as decreased pollution, less seismic “noise” on our planet, increasingly bold activity by wild life, and we can actually hear bird songs in our yards. Likewise, the social isolation has enabled us to focus more on “back burner” projects and to motivate us toward accessing and achieving other internally driven goals.

Also, to many, it has provided a surprising and unexpected privilege to meaningfully connect while in close quarters with spouses, children, and other loved ones, which has improved and cemented relationships under some level of duress, perhaps.

Similarly, and perhaps surprisingly, in addition to the above reasons, many of our patients with chronic mental illness may be functioning reasonably well, too, even better than their “walking wounded” loved ones and peers. They may be reaping the rewards of many years of consistent biopsychosocial support in strong mental health programs.

But another reason might be the lowered expectations. As one stable patient with schizophrenia said, “No one is hassling me now; no one is aggravating me to go to this group or that, to leave the house to volunteer, to get a job. I’m just so much more relaxed; I’ve got this.” And certainly the Freudian “schadenfreude” defense has something to do with this as well. Seeing family members lose their jobs, become financially vulnerable, being unable to or stymied from demonstrating mastery in many different situations and skill sets elicit the empathy and galvanizes the support of well-managed patients with mental illness – already used to existential threats – for their generally higher functioning loved ones.

As one of my struggling patients said, “Welcome to my world!” Years of hardship, lack of intimate relationships because of social anxiety, and psychotic level obsessive-compulsive disorder have trained, indeed, inured her to the daily pain, constriction, and misery of social isolation. Her life, despite working full time, has remained static, while younger siblings have married, started a family, moved away. She is still living at home with her elderly parents. They now worry about catching COVID-19, while she is now their protector with roles reversed, doing their shopping, and providing moral support and encouragement for the whole family.

Many of us have lost jobs, been furloughed, seen our dreams disappear, and are unable to pay rent or mortgages. Those with chronic mental illness, especially those living in states with a strong social safety net, are continuing to receive their Social Security disability checks, and maintain their in-home health and family supports. They also have continued their adherence with the mental health system structure by continuing with telemedicine therapy and regular medications or monthly intramuscular shots. Their families are especially cognizant of the need for ongoing structure and stability, which is now easier to provide. And what of those patients who endured severe anxiety and panic disorders in their prepandemic states? It is true that many do require higher doses of their anxiolytics, especially benzodiazepines. They do know how to “roll with the punches” with their lifetime experience, as opposed to the “newbies” whose incipient anxiety is brought to the forefront and who might not even recognize these debilitating symptoms and are not keen, for reasons of stigma, to be seen by a mental health expert unless compelled to.

It is up to us as psychiatrists and other mental health clinicians to minimize dependence on those medications by using alternative non–dependence-forming anxiolytics and encouraging our patients to hone and develop the skills from cognitive-behavioral therapy. COVID-19 is just one more stressor, superimposed on many others, and unlikely to precipitate any “tipping point” in functioning, even if there are significant losses among loved ones to the virus.

How about our child and adolescent patients? As a rule of thumb, those with anxiety disorders, social anxiety, selective mutism – and those experiencing challenges and bullying in the rough and tumble world of schools – are doing significantly better. Those with ADHD and impulse control disorders, however, might be struggling with school, especially with Zoom calls and very high distractibility, boredom, and motivational challenges. They may need their doses of medications adjusted up, and their parents are struggling. The risk for unwitnessed and unmonitored abuse in home situations is higher.

Those with chronic mental illness often do have increased risk factors for COVID-19 that might be compounded by their psychopharmacologic treatment for conditions/behaviors such as diabetes, obesity, cardiovascular disease, and substance use. By proactively monitoring those comorbid disorders in a multimodal treatment program, we can help mitigate those baseline challenges.

This aspect of the COVID-19 pandemic is, alas, likely to prove to be an illusory positive “blip” on the radar screen for many with chronic mental illness. Nevertheless, the self-knowledge and awareness of hidden strengths rather than weakness, resilience rather than shrinking from challenges, is not insignificant. This “flight into normality” may be a change that can be internalized and nurtured once vaccines are available and life on planet Earth returns to a new normal.
 

Dr. Tofler is affiliated with Kaiser Permanente Psychiatry in Los Angeles. He also is a visiting faculty member in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles. Dr. Tofler has no conflicts of interest.

The COVID-19 pandemic has, like it or not, made experimental labs rats out of us all.

Since the U.S. “shutdown” began in March, we have all had to adjust to a situation in which we are home more, stuck seeing less of our friends, exercising less, often eating and drinking more, or using recreational substances more – in part because of the severe stress. We have been ripped away from many of the social “anchors” of our weeks; that is, the spiritual, social and physical, and tactile supports that sustain and motivate us in our lives.

And yet, many of us, of all ages, stripes, and colors are thriving. Why is that so? Without necessarily being fully fledged, card carrying misanthropes, many of us are actually not bereft when forced to spend some alone time.

CANCER CIFTCI/Getty Images

We may be self-starters and have hobbies and interests that we may have neglected but can fall back on with alacrity. Activities such as gardening, cooking, reading, working at our day jobs, listening to music, streaming TV, and so on are now more available to us.

The pandemic has produced unforeseen side effects, such as decreased pollution, less seismic “noise” on our planet, increasingly bold activity by wild life, and we can actually hear bird songs in our yards. Likewise, the social isolation has enabled us to focus more on “back burner” projects and to motivate us toward accessing and achieving other internally driven goals.

Also, to many, it has provided a surprising and unexpected privilege to meaningfully connect while in close quarters with spouses, children, and other loved ones, which has improved and cemented relationships under some level of duress, perhaps.

Similarly, and perhaps surprisingly, in addition to the above reasons, many of our patients with chronic mental illness may be functioning reasonably well, too, even better than their “walking wounded” loved ones and peers. They may be reaping the rewards of many years of consistent biopsychosocial support in strong mental health programs.

But another reason might be the lowered expectations. As one stable patient with schizophrenia said, “No one is hassling me now; no one is aggravating me to go to this group or that, to leave the house to volunteer, to get a job. I’m just so much more relaxed; I’ve got this.” And certainly the Freudian “schadenfreude” defense has something to do with this as well. Seeing family members lose their jobs, become financially vulnerable, being unable to or stymied from demonstrating mastery in many different situations and skill sets elicit the empathy and galvanizes the support of well-managed patients with mental illness – already used to existential threats – for their generally higher functioning loved ones.

As one of my struggling patients said, “Welcome to my world!” Years of hardship, lack of intimate relationships because of social anxiety, and psychotic level obsessive-compulsive disorder have trained, indeed, inured her to the daily pain, constriction, and misery of social isolation. Her life, despite working full time, has remained static, while younger siblings have married, started a family, moved away. She is still living at home with her elderly parents. They now worry about catching COVID-19, while she is now their protector with roles reversed, doing their shopping, and providing moral support and encouragement for the whole family.

Many of us have lost jobs, been furloughed, seen our dreams disappear, and are unable to pay rent or mortgages. Those with chronic mental illness, especially those living in states with a strong social safety net, are continuing to receive their Social Security disability checks, and maintain their in-home health and family supports. They also have continued their adherence with the mental health system structure by continuing with telemedicine therapy and regular medications or monthly intramuscular shots. Their families are especially cognizant of the need for ongoing structure and stability, which is now easier to provide. And what of those patients who endured severe anxiety and panic disorders in their prepandemic states? It is true that many do require higher doses of their anxiolytics, especially benzodiazepines. They do know how to “roll with the punches” with their lifetime experience, as opposed to the “newbies” whose incipient anxiety is brought to the forefront and who might not even recognize these debilitating symptoms and are not keen, for reasons of stigma, to be seen by a mental health expert unless compelled to.

It is up to us as psychiatrists and other mental health clinicians to minimize dependence on those medications by using alternative non–dependence-forming anxiolytics and encouraging our patients to hone and develop the skills from cognitive-behavioral therapy. COVID-19 is just one more stressor, superimposed on many others, and unlikely to precipitate any “tipping point” in functioning, even if there are significant losses among loved ones to the virus.

How about our child and adolescent patients? As a rule of thumb, those with anxiety disorders, social anxiety, selective mutism – and those experiencing challenges and bullying in the rough and tumble world of schools – are doing significantly better. Those with ADHD and impulse control disorders, however, might be struggling with school, especially with Zoom calls and very high distractibility, boredom, and motivational challenges. They may need their doses of medications adjusted up, and their parents are struggling. The risk for unwitnessed and unmonitored abuse in home situations is higher.

Those with chronic mental illness often do have increased risk factors for COVID-19 that might be compounded by their psychopharmacologic treatment for conditions/behaviors such as diabetes, obesity, cardiovascular disease, and substance use. By proactively monitoring those comorbid disorders in a multimodal treatment program, we can help mitigate those baseline challenges.

This aspect of the COVID-19 pandemic is, alas, likely to prove to be an illusory positive “blip” on the radar screen for many with chronic mental illness. Nevertheless, the self-knowledge and awareness of hidden strengths rather than weakness, resilience rather than shrinking from challenges, is not insignificant. This “flight into normality” may be a change that can be internalized and nurtured once vaccines are available and life on planet Earth returns to a new normal.
 

Dr. Tofler is affiliated with Kaiser Permanente Psychiatry in Los Angeles. He also is a visiting faculty member in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles. Dr. Tofler has no conflicts of interest.

Three over-the-counter antihistamines, clemastine, desloratadine, and loratadine, preferentially induce cell death through lysosomal membrane permeabilization in chronic lymphocytic leukemia cells, compared with normal lymphocytes, according to the results of an in vitro study published in Leukemia Research.

In addition, the antihistamines showed a synergistic effect in killing off chronic lymphocytic leukemia (CLL) cells when combined with the tyrosine kinase inhibitor, ibrutinib, but not with chemotherapy, according to Aaron Chanas-Larue of CancerCare Manitoba, Winnipeg, Man., and colleagues.

Blood from CLL patients and age-matched healthy donors was collected, treated, and compared with two malignant B-cell lines. Cells were treated with the three different antihistamines at various concentrations alone and in the presence of ibrutinib. Cell death was determined by flow cytometry using fluorescent staining and EC50 (half-maximal effective concentration) values were calculated.

Of the three drugs, clemastine demonstrated the greatest degree of cytotoxicity, with a mean EC50 value of 12.3 mcmol in CLL cells. Desloratadine and loratadine also had a greater effect on leukemic cells, with mean EC50 values of 27.2 mcmol and 17.2 mcmol, respectively, according to the researchers.

Clemastine also showed the greatest tumor sensitivity, with an EC50 nearly three times lower for CLL cells (EC50, 12.3 mcmol) than for normal peripheral blood mononuclear cells (EC50, 32 mcmol). In addition, clemastine induced cell death over a 72-hour time course in CLL cells, and was equally effective against CLL cells with del17p, unmutated immunoglobulin heavy chain gene, or high Zeta-chain–associated protein kinase 70 expression.
 

Effective synergy

The researchers found that clemastine enhanced cell death when combined with targeted CLL therapies ibrutinib, idelalisib, or venetoclax, but did not enhance the activities of the chemotherapeutics fludarabine, chlorambucil, or bendamustine.

Ibrutinib increased cell death to the greatest degree when combined with antihistamines. The effect was demonstrated to be synergistic, showing “a unique interaction between the activities of the antihistamines and this inhibitor of the B-cell pathway, suggesting a clinical potential for this combination,” the authors stated.

“Repurposing well-characterized drugs such as antihistamines with defined mechanisms and toxicities allows for repositioning of these drugs to use in CLL treatment in the near future in the context of targeted therapies,” they concluded.

The study was supported by grants from the Cancer Research Society and the CancerCare Manitoba Foundation. The authors reported that they had no conflicts.

mlesney@mdedge.com

SOURCE: Chanas-Larue A et al. Leuk Res. 2020 Jul 17. doi: 10.1016/j.leukres.2020.106423.

Three over-the-counter antihistamines, clemastine, desloratadine, and loratadine, preferentially induce cell death through lysosomal membrane permeabilization in chronic lymphocytic leukemia cells, compared with normal lymphocytes, according to the results of an in vitro study published in Leukemia Research.

In addition, the antihistamines showed a synergistic effect in killing off chronic lymphocytic leukemia (CLL) cells when combined with the tyrosine kinase inhibitor, ibrutinib, but not with chemotherapy, according to Aaron Chanas-Larue of CancerCare Manitoba, Winnipeg, Man., and colleagues.

Blood from CLL patients and age-matched healthy donors was collected, treated, and compared with two malignant B-cell lines. Cells were treated with the three different antihistamines at various concentrations alone and in the presence of ibrutinib. Cell death was determined by flow cytometry using fluorescent staining and EC50 (half-maximal effective concentration) values were calculated.

Of the three drugs, clemastine demonstrated the greatest degree of cytotoxicity, with a mean EC50 value of 12.3 mcmol in CLL cells. Desloratadine and loratadine also had a greater effect on leukemic cells, with mean EC50 values of 27.2 mcmol and 17.2 mcmol, respectively, according to the researchers.

Clemastine also showed the greatest tumor sensitivity, with an EC50 nearly three times lower for CLL cells (EC50, 12.3 mcmol) than for normal peripheral blood mononuclear cells (EC50, 32 mcmol). In addition, clemastine induced cell death over a 72-hour time course in CLL cells, and was equally effective against CLL cells with del17p, unmutated immunoglobulin heavy chain gene, or high Zeta-chain–associated protein kinase 70 expression.
 

Effective synergy

The researchers found that clemastine enhanced cell death when combined with targeted CLL therapies ibrutinib, idelalisib, or venetoclax, but did not enhance the activities of the chemotherapeutics fludarabine, chlorambucil, or bendamustine.

Ibrutinib increased cell death to the greatest degree when combined with antihistamines. The effect was demonstrated to be synergistic, showing “a unique interaction between the activities of the antihistamines and this inhibitor of the B-cell pathway, suggesting a clinical potential for this combination,” the authors stated.

“Repurposing well-characterized drugs such as antihistamines with defined mechanisms and toxicities allows for repositioning of these drugs to use in CLL treatment in the near future in the context of targeted therapies,” they concluded.

The study was supported by grants from the Cancer Research Society and the CancerCare Manitoba Foundation. The authors reported that they had no conflicts.

mlesney@mdedge.com

SOURCE: Chanas-Larue A et al. Leuk Res. 2020 Jul 17. doi: 10.1016/j.leukres.2020.106423.

Three over-the-counter antihistamines, clemastine, desloratadine, and loratadine, preferentially induce cell death through lysosomal membrane permeabilization in chronic lymphocytic leukemia cells, compared with normal lymphocytes, according to the results of an in vitro study published in Leukemia Research.

In addition, the antihistamines showed a synergistic effect in killing off chronic lymphocytic leukemia (CLL) cells when combined with the tyrosine kinase inhibitor, ibrutinib, but not with chemotherapy, according to Aaron Chanas-Larue of CancerCare Manitoba, Winnipeg, Man., and colleagues.

Blood from CLL patients and age-matched healthy donors was collected, treated, and compared with two malignant B-cell lines. Cells were treated with the three different antihistamines at various concentrations alone and in the presence of ibrutinib. Cell death was determined by flow cytometry using fluorescent staining and EC50 (half-maximal effective concentration) values were calculated.

Of the three drugs, clemastine demonstrated the greatest degree of cytotoxicity, with a mean EC50 value of 12.3 mcmol in CLL cells. Desloratadine and loratadine also had a greater effect on leukemic cells, with mean EC50 values of 27.2 mcmol and 17.2 mcmol, respectively, according to the researchers.

Clemastine also showed the greatest tumor sensitivity, with an EC50 nearly three times lower for CLL cells (EC50, 12.3 mcmol) than for normal peripheral blood mononuclear cells (EC50, 32 mcmol). In addition, clemastine induced cell death over a 72-hour time course in CLL cells, and was equally effective against CLL cells with del17p, unmutated immunoglobulin heavy chain gene, or high Zeta-chain–associated protein kinase 70 expression.
 

Effective synergy

The researchers found that clemastine enhanced cell death when combined with targeted CLL therapies ibrutinib, idelalisib, or venetoclax, but did not enhance the activities of the chemotherapeutics fludarabine, chlorambucil, or bendamustine.

Ibrutinib increased cell death to the greatest degree when combined with antihistamines. The effect was demonstrated to be synergistic, showing “a unique interaction between the activities of the antihistamines and this inhibitor of the B-cell pathway, suggesting a clinical potential for this combination,” the authors stated.

“Repurposing well-characterized drugs such as antihistamines with defined mechanisms and toxicities allows for repositioning of these drugs to use in CLL treatment in the near future in the context of targeted therapies,” they concluded.

The study was supported by grants from the Cancer Research Society and the CancerCare Manitoba Foundation. The authors reported that they had no conflicts.

mlesney@mdedge.com

SOURCE: Chanas-Larue A et al. Leuk Res. 2020 Jul 17. doi: 10.1016/j.leukres.2020.106423.

“Times of great calamity and confusion have been productive for the greatest minds. The purest ore is produced from the hottest furnace. The brightest thunderbolt is elicited from the darkest storm.” – Charles Caleb Colton

I walk inside the pediatric unit of our hospital, only to be welcomed by an eerie silence. There are a handful of nurses at the nursing station, faces covered with masks sitting 6 feet apart and quietly working on their computers. The resident work lounge also depicts a similar picture of emptiness. Just over a month ago, these halls were bustling with children, parents, consultants, and a host of ancillary staff. I recall times in which I was running around from one patient room to another talking to families and attending to patient needs. For the past 2 months I have often spent hours alone in my office waiting to see a patient. This is the new norm for many of us.

Across the board in hospitals, pediatric census has dropped since the start of the COVID-19 pandemic. Reasons for these are nonspecific but may include fear among parents of “exposure” to the virus by bringing their sick children to the hospital to get evaluated for other concerns. A few patients that we have seen in our hospital are sicker when they have arrived because their parents avoided seeking medical care earlier, plagued by the same fear. Social distancing and school closure have also limited the amount of infectious diseases going around, which are responsible for a bulk of pediatric admissions.

While many of us are still coming in to see the limited number of patients we have, we are not in the true sense frontline providers during this pandemic. There have been limited cases of COVID-19 in children, most of which – fortunately – present with mild symptoms. Although multisystem inflammatory syndrome in children (MIS-C) is a new disease that COVID-19 has brought us closer to, many of us have yet to see our first case because of its rarity.

I have read through the news daily in the past few months to find many adult provider physicians succumbing to COVID-19 and felt a pang of guilt. My social media is full of heartbreaking stories as adult hospitalists are having difficult conversations with families and supporting them through this unknown territory, often sacrificing their own safety. I feel so proud of them and my profession. My heart tells me, though, I personally may not be living up to the true calling I was expected to have as a physician.

As pediatric hospitalists, while we sit and wait for this pandemic to pass, we have been ruminating on and anxious about our future. As census drops, there is a financial strain that many of us are feeling. Job cuts and furloughing of health care workers in our surroundings leave us with a sense of insecurity and low morale. Many small inpatient pediatric units have had to be shut down temporarily either so they could be used for adult patients or because of lack of pediatric patients. Limiting staffing to avoid exposure and cohorting providers has also been a challenge.

A big question that has risen in these times is how to ensure productivity and stay useful while at the same time being prepared for the unknown that lies ahead. The economics of medicine is staring hard at our years of hard work, questioning the need for our specialty in the first place.

In smaller community settings, the closure of pediatric units has put an additional strain on the overall framework of the community, parents, and referring primary care providers. With the absence of local resources, children who have needed care have had to be transferred to bigger referral centers that are still taking care of pediatric patients. On one end of the spectrum there is concern for pediatric inpatient units not being productive enough for the hospital, but that coexists with a worry that, as we pass through this pandemic, we could see more hospitalizations for vaccine-preventable illnesses, child abuse/medical neglect, and respiratory syncytial virus plus COVID.

The question remains about how best to cope and use this time of uncertainty to be productive and prepare for the worst. A few solutions and suggestions are highlighted below.

• Helping adult providers: Many pediatric hospitalist colleagues in highly affected states have filled the increasing need for clinicians and taken care of adult patients. As pediatric units have closed, providers have continued to offer care where it is needed. Pediatric hospitalists have used this time to take urgent refresher courses in advanced cardiac life support and adult critical care. In states that are not as severely hit, many pediatric hospitalists have utilized this time to plan and prepare protocols for the future as information continues coming in regarding MIS-C and COVID-19 in pediatric patients.
• Use of telemedicine: With the ease in restrictions for use of telemedicine in many states, pediatric hospitalists can consider using it to restructure their staffing model whenever feasible. This can help in cohorting and allowing high risk and quarantined providers to work from home. This model simultaneously provides opportunities for pediatric hospitalists to continue providing their services, while at the same time decreasing financial burden on their institution.
• Reaching out to the community: Engaging with the community during these times can help ensure services and options remain available to our referral providers and patients for pediatric services. Information about COVID-19 can be widely disseminated. We can also play our part by continuing to encourage parents in our maximum capacity to obtain care for their children when needed and to not avoid the hospital because of fears of exposure.
• Supporting each other: There is no doubt that these times are unsettling for the pediatric hospitalist community, and the uncertainty that surrounds us can feel crippling. Strong team building is imperative in these times. While we may not be frequently meeting in work lounges and sharing meals, a good sense of support and camaraderie will go a long way in building morale for the future. Seeking mental health resources if needed is essential for us and should not be looked at with shame or guilt. This is something that many of us have never seen before, and it is okay to ask for help. Seeking help is and always will be a sign of strength.

Today, as I envision myself walking in the hospital on the other side of this pandemic I see a cheerful pediatric unit, smiling faces without masks, my 3-year-old patient cruising around the hallways in a toy car, our therapy dog walking around bringing joy to many, and many healthy patients feeling better and ready to go home. A time when we are not scared to hug each other, shake hands, or share emotion. When our teams are stronger and more well bonded. A time when parents are not scared to bring their sick children to the hospital. Will it be many months before this happens? I don’t know. But I do know that the children I take care of are known for their resilience. I will live up to them today by practicing the same.
 

Dr. Fatima is a pediatric hospitalist at Wesley Children’s Hospital and assistant professor of pediatrics at Kansas University School of Medicine, both in Wichita. Her research interests include medical errors, medical education, and high-value care.

“Times of great calamity and confusion have been productive for the greatest minds. The purest ore is produced from the hottest furnace. The brightest thunderbolt is elicited from the darkest storm.” – Charles Caleb Colton

I walk inside the pediatric unit of our hospital, only to be welcomed by an eerie silence. There are a handful of nurses at the nursing station, faces covered with masks sitting 6 feet apart and quietly working on their computers. The resident work lounge also depicts a similar picture of emptiness. Just over a month ago, these halls were bustling with children, parents, consultants, and a host of ancillary staff. I recall times in which I was running around from one patient room to another talking to families and attending to patient needs. For the past 2 months I have often spent hours alone in my office waiting to see a patient. This is the new norm for many of us.

Across the board in hospitals, pediatric census has dropped since the start of the COVID-19 pandemic. Reasons for these are nonspecific but may include fear among parents of “exposure” to the virus by bringing their sick children to the hospital to get evaluated for other concerns. A few patients that we have seen in our hospital are sicker when they have arrived because their parents avoided seeking medical care earlier, plagued by the same fear. Social distancing and school closure have also limited the amount of infectious diseases going around, which are responsible for a bulk of pediatric admissions.

While many of us are still coming in to see the limited number of patients we have, we are not in the true sense frontline providers during this pandemic. There have been limited cases of COVID-19 in children, most of which – fortunately – present with mild symptoms. Although multisystem inflammatory syndrome in children (MIS-C) is a new disease that COVID-19 has brought us closer to, many of us have yet to see our first case because of its rarity.

I have read through the news daily in the past few months to find many adult provider physicians succumbing to COVID-19 and felt a pang of guilt. My social media is full of heartbreaking stories as adult hospitalists are having difficult conversations with families and supporting them through this unknown territory, often sacrificing their own safety. I feel so proud of them and my profession. My heart tells me, though, I personally may not be living up to the true calling I was expected to have as a physician.

As pediatric hospitalists, while we sit and wait for this pandemic to pass, we have been ruminating on and anxious about our future. As census drops, there is a financial strain that many of us are feeling. Job cuts and furloughing of health care workers in our surroundings leave us with a sense of insecurity and low morale. Many small inpatient pediatric units have had to be shut down temporarily either so they could be used for adult patients or because of lack of pediatric patients. Limiting staffing to avoid exposure and cohorting providers has also been a challenge.

A big question that has risen in these times is how to ensure productivity and stay useful while at the same time being prepared for the unknown that lies ahead. The economics of medicine is staring hard at our years of hard work, questioning the need for our specialty in the first place.

In smaller community settings, the closure of pediatric units has put an additional strain on the overall framework of the community, parents, and referring primary care providers. With the absence of local resources, children who have needed care have had to be transferred to bigger referral centers that are still taking care of pediatric patients. On one end of the spectrum there is concern for pediatric inpatient units not being productive enough for the hospital, but that coexists with a worry that, as we pass through this pandemic, we could see more hospitalizations for vaccine-preventable illnesses, child abuse/medical neglect, and respiratory syncytial virus plus COVID.

The question remains about how best to cope and use this time of uncertainty to be productive and prepare for the worst. A few solutions and suggestions are highlighted below.

• Helping adult providers: Many pediatric hospitalist colleagues in highly affected states have filled the increasing need for clinicians and taken care of adult patients. As pediatric units have closed, providers have continued to offer care where it is needed. Pediatric hospitalists have used this time to take urgent refresher courses in advanced cardiac life support and adult critical care. In states that are not as severely hit, many pediatric hospitalists have utilized this time to plan and prepare protocols for the future as information continues coming in regarding MIS-C and COVID-19 in pediatric patients.
• Use of telemedicine: With the ease in restrictions for use of telemedicine in many states, pediatric hospitalists can consider using it to restructure their staffing model whenever feasible. This can help in cohorting and allowing high risk and quarantined providers to work from home. This model simultaneously provides opportunities for pediatric hospitalists to continue providing their services, while at the same time decreasing financial burden on their institution.
• Reaching out to the community: Engaging with the community during these times can help ensure services and options remain available to our referral providers and patients for pediatric services. Information about COVID-19 can be widely disseminated. We can also play our part by continuing to encourage parents in our maximum capacity to obtain care for their children when needed and to not avoid the hospital because of fears of exposure.
• Supporting each other: There is no doubt that these times are unsettling for the pediatric hospitalist community, and the uncertainty that surrounds us can feel crippling. Strong team building is imperative in these times. While we may not be frequently meeting in work lounges and sharing meals, a good sense of support and camaraderie will go a long way in building morale for the future. Seeking mental health resources if needed is essential for us and should not be looked at with shame or guilt. This is something that many of us have never seen before, and it is okay to ask for help. Seeking help is and always will be a sign of strength.

Today, as I envision myself walking in the hospital on the other side of this pandemic I see a cheerful pediatric unit, smiling faces without masks, my 3-year-old patient cruising around the hallways in a toy car, our therapy dog walking around bringing joy to many, and many healthy patients feeling better and ready to go home. A time when we are not scared to hug each other, shake hands, or share emotion. When our teams are stronger and more well bonded. A time when parents are not scared to bring their sick children to the hospital. Will it be many months before this happens? I don’t know. But I do know that the children I take care of are known for their resilience. I will live up to them today by practicing the same.
 

Dr. Fatima is a pediatric hospitalist at Wesley Children’s Hospital and assistant professor of pediatrics at Kansas University School of Medicine, both in Wichita. Her research interests include medical errors, medical education, and high-value care.

“Times of great calamity and confusion have been productive for the greatest minds. The purest ore is produced from the hottest furnace. The brightest thunderbolt is elicited from the darkest storm.” – Charles Caleb Colton

I walk inside the pediatric unit of our hospital, only to be welcomed by an eerie silence. There are a handful of nurses at the nursing station, faces covered with masks sitting 6 feet apart and quietly working on their computers. The resident work lounge also depicts a similar picture of emptiness. Just over a month ago, these halls were bustling with children, parents, consultants, and a host of ancillary staff. I recall times in which I was running around from one patient room to another talking to families and attending to patient needs. For the past 2 months I have often spent hours alone in my office waiting to see a patient. This is the new norm for many of us.

Across the board in hospitals, pediatric census has dropped since the start of the COVID-19 pandemic. Reasons for these are nonspecific but may include fear among parents of “exposure” to the virus by bringing their sick children to the hospital to get evaluated for other concerns. A few patients that we have seen in our hospital are sicker when they have arrived because their parents avoided seeking medical care earlier, plagued by the same fear. Social distancing and school closure have also limited the amount of infectious diseases going around, which are responsible for a bulk of pediatric admissions.

While many of us are still coming in to see the limited number of patients we have, we are not in the true sense frontline providers during this pandemic. There have been limited cases of COVID-19 in children, most of which – fortunately – present with mild symptoms. Although multisystem inflammatory syndrome in children (MIS-C) is a new disease that COVID-19 has brought us closer to, many of us have yet to see our first case because of its rarity.

I have read through the news daily in the past few months to find many adult provider physicians succumbing to COVID-19 and felt a pang of guilt. My social media is full of heartbreaking stories as adult hospitalists are having difficult conversations with families and supporting them through this unknown territory, often sacrificing their own safety. I feel so proud of them and my profession. My heart tells me, though, I personally may not be living up to the true calling I was expected to have as a physician.

As pediatric hospitalists, while we sit and wait for this pandemic to pass, we have been ruminating on and anxious about our future. As census drops, there is a financial strain that many of us are feeling. Job cuts and furloughing of health care workers in our surroundings leave us with a sense of insecurity and low morale. Many small inpatient pediatric units have had to be shut down temporarily either so they could be used for adult patients or because of lack of pediatric patients. Limiting staffing to avoid exposure and cohorting providers has also been a challenge.

A big question that has risen in these times is how to ensure productivity and stay useful while at the same time being prepared for the unknown that lies ahead. The economics of medicine is staring hard at our years of hard work, questioning the need for our specialty in the first place.

In smaller community settings, the closure of pediatric units has put an additional strain on the overall framework of the community, parents, and referring primary care providers. With the absence of local resources, children who have needed care have had to be transferred to bigger referral centers that are still taking care of pediatric patients. On one end of the spectrum there is concern for pediatric inpatient units not being productive enough for the hospital, but that coexists with a worry that, as we pass through this pandemic, we could see more hospitalizations for vaccine-preventable illnesses, child abuse/medical neglect, and respiratory syncytial virus plus COVID.

The question remains about how best to cope and use this time of uncertainty to be productive and prepare for the worst. A few solutions and suggestions are highlighted below.

• Helping adult providers: Many pediatric hospitalist colleagues in highly affected states have filled the increasing need for clinicians and taken care of adult patients. As pediatric units have closed, providers have continued to offer care where it is needed. Pediatric hospitalists have used this time to take urgent refresher courses in advanced cardiac life support and adult critical care. In states that are not as severely hit, many pediatric hospitalists have utilized this time to plan and prepare protocols for the future as information continues coming in regarding MIS-C and COVID-19 in pediatric patients.
• Use of telemedicine: With the ease in restrictions for use of telemedicine in many states, pediatric hospitalists can consider using it to restructure their staffing model whenever feasible. This can help in cohorting and allowing high risk and quarantined providers to work from home. This model simultaneously provides opportunities for pediatric hospitalists to continue providing their services, while at the same time decreasing financial burden on their institution.
• Reaching out to the community: Engaging with the community during these times can help ensure services and options remain available to our referral providers and patients for pediatric services. Information about COVID-19 can be widely disseminated. We can also play our part by continuing to encourage parents in our maximum capacity to obtain care for their children when needed and to not avoid the hospital because of fears of exposure.
• Supporting each other: There is no doubt that these times are unsettling for the pediatric hospitalist community, and the uncertainty that surrounds us can feel crippling. Strong team building is imperative in these times. While we may not be frequently meeting in work lounges and sharing meals, a good sense of support and camaraderie will go a long way in building morale for the future. Seeking mental health resources if needed is essential for us and should not be looked at with shame or guilt. This is something that many of us have never seen before, and it is okay to ask for help. Seeking help is and always will be a sign of strength.

Today, as I envision myself walking in the hospital on the other side of this pandemic I see a cheerful pediatric unit, smiling faces without masks, my 3-year-old patient cruising around the hallways in a toy car, our therapy dog walking around bringing joy to many, and many healthy patients feeling better and ready to go home. A time when we are not scared to hug each other, shake hands, or share emotion. When our teams are stronger and more well bonded. A time when parents are not scared to bring their sick children to the hospital. Will it be many months before this happens? I don’t know. But I do know that the children I take care of are known for their resilience. I will live up to them today by practicing the same.
 

Dr. Fatima is a pediatric hospitalist at Wesley Children’s Hospital and assistant professor of pediatrics at Kansas University School of Medicine, both in Wichita. Her research interests include medical errors, medical education, and high-value care.

The coronavirus may have quashed plans to socialize and stroll the canals of Amsterdam while at this year’s European Society of Cardiology (ESC) Congress, but organizers are promising a historic digital experience that will “once again, be a celebration of discovery and ground-breaking science.”

“My message — if I have to choose only one thing why ESC 2020 will be a historic event — is that the physician working at the Cleveland Clinic, who was planning to attend this year in Amsterdam, as well as the colleague in a bush hospital in Uganda, who would have never have dreamed to be part of the ESC Congress, both will have for the first time the same access at the same time to knowledge shared at the worldwide leading cardiovascular meeting,” Marco Roffi, MD, co-chair of the scientific program, told theheart.org | Medscape Cardiology.

Taking a page from the American College of Cardiology, which set the virtual bar early in the pandemic with its highly interactive ACC 2020, ESC is taking some 80 Hot Line, clinical practice guidelines, and special sessions live with question-and-answer interactions and panel discussions.

The latest COVID-19 research and four new guideline documents — including recommendations on atrial fibrillation (AF), non-ST-segment elevation acute coronary syndromes, sports cardiology and exercise in patients with cardiovascular disease, and adult congenital heart disease — will be featured at the ESC Congress 2020, scheduled for August 29 to September 1.

Presentations will be shorter and sessions more focused, but more than 500 scientific and educational sessions will be streamed in addition to more than 4000 abstracts available live or on demand as full presentations or e-posters, said Roffi, University Hospital of Geneva, Switzerland.

To pull off the virtual event, a digital studio in Amsterdam will host hundreds of key opinion leaders, and ESC employed more than 1000 satellite studios around the world to gather contributions from scientists and experts with the help of 70 behind-the-scenes experts.

Nevertheless, a “strategic decision” was made to provide free access to the event and its content for 30 days — a strategy that has attracted some 58,000 registrants thus far, up from a record 32,000 attendees at last year’s congress in Paris, Roffi said.

“Obviously, the income will not be the same as a physical congress, but we felt there was too much at stake to make a compromise,” he said. “We believe we are the leaders in cardiovascular meetings in the physical ones and we want to keep this position even in the new era. And we believe this is the beginning of a new era in whatever form will be.”

Hot Line Sessions 1-3, Saturday (14:00 CEST)

The Hot Line sessions will feature 13 clinical trials and kick off with EMPEROR-Reduced, which compared the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) added to standard care in patients with heart failure with reduced ejection fraction (HFrEF), with and without diabetes.

Eli Lilly and Boehringer Ingelheim already announced the trial met its composite primary endpoint of reducing cardiovascular (CV) death or HF hospitalization risk but the details will be important given the SGLT2 inhibitors› rapid shift beyond diabetes to HF and chronic kidney disease (CKD).

Results presented at ESC 2019 from the landmark DAPA-HF trial led to the recent new indication for dapagliflozin (Farxiga, AstraZeneca) for HFrEF in the absence of diabetes. New data will be released in a Sunday Hot Line session looking at the SGLT2 inhibitor among diabetic and nondiabetic CKD patients in DAPA-CKD, which was halted early because of overwhelming efficacy.

As the indication evolved, the SGLT2 inhibitors became truly cardiovascular disease drugs, Roffi said, “so all the cardiologists will have to become familiar with these agents.”

Hot Line 2 will look at the oral cardiac myosin inhibitor mavacamten as an alternative to surgery or percutaneous interventions to treat obstructive hypertrophic cardiomyopathy (HCM). The first-in-class investigational agent is thought to reduce the hypercontractility characteristic of HCM by inhibiting excessive actin-myosin cross-bridges, and it showed promise in the recent phase 2 dose-finding MAVERICK HCM trial.

Investigators are expected to flesh out details from the 251-patient phase 3 EXPLORER-HCM trial, which reported functional and symptomatic gains with once-daily dosing in top-line results released by developer MyoKardia.

“This is really a revolutionary way to treat — hopefully successfully — this very complex disease,” Roffi said.

Rounding out the day is the EAST-AFNET 4 trial, which has been almost 10 years in the making and examined whether early rhythm control with antiarrhythmic drugs and catheter ablation can prevent adverse outcomes in patients with AF compared with usual care alone based on the ESC 2010 AF treatment guidelines.

Hot Line Sessions 4-6, Sunday (14:00 CEST)

Hot Line 4 features the ATPCI study examining the addition of the oral antianginal agent trimetazidine to standard of care in 6007 patients with angina after recent successful percutaneous coronary intervention.

Next up is POPULAR-TAVI looking at aspirin with or without clopidogrel in patients undergoing transcatheter aortic valve implantation (TAVI).

“This is a dilemma that we have every day in the cath lab when we perform a TAVI because we have in front of us patients who, by definition, are at high bleeding risk, are old, and have comorbidities such as renal insufficiencies,” Roffi said. “I like this very much because it’s a very practical study. Whatever the response will be of this study, it will impact clinical practice.”

Hot Line 6 is devoted to the PARALLAX trial comparing sacubitril/valsartan (Entresto, Novartis) with individualized medical therapy in 2569 heart failure with preserved ejection fraction (HFpEF) patients. The primary outcomes are 12-week change in N-terminal pro-brain natriuretic peptide and 24-week change in 6-minute walk distance.

Hot Line Sessions 7-9, Monday (14:00 CEST)

The next day starts with the timely topic of inflammation with the LoDoCo2 trial, in which 5522 patients with stable coronary artery disease were randomized to low-dose colchicine 0.5 mg daily or placebo on top of optimal medical therapy. The primary composite endpoint is CV death, myocardial infarction (MI), ischemic stroke, and ischemia-driven revascularization.

Additional colchicine data also will be presented in a late-breaking science session on Saturday that includes the Australian COPS trial in acute coronary syndromes and new analyses from COLCOT, which demonstrated a 23% reduction in the risk of first ischemic CV events following an MI but no mortality benefit. The low-cost anti-inflammatory drug is also being tested in the mammoth 6000-patient phase 3 Colchicine Coronavirus SARS-CoV-2 (COLCORONA) trial, expected to be completed by the end of September.

Hot Line 8 switches gears with the open-label randomized HOME-PE trial comparing outpatient management of pulmonary embolism (PE) in 1975 select patients based on either the simplified Pulmonary Embolism Severity Index (PESI) score, featured in the most recent ESC acute PE guidelines, or the HESTIA criteria, developed in the HESTIA study. The event-driven primary end point is the composite of recurrent venous thromboembolism, major bleeding, and all-cause death at 30 days.

Last up on Monday is a new analysis on the effects of lowering blood pressure for prevention of CV events across various BP levels from the BPLTTC, which is the largest resource of patient-level randomized clinical trial data, at more than 350,000 patients.


Tuesday Hot Line Sessions 10-12 (14:00 CEST)

The final day of the Congress ends with bang, with the randomized BRACE-CORONA trial examining the effect of continuing or suspending angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in 700 patients with SARS-CoV-2 infection.

Although several cardiovascular societies including ESC recommend continuation of renin-angiotensin-aldosterone system (RAAS) antagonists in COVID-19 patients, randomized data are lacking and patients have been rattled by early observations suggesting that ACE2 upregulation from RAAS antagonists could increase the risk of developing severe COVID-19.

“BRACE-CORONA will answer the question that everybody’s been asking, whether or not you should continue ARBs and ACE inhibitors in COVID-19 patients. This is a randomized trial and we are all very excited about it,” Roffi said.

COVID-19 will also be discussed in a late-breaking science session on Sunday and in three industry Q&A sessions scattered over the 4 days.

Rounding out the last Hot Line session is IMPACT-AFib, a claims database analysis of early vs delayed educational interventions to improve oral anticoagulation use in a whopping 80,000 patients with AF, and REALITY, a much-needed cost-effectiveness analysis of liberal vs restrictive transfusion strategies in 630 patients with acute MI and anemia.
 

This article first appeared on Medscape.com.

The coronavirus may have quashed plans to socialize and stroll the canals of Amsterdam while at this year’s European Society of Cardiology (ESC) Congress, but organizers are promising a historic digital experience that will “once again, be a celebration of discovery and ground-breaking science.”

“My message — if I have to choose only one thing why ESC 2020 will be a historic event — is that the physician working at the Cleveland Clinic, who was planning to attend this year in Amsterdam, as well as the colleague in a bush hospital in Uganda, who would have never have dreamed to be part of the ESC Congress, both will have for the first time the same access at the same time to knowledge shared at the worldwide leading cardiovascular meeting,” Marco Roffi, MD, co-chair of the scientific program, told theheart.org | Medscape Cardiology.

Taking a page from the American College of Cardiology, which set the virtual bar early in the pandemic with its highly interactive ACC 2020, ESC is taking some 80 Hot Line, clinical practice guidelines, and special sessions live with question-and-answer interactions and panel discussions.

The latest COVID-19 research and four new guideline documents — including recommendations on atrial fibrillation (AF), non-ST-segment elevation acute coronary syndromes, sports cardiology and exercise in patients with cardiovascular disease, and adult congenital heart disease — will be featured at the ESC Congress 2020, scheduled for August 29 to September 1.

Presentations will be shorter and sessions more focused, but more than 500 scientific and educational sessions will be streamed in addition to more than 4000 abstracts available live or on demand as full presentations or e-posters, said Roffi, University Hospital of Geneva, Switzerland.

To pull off the virtual event, a digital studio in Amsterdam will host hundreds of key opinion leaders, and ESC employed more than 1000 satellite studios around the world to gather contributions from scientists and experts with the help of 70 behind-the-scenes experts.

Nevertheless, a “strategic decision” was made to provide free access to the event and its content for 30 days — a strategy that has attracted some 58,000 registrants thus far, up from a record 32,000 attendees at last year’s congress in Paris, Roffi said.

“Obviously, the income will not be the same as a physical congress, but we felt there was too much at stake to make a compromise,” he said. “We believe we are the leaders in cardiovascular meetings in the physical ones and we want to keep this position even in the new era. And we believe this is the beginning of a new era in whatever form will be.”

Hot Line Sessions 1-3, Saturday (14:00 CEST)

The Hot Line sessions will feature 13 clinical trials and kick off with EMPEROR-Reduced, which compared the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) added to standard care in patients with heart failure with reduced ejection fraction (HFrEF), with and without diabetes.

Eli Lilly and Boehringer Ingelheim already announced the trial met its composite primary endpoint of reducing cardiovascular (CV) death or HF hospitalization risk but the details will be important given the SGLT2 inhibitors› rapid shift beyond diabetes to HF and chronic kidney disease (CKD).

Results presented at ESC 2019 from the landmark DAPA-HF trial led to the recent new indication for dapagliflozin (Farxiga, AstraZeneca) for HFrEF in the absence of diabetes. New data will be released in a Sunday Hot Line session looking at the SGLT2 inhibitor among diabetic and nondiabetic CKD patients in DAPA-CKD, which was halted early because of overwhelming efficacy.

As the indication evolved, the SGLT2 inhibitors became truly cardiovascular disease drugs, Roffi said, “so all the cardiologists will have to become familiar with these agents.”

Hot Line 2 will look at the oral cardiac myosin inhibitor mavacamten as an alternative to surgery or percutaneous interventions to treat obstructive hypertrophic cardiomyopathy (HCM). The first-in-class investigational agent is thought to reduce the hypercontractility characteristic of HCM by inhibiting excessive actin-myosin cross-bridges, and it showed promise in the recent phase 2 dose-finding MAVERICK HCM trial.

Investigators are expected to flesh out details from the 251-patient phase 3 EXPLORER-HCM trial, which reported functional and symptomatic gains with once-daily dosing in top-line results released by developer MyoKardia.

“This is really a revolutionary way to treat — hopefully successfully — this very complex disease,” Roffi said.

Rounding out the day is the EAST-AFNET 4 trial, which has been almost 10 years in the making and examined whether early rhythm control with antiarrhythmic drugs and catheter ablation can prevent adverse outcomes in patients with AF compared with usual care alone based on the ESC 2010 AF treatment guidelines.

Hot Line Sessions 4-6, Sunday (14:00 CEST)

Hot Line 4 features the ATPCI study examining the addition of the oral antianginal agent trimetazidine to standard of care in 6007 patients with angina after recent successful percutaneous coronary intervention.

Next up is POPULAR-TAVI looking at aspirin with or without clopidogrel in patients undergoing transcatheter aortic valve implantation (TAVI).

“This is a dilemma that we have every day in the cath lab when we perform a TAVI because we have in front of us patients who, by definition, are at high bleeding risk, are old, and have comorbidities such as renal insufficiencies,” Roffi said. “I like this very much because it’s a very practical study. Whatever the response will be of this study, it will impact clinical practice.”

Hot Line 6 is devoted to the PARALLAX trial comparing sacubitril/valsartan (Entresto, Novartis) with individualized medical therapy in 2569 heart failure with preserved ejection fraction (HFpEF) patients. The primary outcomes are 12-week change in N-terminal pro-brain natriuretic peptide and 24-week change in 6-minute walk distance.

Hot Line Sessions 7-9, Monday (14:00 CEST)

The next day starts with the timely topic of inflammation with the LoDoCo2 trial, in which 5522 patients with stable coronary artery disease were randomized to low-dose colchicine 0.5 mg daily or placebo on top of optimal medical therapy. The primary composite endpoint is CV death, myocardial infarction (MI), ischemic stroke, and ischemia-driven revascularization.

Additional colchicine data also will be presented in a late-breaking science session on Saturday that includes the Australian COPS trial in acute coronary syndromes and new analyses from COLCOT, which demonstrated a 23% reduction in the risk of first ischemic CV events following an MI but no mortality benefit. The low-cost anti-inflammatory drug is also being tested in the mammoth 6000-patient phase 3 Colchicine Coronavirus SARS-CoV-2 (COLCORONA) trial, expected to be completed by the end of September.

Hot Line 8 switches gears with the open-label randomized HOME-PE trial comparing outpatient management of pulmonary embolism (PE) in 1975 select patients based on either the simplified Pulmonary Embolism Severity Index (PESI) score, featured in the most recent ESC acute PE guidelines, or the HESTIA criteria, developed in the HESTIA study. The event-driven primary end point is the composite of recurrent venous thromboembolism, major bleeding, and all-cause death at 30 days.

Last up on Monday is a new analysis on the effects of lowering blood pressure for prevention of CV events across various BP levels from the BPLTTC, which is the largest resource of patient-level randomized clinical trial data, at more than 350,000 patients.


Tuesday Hot Line Sessions 10-12 (14:00 CEST)

The final day of the Congress ends with bang, with the randomized BRACE-CORONA trial examining the effect of continuing or suspending angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in 700 patients with SARS-CoV-2 infection.

Although several cardiovascular societies including ESC recommend continuation of renin-angiotensin-aldosterone system (RAAS) antagonists in COVID-19 patients, randomized data are lacking and patients have been rattled by early observations suggesting that ACE2 upregulation from RAAS antagonists could increase the risk of developing severe COVID-19.

“BRACE-CORONA will answer the question that everybody’s been asking, whether or not you should continue ARBs and ACE inhibitors in COVID-19 patients. This is a randomized trial and we are all very excited about it,” Roffi said.

COVID-19 will also be discussed in a late-breaking science session on Sunday and in three industry Q&A sessions scattered over the 4 days.

Rounding out the last Hot Line session is IMPACT-AFib, a claims database analysis of early vs delayed educational interventions to improve oral anticoagulation use in a whopping 80,000 patients with AF, and REALITY, a much-needed cost-effectiveness analysis of liberal vs restrictive transfusion strategies in 630 patients with acute MI and anemia.
 

This article first appeared on Medscape.com.

The coronavirus may have quashed plans to socialize and stroll the canals of Amsterdam while at this year’s European Society of Cardiology (ESC) Congress, but organizers are promising a historic digital experience that will “once again, be a celebration of discovery and ground-breaking science.”

“My message — if I have to choose only one thing why ESC 2020 will be a historic event — is that the physician working at the Cleveland Clinic, who was planning to attend this year in Amsterdam, as well as the colleague in a bush hospital in Uganda, who would have never have dreamed to be part of the ESC Congress, both will have for the first time the same access at the same time to knowledge shared at the worldwide leading cardiovascular meeting,” Marco Roffi, MD, co-chair of the scientific program, told theheart.org | Medscape Cardiology.

Taking a page from the American College of Cardiology, which set the virtual bar early in the pandemic with its highly interactive ACC 2020, ESC is taking some 80 Hot Line, clinical practice guidelines, and special sessions live with question-and-answer interactions and panel discussions.

The latest COVID-19 research and four new guideline documents — including recommendations on atrial fibrillation (AF), non-ST-segment elevation acute coronary syndromes, sports cardiology and exercise in patients with cardiovascular disease, and adult congenital heart disease — will be featured at the ESC Congress 2020, scheduled for August 29 to September 1.

Presentations will be shorter and sessions more focused, but more than 500 scientific and educational sessions will be streamed in addition to more than 4000 abstracts available live or on demand as full presentations or e-posters, said Roffi, University Hospital of Geneva, Switzerland.

To pull off the virtual event, a digital studio in Amsterdam will host hundreds of key opinion leaders, and ESC employed more than 1000 satellite studios around the world to gather contributions from scientists and experts with the help of 70 behind-the-scenes experts.

Nevertheless, a “strategic decision” was made to provide free access to the event and its content for 30 days — a strategy that has attracted some 58,000 registrants thus far, up from a record 32,000 attendees at last year’s congress in Paris, Roffi said.

“Obviously, the income will not be the same as a physical congress, but we felt there was too much at stake to make a compromise,” he said. “We believe we are the leaders in cardiovascular meetings in the physical ones and we want to keep this position even in the new era. And we believe this is the beginning of a new era in whatever form will be.”

Hot Line Sessions 1-3, Saturday (14:00 CEST)

The Hot Line sessions will feature 13 clinical trials and kick off with EMPEROR-Reduced, which compared the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) added to standard care in patients with heart failure with reduced ejection fraction (HFrEF), with and without diabetes.

Eli Lilly and Boehringer Ingelheim already announced the trial met its composite primary endpoint of reducing cardiovascular (CV) death or HF hospitalization risk but the details will be important given the SGLT2 inhibitors› rapid shift beyond diabetes to HF and chronic kidney disease (CKD).

Results presented at ESC 2019 from the landmark DAPA-HF trial led to the recent new indication for dapagliflozin (Farxiga, AstraZeneca) for HFrEF in the absence of diabetes. New data will be released in a Sunday Hot Line session looking at the SGLT2 inhibitor among diabetic and nondiabetic CKD patients in DAPA-CKD, which was halted early because of overwhelming efficacy.

As the indication evolved, the SGLT2 inhibitors became truly cardiovascular disease drugs, Roffi said, “so all the cardiologists will have to become familiar with these agents.”

Hot Line 2 will look at the oral cardiac myosin inhibitor mavacamten as an alternative to surgery or percutaneous interventions to treat obstructive hypertrophic cardiomyopathy (HCM). The first-in-class investigational agent is thought to reduce the hypercontractility characteristic of HCM by inhibiting excessive actin-myosin cross-bridges, and it showed promise in the recent phase 2 dose-finding MAVERICK HCM trial.

Investigators are expected to flesh out details from the 251-patient phase 3 EXPLORER-HCM trial, which reported functional and symptomatic gains with once-daily dosing in top-line results released by developer MyoKardia.

“This is really a revolutionary way to treat — hopefully successfully — this very complex disease,” Roffi said.

Rounding out the day is the EAST-AFNET 4 trial, which has been almost 10 years in the making and examined whether early rhythm control with antiarrhythmic drugs and catheter ablation can prevent adverse outcomes in patients with AF compared with usual care alone based on the ESC 2010 AF treatment guidelines.

Hot Line Sessions 4-6, Sunday (14:00 CEST)

Hot Line 4 features the ATPCI study examining the addition of the oral antianginal agent trimetazidine to standard of care in 6007 patients with angina after recent successful percutaneous coronary intervention.

Next up is POPULAR-TAVI looking at aspirin with or without clopidogrel in patients undergoing transcatheter aortic valve implantation (TAVI).

“This is a dilemma that we have every day in the cath lab when we perform a TAVI because we have in front of us patients who, by definition, are at high bleeding risk, are old, and have comorbidities such as renal insufficiencies,” Roffi said. “I like this very much because it’s a very practical study. Whatever the response will be of this study, it will impact clinical practice.”

Hot Line 6 is devoted to the PARALLAX trial comparing sacubitril/valsartan (Entresto, Novartis) with individualized medical therapy in 2569 heart failure with preserved ejection fraction (HFpEF) patients. The primary outcomes are 12-week change in N-terminal pro-brain natriuretic peptide and 24-week change in 6-minute walk distance.

Hot Line Sessions 7-9, Monday (14:00 CEST)

The next day starts with the timely topic of inflammation with the LoDoCo2 trial, in which 5522 patients with stable coronary artery disease were randomized to low-dose colchicine 0.5 mg daily or placebo on top of optimal medical therapy. The primary composite endpoint is CV death, myocardial infarction (MI), ischemic stroke, and ischemia-driven revascularization.

Additional colchicine data also will be presented in a late-breaking science session on Saturday that includes the Australian COPS trial in acute coronary syndromes and new analyses from COLCOT, which demonstrated a 23% reduction in the risk of first ischemic CV events following an MI but no mortality benefit. The low-cost anti-inflammatory drug is also being tested in the mammoth 6000-patient phase 3 Colchicine Coronavirus SARS-CoV-2 (COLCORONA) trial, expected to be completed by the end of September.

Hot Line 8 switches gears with the open-label randomized HOME-PE trial comparing outpatient management of pulmonary embolism (PE) in 1975 select patients based on either the simplified Pulmonary Embolism Severity Index (PESI) score, featured in the most recent ESC acute PE guidelines, or the HESTIA criteria, developed in the HESTIA study. The event-driven primary end point is the composite of recurrent venous thromboembolism, major bleeding, and all-cause death at 30 days.

Last up on Monday is a new analysis on the effects of lowering blood pressure for prevention of CV events across various BP levels from the BPLTTC, which is the largest resource of patient-level randomized clinical trial data, at more than 350,000 patients.


Tuesday Hot Line Sessions 10-12 (14:00 CEST)

The final day of the Congress ends with bang, with the randomized BRACE-CORONA trial examining the effect of continuing or suspending angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in 700 patients with SARS-CoV-2 infection.

Although several cardiovascular societies including ESC recommend continuation of renin-angiotensin-aldosterone system (RAAS) antagonists in COVID-19 patients, randomized data are lacking and patients have been rattled by early observations suggesting that ACE2 upregulation from RAAS antagonists could increase the risk of developing severe COVID-19.

“BRACE-CORONA will answer the question that everybody’s been asking, whether or not you should continue ARBs and ACE inhibitors in COVID-19 patients. This is a randomized trial and we are all very excited about it,” Roffi said.

COVID-19 will also be discussed in a late-breaking science session on Sunday and in three industry Q&A sessions scattered over the 4 days.

Rounding out the last Hot Line session is IMPACT-AFib, a claims database analysis of early vs delayed educational interventions to improve oral anticoagulation use in a whopping 80,000 patients with AF, and REALITY, a much-needed cost-effectiveness analysis of liberal vs restrictive transfusion strategies in 630 patients with acute MI and anemia.
 

This article first appeared on Medscape.com.

The medical community is about to find out how prepared it is for the double whammy of influenza and COVID-19 that has been predicted for the fall of 2020. The complexities of diagnosis, management of vulnerable patients, and overflowing medical centers that have made the COVID-19 crisis so brutal may all be exacerbated by the arrival of seasonal influenza.

Lewis Jay Kaplan, MD, FCCP, a critical care surgeon at the University of Pennsylvania, Philadelphia, has seen his share of critically ill COVID-19 patients in the surgical ICU that he oversees. He’s approaching the upcoming flu season, poised to collide with the ongoing COVID-19 pandemic, ready to listen to each patient’s story to distinguish one from the other and determine treatment.

“The patients that have underlying comorbidities all have a story, and it’s up to you to figure out which chapter you’re in and how far along you happen to be,” he said. “It’s a very interesting approach to care, medical storytelling.”

With flu season closing in, pulmonologists are ruminating about how they’ll distinguish symptoms of COVID-19 and traditional influenza and how they’ll manage the most vulnerable patients, namely those with underlying respiratory disease and children. Influenza kills 12,000-61,000 people a year, according to the Centers for Disease Control, and results in 140,000-810,00 hospitalizations. Having a flu season in the midst of a pandemic of a disease with multiple overlapping symptoms threatens to overwhelm practitioners, hospitals, and the health system.

Dr. Kaplan said each patient’s story can point to the correct clinical approach. “Instead of just sharing data when you are on rounds, you’re really telling someone’s story.” It arises from a series of questions about how the disease has impacted them, specifics of their presentation, how their signs and symptoms differ from the usual, and how they responded to treatment. “It also helps you to then take what you’re doing, which can seem very, very complicated to individuals who are not medically sophisticated, and then help them to understand why you’re doing what you’re doing at this point.”

That can help get through to a patient with respiratory disease who insists he or she has or doesn’t have COVID-19 rather than the flu. “They form a different group that brings with them different fears and concerns, and you have to help them navigate that, too: all of this data and your decision-making around testing and admissions, and what you can omit doing and what you must do help them to navigate their own story,” Dr. Kaplan said.

Benjamin D. Singer, MD, a pulmonologist at Northwestern University, Chicago, authored an editorial in Science Advances that addressed four factors that will determine the scope of flu spread in the upcoming season: rate of transmission; vaccination rates; coinfection rates; and health disparities in minority populations, which are prone to higher rates of flu as well as COVID-19.
 

Flu vaccine ‘extra important’

The convergence of COVID-19 and influenza has the potential to overwhelm the health system, said Daniel A. Solomon, MD, of Brigham and Women’s in Boston. He coauthored a JAMA Insights clinical update on flu season during the COVID-19 pandemic that lists distinguishing and overlapping signs and symptoms of the two diseases.

The flu vaccine, he said, is “extra important this year,” especially in patients with existing respiratory disease, but COVID-19 has thrown up barriers to vaccination. Telemedicine has supplanted office visits. “People may miss that easy-touch opportunity to get the flu vaccine, so we have to be creative about making the flu vaccine highly accessible, maybe in nontraditional ways,” Dr. Solomon said. Some ideas he offered are pop-up vaccine fairs at schools and churches.

But just as COVID-19 may hinder flu vaccines, it may also be helping to mitigate flu transmission. “The interesting thing about transmission of the flu is that it’s transmitted the same way COVID is, so if we actually know how to decrease transmission of COVID, which we do – we’ve done it – we can actually decrease transmission of influenza as well,” Dr. Solomon said. Studies out of Hong Kong and Japan have reported a reduction in influenza cases during COVID-19 outbreaks in those places (Lancet Public Health. 2020;5:e279-88; JAMA. 2020;323:1969-71).
 

Risks of coinfection

About one in four COVID-19 patients have been diagnosed with an additional respiratory infection, including influenza (JAMA. 2020:323:2085-6). Pulmonologists must keep that in mind when managing COVID-19 suspects, said Dr. Singer.

“While it is true that most of the time COVID-19 travels alone, we have numerous examples in the literature and in our own experience that COVID-19 is accompanied by either another virus or another bacterial infection, including influenza,” Dr. Singer said. “The distinction is important. One is just for diagnostic reasons and public reporting reasons, but also because flu and COVID-19 have different requirements for how you care for patients in terms of the health system.”

Clinical suspicion for coinfection should remain high if the community spread of both COVID-19 and influenza is high, said Megan Conroy, MD, chief pulmonary and critical care fellow at Ohio State University, Columbus. “As the coronavirus first took hold in the United States in March 2020, we were at the tail end of influenza season, so it’s hard to predict what the upcoming influenza season will really look like with regards to coinfection.”
 

Distinguishing COVID-19 from flu

Multiple signs and symptoms between COVID-19 and the flu overlap. They include fever, chills, headache, myalgia, cough, and fatigue. Nasal congestion and sore throat are characteristic of the flu; shortness of breath and loss of the sense of smell have been widely reported in COVID-19. “While many upper respiratory infections can result in loss of smell, this may be more prevalent in COVID-19,” Dr. Conroy said. Other symptoms unique to COVID-19 are GI symptoms such as diarrhea and skin rashes such as acral ischemia.

Testing, however, is the cornerstone of the differential diagnosis. “You can’t confidently distinguish between them on symptoms alone,” Dr. Conroy added.

“I think the challenge we’ll face as clinicians, is caring for people with nonspecific symptoms of a respiratory viral illness, especially in the early phase of the illness,” said Dr. Solomon.

But even after that, symptoms can be difficult to distinguish.

“Later in the illness, COVID is more associated with a hypercoagulable state,” he said. “It is more associated with viral pneumonia on chest imaging, like the diffuse ground-glass infiltrates that we’ve all gotten used to seeing – but flu can do both of those things as well. So, without a test, it’s impossible to distinguish between the two infections in the clinic.”

But testing can have its shortcomings when flu season clashes with the COVID-19 pandemic. “Getting the test is not the same as getting the test results,” Dr. Solomon added. “Though a lot of people can get a test, if it takes 7 or 8 days to get the test result back, the result is useless.”

Widespread, rapid testing also depends on having adequate supplies of viral media transport and swabs. “I think that this is what we should be focusing on now: scaling up access to rapid turnaround testing,” he said. Distinguishing between the two is also important to preserve hospital resources. COVID-19 has more rigorous standards than flu for personal protective equipment and isolation of patients within the hospital.

Having chronic lung disease isn’t necessarily a risk factor for contracting COVID-19 or the flu, or both, Dr. Solomon said. “It’s a risk factor for having severe disease.” Again, he noted that flu vaccines are still necessary in these patients, as well as patients of advanced age and underlying medical conditions such as heart disease, diabetes, and obesity.

In managing children, it’s important to keep in mind that they communicate differently about their illnesses than adults, said Dr. Kaplan. “They may not have the words to tell you the same kind of thing that the adult tells you.” That’s where family members can help to flesh out the history. “They may present with an initially much milder form, if you will, where they’re not as critical up front, but then that small proportion of them comes back with the multi-inflammatory syndrome and then they are profoundly ill.”

Younger people make up a larger share of COVID-19 patients now, compared with the initial wave that hit the Northeast in the spring, Dr. Kaplan said. “We don’t know if that’s because the virus is a little different or the people that are getting sick are a little bit different.”

The COVID-19 strain now emerging may be less virulent than the strain that hit in early spring, he said. “That doesn’t mean that there aren’t still profoundly critical ill people with COVID of many different age ranges, that is true, but there are a lot of people that we now see will test positive, but aren’t really as profoundly ill as when it first landed here in the United States.”

That may be somewhat welcome as flu season arrives.

The physicians interviewed have no relevant disclosures.

The medical community is about to find out how prepared it is for the double whammy of influenza and COVID-19 that has been predicted for the fall of 2020. The complexities of diagnosis, management of vulnerable patients, and overflowing medical centers that have made the COVID-19 crisis so brutal may all be exacerbated by the arrival of seasonal influenza.

Lewis Jay Kaplan, MD, FCCP, a critical care surgeon at the University of Pennsylvania, Philadelphia, has seen his share of critically ill COVID-19 patients in the surgical ICU that he oversees. He’s approaching the upcoming flu season, poised to collide with the ongoing COVID-19 pandemic, ready to listen to each patient’s story to distinguish one from the other and determine treatment.

“The patients that have underlying comorbidities all have a story, and it’s up to you to figure out which chapter you’re in and how far along you happen to be,” he said. “It’s a very interesting approach to care, medical storytelling.”

With flu season closing in, pulmonologists are ruminating about how they’ll distinguish symptoms of COVID-19 and traditional influenza and how they’ll manage the most vulnerable patients, namely those with underlying respiratory disease and children. Influenza kills 12,000-61,000 people a year, according to the Centers for Disease Control, and results in 140,000-810,00 hospitalizations. Having a flu season in the midst of a pandemic of a disease with multiple overlapping symptoms threatens to overwhelm practitioners, hospitals, and the health system.

Dr. Kaplan said each patient’s story can point to the correct clinical approach. “Instead of just sharing data when you are on rounds, you’re really telling someone’s story.” It arises from a series of questions about how the disease has impacted them, specifics of their presentation, how their signs and symptoms differ from the usual, and how they responded to treatment. “It also helps you to then take what you’re doing, which can seem very, very complicated to individuals who are not medically sophisticated, and then help them to understand why you’re doing what you’re doing at this point.”

That can help get through to a patient with respiratory disease who insists he or she has or doesn’t have COVID-19 rather than the flu. “They form a different group that brings with them different fears and concerns, and you have to help them navigate that, too: all of this data and your decision-making around testing and admissions, and what you can omit doing and what you must do help them to navigate their own story,” Dr. Kaplan said.

Benjamin D. Singer, MD, a pulmonologist at Northwestern University, Chicago, authored an editorial in Science Advances that addressed four factors that will determine the scope of flu spread in the upcoming season: rate of transmission; vaccination rates; coinfection rates; and health disparities in minority populations, which are prone to higher rates of flu as well as COVID-19.
 

Flu vaccine ‘extra important’

The convergence of COVID-19 and influenza has the potential to overwhelm the health system, said Daniel A. Solomon, MD, of Brigham and Women’s in Boston. He coauthored a JAMA Insights clinical update on flu season during the COVID-19 pandemic that lists distinguishing and overlapping signs and symptoms of the two diseases.

The flu vaccine, he said, is “extra important this year,” especially in patients with existing respiratory disease, but COVID-19 has thrown up barriers to vaccination. Telemedicine has supplanted office visits. “People may miss that easy-touch opportunity to get the flu vaccine, so we have to be creative about making the flu vaccine highly accessible, maybe in nontraditional ways,” Dr. Solomon said. Some ideas he offered are pop-up vaccine fairs at schools and churches.

But just as COVID-19 may hinder flu vaccines, it may also be helping to mitigate flu transmission. “The interesting thing about transmission of the flu is that it’s transmitted the same way COVID is, so if we actually know how to decrease transmission of COVID, which we do – we’ve done it – we can actually decrease transmission of influenza as well,” Dr. Solomon said. Studies out of Hong Kong and Japan have reported a reduction in influenza cases during COVID-19 outbreaks in those places (Lancet Public Health. 2020;5:e279-88; JAMA. 2020;323:1969-71).
 

Risks of coinfection

About one in four COVID-19 patients have been diagnosed with an additional respiratory infection, including influenza (JAMA. 2020:323:2085-6). Pulmonologists must keep that in mind when managing COVID-19 suspects, said Dr. Singer.

“While it is true that most of the time COVID-19 travels alone, we have numerous examples in the literature and in our own experience that COVID-19 is accompanied by either another virus or another bacterial infection, including influenza,” Dr. Singer said. “The distinction is important. One is just for diagnostic reasons and public reporting reasons, but also because flu and COVID-19 have different requirements for how you care for patients in terms of the health system.”

Clinical suspicion for coinfection should remain high if the community spread of both COVID-19 and influenza is high, said Megan Conroy, MD, chief pulmonary and critical care fellow at Ohio State University, Columbus. “As the coronavirus first took hold in the United States in March 2020, we were at the tail end of influenza season, so it’s hard to predict what the upcoming influenza season will really look like with regards to coinfection.”
 

Distinguishing COVID-19 from flu

Multiple signs and symptoms between COVID-19 and the flu overlap. They include fever, chills, headache, myalgia, cough, and fatigue. Nasal congestion and sore throat are characteristic of the flu; shortness of breath and loss of the sense of smell have been widely reported in COVID-19. “While many upper respiratory infections can result in loss of smell, this may be more prevalent in COVID-19,” Dr. Conroy said. Other symptoms unique to COVID-19 are GI symptoms such as diarrhea and skin rashes such as acral ischemia.

Testing, however, is the cornerstone of the differential diagnosis. “You can’t confidently distinguish between them on symptoms alone,” Dr. Conroy added.

“I think the challenge we’ll face as clinicians, is caring for people with nonspecific symptoms of a respiratory viral illness, especially in the early phase of the illness,” said Dr. Solomon.

But even after that, symptoms can be difficult to distinguish.

“Later in the illness, COVID is more associated with a hypercoagulable state,” he said. “It is more associated with viral pneumonia on chest imaging, like the diffuse ground-glass infiltrates that we’ve all gotten used to seeing – but flu can do both of those things as well. So, without a test, it’s impossible to distinguish between the two infections in the clinic.”

But testing can have its shortcomings when flu season clashes with the COVID-19 pandemic. “Getting the test is not the same as getting the test results,” Dr. Solomon added. “Though a lot of people can get a test, if it takes 7 or 8 days to get the test result back, the result is useless.”

Widespread, rapid testing also depends on having adequate supplies of viral media transport and swabs. “I think that this is what we should be focusing on now: scaling up access to rapid turnaround testing,” he said. Distinguishing between the two is also important to preserve hospital resources. COVID-19 has more rigorous standards than flu for personal protective equipment and isolation of patients within the hospital.

Having chronic lung disease isn’t necessarily a risk factor for contracting COVID-19 or the flu, or both, Dr. Solomon said. “It’s a risk factor for having severe disease.” Again, he noted that flu vaccines are still necessary in these patients, as well as patients of advanced age and underlying medical conditions such as heart disease, diabetes, and obesity.

In managing children, it’s important to keep in mind that they communicate differently about their illnesses than adults, said Dr. Kaplan. “They may not have the words to tell you the same kind of thing that the adult tells you.” That’s where family members can help to flesh out the history. “They may present with an initially much milder form, if you will, where they’re not as critical up front, but then that small proportion of them comes back with the multi-inflammatory syndrome and then they are profoundly ill.”

Younger people make up a larger share of COVID-19 patients now, compared with the initial wave that hit the Northeast in the spring, Dr. Kaplan said. “We don’t know if that’s because the virus is a little different or the people that are getting sick are a little bit different.”

The COVID-19 strain now emerging may be less virulent than the strain that hit in early spring, he said. “That doesn’t mean that there aren’t still profoundly critical ill people with COVID of many different age ranges, that is true, but there are a lot of people that we now see will test positive, but aren’t really as profoundly ill as when it first landed here in the United States.”

That may be somewhat welcome as flu season arrives.

The physicians interviewed have no relevant disclosures.

The medical community is about to find out how prepared it is for the double whammy of influenza and COVID-19 that has been predicted for the fall of 2020. The complexities of diagnosis, management of vulnerable patients, and overflowing medical centers that have made the COVID-19 crisis so brutal may all be exacerbated by the arrival of seasonal influenza.

Lewis Jay Kaplan, MD, FCCP, a critical care surgeon at the University of Pennsylvania, Philadelphia, has seen his share of critically ill COVID-19 patients in the surgical ICU that he oversees. He’s approaching the upcoming flu season, poised to collide with the ongoing COVID-19 pandemic, ready to listen to each patient’s story to distinguish one from the other and determine treatment.

“The patients that have underlying comorbidities all have a story, and it’s up to you to figure out which chapter you’re in and how far along you happen to be,” he said. “It’s a very interesting approach to care, medical storytelling.”

With flu season closing in, pulmonologists are ruminating about how they’ll distinguish symptoms of COVID-19 and traditional influenza and how they’ll manage the most vulnerable patients, namely those with underlying respiratory disease and children. Influenza kills 12,000-61,000 people a year, according to the Centers for Disease Control, and results in 140,000-810,00 hospitalizations. Having a flu season in the midst of a pandemic of a disease with multiple overlapping symptoms threatens to overwhelm practitioners, hospitals, and the health system.

Dr. Kaplan said each patient’s story can point to the correct clinical approach. “Instead of just sharing data when you are on rounds, you’re really telling someone’s story.” It arises from a series of questions about how the disease has impacted them, specifics of their presentation, how their signs and symptoms differ from the usual, and how they responded to treatment. “It also helps you to then take what you’re doing, which can seem very, very complicated to individuals who are not medically sophisticated, and then help them to understand why you’re doing what you’re doing at this point.”

That can help get through to a patient with respiratory disease who insists he or she has or doesn’t have COVID-19 rather than the flu. “They form a different group that brings with them different fears and concerns, and you have to help them navigate that, too: all of this data and your decision-making around testing and admissions, and what you can omit doing and what you must do help them to navigate their own story,” Dr. Kaplan said.

Benjamin D. Singer, MD, a pulmonologist at Northwestern University, Chicago, authored an editorial in Science Advances that addressed four factors that will determine the scope of flu spread in the upcoming season: rate of transmission; vaccination rates; coinfection rates; and health disparities in minority populations, which are prone to higher rates of flu as well as COVID-19.
 

Flu vaccine ‘extra important’

The convergence of COVID-19 and influenza has the potential to overwhelm the health system, said Daniel A. Solomon, MD, of Brigham and Women’s in Boston. He coauthored a JAMA Insights clinical update on flu season during the COVID-19 pandemic that lists distinguishing and overlapping signs and symptoms of the two diseases.

The flu vaccine, he said, is “extra important this year,” especially in patients with existing respiratory disease, but COVID-19 has thrown up barriers to vaccination. Telemedicine has supplanted office visits. “People may miss that easy-touch opportunity to get the flu vaccine, so we have to be creative about making the flu vaccine highly accessible, maybe in nontraditional ways,” Dr. Solomon said. Some ideas he offered are pop-up vaccine fairs at schools and churches.

But just as COVID-19 may hinder flu vaccines, it may also be helping to mitigate flu transmission. “The interesting thing about transmission of the flu is that it’s transmitted the same way COVID is, so if we actually know how to decrease transmission of COVID, which we do – we’ve done it – we can actually decrease transmission of influenza as well,” Dr. Solomon said. Studies out of Hong Kong and Japan have reported a reduction in influenza cases during COVID-19 outbreaks in those places (Lancet Public Health. 2020;5:e279-88; JAMA. 2020;323:1969-71).
 

Risks of coinfection

About one in four COVID-19 patients have been diagnosed with an additional respiratory infection, including influenza (JAMA. 2020:323:2085-6). Pulmonologists must keep that in mind when managing COVID-19 suspects, said Dr. Singer.

“While it is true that most of the time COVID-19 travels alone, we have numerous examples in the literature and in our own experience that COVID-19 is accompanied by either another virus or another bacterial infection, including influenza,” Dr. Singer said. “The distinction is important. One is just for diagnostic reasons and public reporting reasons, but also because flu and COVID-19 have different requirements for how you care for patients in terms of the health system.”

Clinical suspicion for coinfection should remain high if the community spread of both COVID-19 and influenza is high, said Megan Conroy, MD, chief pulmonary and critical care fellow at Ohio State University, Columbus. “As the coronavirus first took hold in the United States in March 2020, we were at the tail end of influenza season, so it’s hard to predict what the upcoming influenza season will really look like with regards to coinfection.”
 

Distinguishing COVID-19 from flu

Multiple signs and symptoms between COVID-19 and the flu overlap. They include fever, chills, headache, myalgia, cough, and fatigue. Nasal congestion and sore throat are characteristic of the flu; shortness of breath and loss of the sense of smell have been widely reported in COVID-19. “While many upper respiratory infections can result in loss of smell, this may be more prevalent in COVID-19,” Dr. Conroy said. Other symptoms unique to COVID-19 are GI symptoms such as diarrhea and skin rashes such as acral ischemia.

Testing, however, is the cornerstone of the differential diagnosis. “You can’t confidently distinguish between them on symptoms alone,” Dr. Conroy added.

“I think the challenge we’ll face as clinicians, is caring for people with nonspecific symptoms of a respiratory viral illness, especially in the early phase of the illness,” said Dr. Solomon.

But even after that, symptoms can be difficult to distinguish.

“Later in the illness, COVID is more associated with a hypercoagulable state,” he said. “It is more associated with viral pneumonia on chest imaging, like the diffuse ground-glass infiltrates that we’ve all gotten used to seeing – but flu can do both of those things as well. So, without a test, it’s impossible to distinguish between the two infections in the clinic.”

But testing can have its shortcomings when flu season clashes with the COVID-19 pandemic. “Getting the test is not the same as getting the test results,” Dr. Solomon added. “Though a lot of people can get a test, if it takes 7 or 8 days to get the test result back, the result is useless.”

Widespread, rapid testing also depends on having adequate supplies of viral media transport and swabs. “I think that this is what we should be focusing on now: scaling up access to rapid turnaround testing,” he said. Distinguishing between the two is also important to preserve hospital resources. COVID-19 has more rigorous standards than flu for personal protective equipment and isolation of patients within the hospital.

Having chronic lung disease isn’t necessarily a risk factor for contracting COVID-19 or the flu, or both, Dr. Solomon said. “It’s a risk factor for having severe disease.” Again, he noted that flu vaccines are still necessary in these patients, as well as patients of advanced age and underlying medical conditions such as heart disease, diabetes, and obesity.

In managing children, it’s important to keep in mind that they communicate differently about their illnesses than adults, said Dr. Kaplan. “They may not have the words to tell you the same kind of thing that the adult tells you.” That’s where family members can help to flesh out the history. “They may present with an initially much milder form, if you will, where they’re not as critical up front, but then that small proportion of them comes back with the multi-inflammatory syndrome and then they are profoundly ill.”

Younger people make up a larger share of COVID-19 patients now, compared with the initial wave that hit the Northeast in the spring, Dr. Kaplan said. “We don’t know if that’s because the virus is a little different or the people that are getting sick are a little bit different.”

The COVID-19 strain now emerging may be less virulent than the strain that hit in early spring, he said. “That doesn’t mean that there aren’t still profoundly critical ill people with COVID of many different age ranges, that is true, but there are a lot of people that we now see will test positive, but aren’t really as profoundly ill as when it first landed here in the United States.”

That may be somewhat welcome as flu season arrives.

The physicians interviewed have no relevant disclosures.

Long-term outcomes now being reported confirm earlier reports from the same trial showing efficacy for the use of targeted intraoperative radiotherapy (TARGIT) in patients with early breast cancer.

This novel approach, which delivers a one-off blast of radiation directed at the tumor bed and is given during lumpectomy, has similar efficacy and lowers non–breast cancer mortality when compared with whole-breast external beam radiotherapy (EBRT), which is delivered in fractions over 3-6 weeks after surgery.

Giving the boost of radiation during surgery has numerous benefits, say the authors: it is more convenient for patients and saves on healthcare costs.

However, the controversy over local recurrence rates, sparked by the earlier results, still remains. The difference in the 5-year local recurrence rate between TARGIT and EBRT was within the 2.5% margin for non-inferiority: the rate was 2.11% in 1140 TARGIT recipients, compared with 0.95% in 1158 EBRT recipients, for a difference of 1.16% (13 recurrences).

The new longer-term results from the TARGIT-A trial were published August 20 in the BMJ, and confirm earlier results from this trial published in 2014. Meanwhile, other approaches to intraoperative radiotherapy (IORT) have also been reported.  

Nevertheless, whole-breast radiotherapy remains the standard of care today, note the authors.

“The biggest battle the TARGIT investigator family has faced is our challenge to the conventional dogma that radiotherapy has to be given in multiple daily doses, and moreover that whole-breast radiotherapy is always essential,” said lead author Jayant Vaidya, MD, professor of surgery and oncology at University College London, UK. He was one of the team of investigators that together developed the TARGIT approach in the 1990s, as he recalls in a related BMJ blog post.

It is unclear whether the TARGIT-A long-term outcomes will change practice, Rachel Jimenez, MD, associate program director of the Harvard Radiation Oncology Residency Program and assistant professor of radiation oncology at Massachusetts General Hospital, Boston, told Medscape Medical News.

She noted there was controversy and debate over the earlier reports from TARGIT-A, and those findings “did little to change practice patterns over the past 6 years,” she said.

“With the publication of longer-term follow-up, my expectation would be that perceptions of IORT will remain unchanged in the radiation oncology community, and that those previously supportive of the TARGIT-A approach will continue to embrace it while those initially skeptical will be unlikely to change practice despite the longer-term results,” she said.

“However, despite the controversy surrounding TARGIT-A, it is heartening as a clinician who cares for breast cancer patients to see a trend within the early breast cancer clinical trials space toward the evaluation of increasingly targeted and abbreviated courses of radiation,” Jimenez commented.
 

Details of new long-term results

TARGIT-A is an open-label, 32-center multinational study conducted in 2298 women aged 45 years or older with early-stage invasive ductal carcinoma who were eligible for breast-conserving surgery. Between March 24, 2000, and June 25, 2012, participants were randomized 1:1 to risk-adapted TARGIT immediately after lumpectomy or to whole-breast EBRT delivered for the standard 3-6 week daily fractionated course.

At a median follow-up of 8.6 years — with some patients followed for nearly 19 years — no significant difference was seen between the treatment groups in local recurrence-free survival (167 vs 147 events; hazard ratio, 1.13); invasive local recurrence-free survival (154 vs 146 events; HR, 1.04); mastectomy-free survival (170 vs 175 events; HR, 0.96); distant disease-free survival (133 vs 148 events; HR, 0.88); overall survival (110 vs 131 events; HR, 0.82); or breast cancer mortality (6 vs 57 events; HR, 1.12).

“Mortality from other causes was significantly lower (45 vs 74 events; HR, 0.59),” the authors note.
 

Controversy of Earlier Results

Vaidya and colleagues comment that these new results confirm earlier findings from this trial. They were initially presented in 2012 by Vaidya at the San Antonio Breast Cancer Symposium and subsequently published in The Lancet, as previously reported by Medscape Medical News. Those earlier results showed a trend toward lower overall mortality with TARGIT (absolute difference, -1.3%; P = .01) and significantly fewer deaths from causes other than breast cancer (absolute difference, -2.1%; P = .009).

However, TARGIT was associated with slightly more same-breast recurrences at that time (3.3% vs 1.3%; P = 0.42), even though this was still within the 2.5% margin for non-inferiority.

The new longer-term results show a similar pattern.

It was this risk of same-breast recurrences that sparked the heated debate over the findings, as some breast cancer experts argued that this needs to be weighed against various potential benefits of IORT for patients: greater convenience, potentially improved mortality, and lower costs.

The extent of that “vigorous debate” was highlighted in 2015 in the International Journal of Radiation Oncology, Biology, Physics, (the Red Journal), in which editor-in-chief Anthony Zietman, MD, shared numerous letters to the editor, written in response to two editorials, that contained “passionately and articulately expressed” views from “senior investigators and breast cancer physicians from around the globe.”

At the same time, in 2015, another approach to IORT was reported at the American Society for Radiation Oncology (ASTRO) annual meeting and simultaneously published online in The Lancet. This was accelerated partial-breast irradiation (APBI) delivered directly to the tumor bed using multicatheter brachytherapy at the time of lumpectomy in women with early breast cancer. The results showed outcomes that were comparable with whole-breast irradiation, but with fewer side effects.

Those findings prompted a 2016 update to the ASTRO consensus statement on APBI to note that APBI after lumpectomy may be suitable for more women with early-stage breast cancer, including younger patients and those with ductal carcinoma in situ.

In comments to Medscape Medical News, Jimenez noted that several recent studies have shown efficacy for various IORT approaches. There have been two phase 3 non-inferiority studies, namely the NSABP B-39 and the RAPID trial, that evaluate the use of APBI in lieu of whole-breast radiation. There have also been two trials as well as the evaluation of a 5-day ultrahypofractionated whole-breast radiation course per the UK Fast and Fast-Forward trials, compared with several weeks of whole-breast radiation.  

“Collectively, these studies lend support for fewer and/or more targeted radiotherapy treatments for our patients and have the potential to reduce patient burden and limit healthcare costs,” Jimenez told Medscape Medical News.

Indeed, the TARGIT-A researchers write that their long-term findings “have shown that risk-adapted single-dose TARGIT-IORT given during lumpectomy can effectively replace the mandatory use of several weeks of daily postoperative whole-breast radiotherapy in patients with breast cancer undergoing breast conservation.”

Given the numerous benefits to patients that this approach provides, the choice should ultimately rest with the patient, the authors conclude.

An extended follow-up of the trial (TARGIT-Ex) is ongoing, as is the TARGIT-B(oost) trial looking at TARGIT-IORT as a tumor bed boost with EBRT boost in younger women and those with higher-risk disease.

The TARGIT-A trial was sponsored by University College London Hospitals (UCLH) Comprehensive Biomedical Research Centre and funded by UCLH Charities, the National Institute for Health Research Health Technology Assessment program, Ninewells Cancer Campaign, the National Health and Medical Research Council, and the German Federal Ministry of Education and Research. The authors reported numerous disclosures, as detailed in the publication.
 

This article first appeared on Medscape.com.

Long-term outcomes now being reported confirm earlier reports from the same trial showing efficacy for the use of targeted intraoperative radiotherapy (TARGIT) in patients with early breast cancer.

This novel approach, which delivers a one-off blast of radiation directed at the tumor bed and is given during lumpectomy, has similar efficacy and lowers non–breast cancer mortality when compared with whole-breast external beam radiotherapy (EBRT), which is delivered in fractions over 3-6 weeks after surgery.

Giving the boost of radiation during surgery has numerous benefits, say the authors: it is more convenient for patients and saves on healthcare costs.

However, the controversy over local recurrence rates, sparked by the earlier results, still remains. The difference in the 5-year local recurrence rate between TARGIT and EBRT was within the 2.5% margin for non-inferiority: the rate was 2.11% in 1140 TARGIT recipients, compared with 0.95% in 1158 EBRT recipients, for a difference of 1.16% (13 recurrences).

The new longer-term results from the TARGIT-A trial were published August 20 in the BMJ, and confirm earlier results from this trial published in 2014. Meanwhile, other approaches to intraoperative radiotherapy (IORT) have also been reported.  

Nevertheless, whole-breast radiotherapy remains the standard of care today, note the authors.

“The biggest battle the TARGIT investigator family has faced is our challenge to the conventional dogma that radiotherapy has to be given in multiple daily doses, and moreover that whole-breast radiotherapy is always essential,” said lead author Jayant Vaidya, MD, professor of surgery and oncology at University College London, UK. He was one of the team of investigators that together developed the TARGIT approach in the 1990s, as he recalls in a related BMJ blog post.

It is unclear whether the TARGIT-A long-term outcomes will change practice, Rachel Jimenez, MD, associate program director of the Harvard Radiation Oncology Residency Program and assistant professor of radiation oncology at Massachusetts General Hospital, Boston, told Medscape Medical News.

She noted there was controversy and debate over the earlier reports from TARGIT-A, and those findings “did little to change practice patterns over the past 6 years,” she said.

“With the publication of longer-term follow-up, my expectation would be that perceptions of IORT will remain unchanged in the radiation oncology community, and that those previously supportive of the TARGIT-A approach will continue to embrace it while those initially skeptical will be unlikely to change practice despite the longer-term results,” she said.

“However, despite the controversy surrounding TARGIT-A, it is heartening as a clinician who cares for breast cancer patients to see a trend within the early breast cancer clinical trials space toward the evaluation of increasingly targeted and abbreviated courses of radiation,” Jimenez commented.
 

Details of new long-term results

TARGIT-A is an open-label, 32-center multinational study conducted in 2298 women aged 45 years or older with early-stage invasive ductal carcinoma who were eligible for breast-conserving surgery. Between March 24, 2000, and June 25, 2012, participants were randomized 1:1 to risk-adapted TARGIT immediately after lumpectomy or to whole-breast EBRT delivered for the standard 3-6 week daily fractionated course.

At a median follow-up of 8.6 years — with some patients followed for nearly 19 years — no significant difference was seen between the treatment groups in local recurrence-free survival (167 vs 147 events; hazard ratio, 1.13); invasive local recurrence-free survival (154 vs 146 events; HR, 1.04); mastectomy-free survival (170 vs 175 events; HR, 0.96); distant disease-free survival (133 vs 148 events; HR, 0.88); overall survival (110 vs 131 events; HR, 0.82); or breast cancer mortality (6 vs 57 events; HR, 1.12).

“Mortality from other causes was significantly lower (45 vs 74 events; HR, 0.59),” the authors note.
 

Controversy of Earlier Results

Vaidya and colleagues comment that these new results confirm earlier findings from this trial. They were initially presented in 2012 by Vaidya at the San Antonio Breast Cancer Symposium and subsequently published in The Lancet, as previously reported by Medscape Medical News. Those earlier results showed a trend toward lower overall mortality with TARGIT (absolute difference, -1.3%; P = .01) and significantly fewer deaths from causes other than breast cancer (absolute difference, -2.1%; P = .009).

However, TARGIT was associated with slightly more same-breast recurrences at that time (3.3% vs 1.3%; P = 0.42), even though this was still within the 2.5% margin for non-inferiority.

The new longer-term results show a similar pattern.

It was this risk of same-breast recurrences that sparked the heated debate over the findings, as some breast cancer experts argued that this needs to be weighed against various potential benefits of IORT for patients: greater convenience, potentially improved mortality, and lower costs.

The extent of that “vigorous debate” was highlighted in 2015 in the International Journal of Radiation Oncology, Biology, Physics, (the Red Journal), in which editor-in-chief Anthony Zietman, MD, shared numerous letters to the editor, written in response to two editorials, that contained “passionately and articulately expressed” views from “senior investigators and breast cancer physicians from around the globe.”

At the same time, in 2015, another approach to IORT was reported at the American Society for Radiation Oncology (ASTRO) annual meeting and simultaneously published online in The Lancet. This was accelerated partial-breast irradiation (APBI) delivered directly to the tumor bed using multicatheter brachytherapy at the time of lumpectomy in women with early breast cancer. The results showed outcomes that were comparable with whole-breast irradiation, but with fewer side effects.

Those findings prompted a 2016 update to the ASTRO consensus statement on APBI to note that APBI after lumpectomy may be suitable for more women with early-stage breast cancer, including younger patients and those with ductal carcinoma in situ.

In comments to Medscape Medical News, Jimenez noted that several recent studies have shown efficacy for various IORT approaches. There have been two phase 3 non-inferiority studies, namely the NSABP B-39 and the RAPID trial, that evaluate the use of APBI in lieu of whole-breast radiation. There have also been two trials as well as the evaluation of a 5-day ultrahypofractionated whole-breast radiation course per the UK Fast and Fast-Forward trials, compared with several weeks of whole-breast radiation.  

“Collectively, these studies lend support for fewer and/or more targeted radiotherapy treatments for our patients and have the potential to reduce patient burden and limit healthcare costs,” Jimenez told Medscape Medical News.

Indeed, the TARGIT-A researchers write that their long-term findings “have shown that risk-adapted single-dose TARGIT-IORT given during lumpectomy can effectively replace the mandatory use of several weeks of daily postoperative whole-breast radiotherapy in patients with breast cancer undergoing breast conservation.”

Given the numerous benefits to patients that this approach provides, the choice should ultimately rest with the patient, the authors conclude.

An extended follow-up of the trial (TARGIT-Ex) is ongoing, as is the TARGIT-B(oost) trial looking at TARGIT-IORT as a tumor bed boost with EBRT boost in younger women and those with higher-risk disease.

The TARGIT-A trial was sponsored by University College London Hospitals (UCLH) Comprehensive Biomedical Research Centre and funded by UCLH Charities, the National Institute for Health Research Health Technology Assessment program, Ninewells Cancer Campaign, the National Health and Medical Research Council, and the German Federal Ministry of Education and Research. The authors reported numerous disclosures, as detailed in the publication.
 

This article first appeared on Medscape.com.

Long-term outcomes now being reported confirm earlier reports from the same trial showing efficacy for the use of targeted intraoperative radiotherapy (TARGIT) in patients with early breast cancer.

This novel approach, which delivers a one-off blast of radiation directed at the tumor bed and is given during lumpectomy, has similar efficacy and lowers non–breast cancer mortality when compared with whole-breast external beam radiotherapy (EBRT), which is delivered in fractions over 3-6 weeks after surgery.

Giving the boost of radiation during surgery has numerous benefits, say the authors: it is more convenient for patients and saves on healthcare costs.

However, the controversy over local recurrence rates, sparked by the earlier results, still remains. The difference in the 5-year local recurrence rate between TARGIT and EBRT was within the 2.5% margin for non-inferiority: the rate was 2.11% in 1140 TARGIT recipients, compared with 0.95% in 1158 EBRT recipients, for a difference of 1.16% (13 recurrences).

The new longer-term results from the TARGIT-A trial were published August 20 in the BMJ, and confirm earlier results from this trial published in 2014. Meanwhile, other approaches to intraoperative radiotherapy (IORT) have also been reported.  

Nevertheless, whole-breast radiotherapy remains the standard of care today, note the authors.

“The biggest battle the TARGIT investigator family has faced is our challenge to the conventional dogma that radiotherapy has to be given in multiple daily doses, and moreover that whole-breast radiotherapy is always essential,” said lead author Jayant Vaidya, MD, professor of surgery and oncology at University College London, UK. He was one of the team of investigators that together developed the TARGIT approach in the 1990s, as he recalls in a related BMJ blog post.

It is unclear whether the TARGIT-A long-term outcomes will change practice, Rachel Jimenez, MD, associate program director of the Harvard Radiation Oncology Residency Program and assistant professor of radiation oncology at Massachusetts General Hospital, Boston, told Medscape Medical News.

She noted there was controversy and debate over the earlier reports from TARGIT-A, and those findings “did little to change practice patterns over the past 6 years,” she said.

“With the publication of longer-term follow-up, my expectation would be that perceptions of IORT will remain unchanged in the radiation oncology community, and that those previously supportive of the TARGIT-A approach will continue to embrace it while those initially skeptical will be unlikely to change practice despite the longer-term results,” she said.

“However, despite the controversy surrounding TARGIT-A, it is heartening as a clinician who cares for breast cancer patients to see a trend within the early breast cancer clinical trials space toward the evaluation of increasingly targeted and abbreviated courses of radiation,” Jimenez commented.
 

Details of new long-term results

TARGIT-A is an open-label, 32-center multinational study conducted in 2298 women aged 45 years or older with early-stage invasive ductal carcinoma who were eligible for breast-conserving surgery. Between March 24, 2000, and June 25, 2012, participants were randomized 1:1 to risk-adapted TARGIT immediately after lumpectomy or to whole-breast EBRT delivered for the standard 3-6 week daily fractionated course.

At a median follow-up of 8.6 years — with some patients followed for nearly 19 years — no significant difference was seen between the treatment groups in local recurrence-free survival (167 vs 147 events; hazard ratio, 1.13); invasive local recurrence-free survival (154 vs 146 events; HR, 1.04); mastectomy-free survival (170 vs 175 events; HR, 0.96); distant disease-free survival (133 vs 148 events; HR, 0.88); overall survival (110 vs 131 events; HR, 0.82); or breast cancer mortality (6 vs 57 events; HR, 1.12).

“Mortality from other causes was significantly lower (45 vs 74 events; HR, 0.59),” the authors note.
 

Controversy of Earlier Results

Vaidya and colleagues comment that these new results confirm earlier findings from this trial. They were initially presented in 2012 by Vaidya at the San Antonio Breast Cancer Symposium and subsequently published in The Lancet, as previously reported by Medscape Medical News. Those earlier results showed a trend toward lower overall mortality with TARGIT (absolute difference, -1.3%; P = .01) and significantly fewer deaths from causes other than breast cancer (absolute difference, -2.1%; P = .009).

However, TARGIT was associated with slightly more same-breast recurrences at that time (3.3% vs 1.3%; P = 0.42), even though this was still within the 2.5% margin for non-inferiority.

The new longer-term results show a similar pattern.

It was this risk of same-breast recurrences that sparked the heated debate over the findings, as some breast cancer experts argued that this needs to be weighed against various potential benefits of IORT for patients: greater convenience, potentially improved mortality, and lower costs.

The extent of that “vigorous debate” was highlighted in 2015 in the International Journal of Radiation Oncology, Biology, Physics, (the Red Journal), in which editor-in-chief Anthony Zietman, MD, shared numerous letters to the editor, written in response to two editorials, that contained “passionately and articulately expressed” views from “senior investigators and breast cancer physicians from around the globe.”

At the same time, in 2015, another approach to IORT was reported at the American Society for Radiation Oncology (ASTRO) annual meeting and simultaneously published online in The Lancet. This was accelerated partial-breast irradiation (APBI) delivered directly to the tumor bed using multicatheter brachytherapy at the time of lumpectomy in women with early breast cancer. The results showed outcomes that were comparable with whole-breast irradiation, but with fewer side effects.

Those findings prompted a 2016 update to the ASTRO consensus statement on APBI to note that APBI after lumpectomy may be suitable for more women with early-stage breast cancer, including younger patients and those with ductal carcinoma in situ.

In comments to Medscape Medical News, Jimenez noted that several recent studies have shown efficacy for various IORT approaches. There have been two phase 3 non-inferiority studies, namely the NSABP B-39 and the RAPID trial, that evaluate the use of APBI in lieu of whole-breast radiation. There have also been two trials as well as the evaluation of a 5-day ultrahypofractionated whole-breast radiation course per the UK Fast and Fast-Forward trials, compared with several weeks of whole-breast radiation.  

“Collectively, these studies lend support for fewer and/or more targeted radiotherapy treatments for our patients and have the potential to reduce patient burden and limit healthcare costs,” Jimenez told Medscape Medical News.

Indeed, the TARGIT-A researchers write that their long-term findings “have shown that risk-adapted single-dose TARGIT-IORT given during lumpectomy can effectively replace the mandatory use of several weeks of daily postoperative whole-breast radiotherapy in patients with breast cancer undergoing breast conservation.”

Given the numerous benefits to patients that this approach provides, the choice should ultimately rest with the patient, the authors conclude.

An extended follow-up of the trial (TARGIT-Ex) is ongoing, as is the TARGIT-B(oost) trial looking at TARGIT-IORT as a tumor bed boost with EBRT boost in younger women and those with higher-risk disease.

The TARGIT-A trial was sponsored by University College London Hospitals (UCLH) Comprehensive Biomedical Research Centre and funded by UCLH Charities, the National Institute for Health Research Health Technology Assessment program, Ninewells Cancer Campaign, the National Health and Medical Research Council, and the German Federal Ministry of Education and Research. The authors reported numerous disclosures, as detailed in the publication.
 

This article first appeared on Medscape.com.

Children represented 9.3% of all U.S. COVID-19 cases as of Aug. 20, 2020 – an increase from 9.1% the previous week – but only 0.06% of all U.S. deaths reported, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

The cumulative number of pediatric cases reported up to that date was 442,785, or 9.3% of the total COVID-19 case load of more than 4.76 million among all ages. There have been only 92 pediatric deaths, however, which works out to just 0.06% of the 154,279 reported for all ages, the AAP and the CHA said Aug. 24 in their most recent update.

Child hospitalizations also were on the low side, representing 1.7% (4,062) of the cumulative total of 234,810 admissions among all ages as of Aug. 20, based on data from 21 states and New York City.

Nationally, the cumulative number of reported child cases is now up to 583 per 100,000 children, and that figure covers 49 states, Washington, D.C., Guam, New York City, and Puerto Rico.

There is some disagreement among the states, though, about the definition of “child.” Most states use an age range of 0-17, 0-18, or 0-19, but Florida and Utah go with a range of 0-14 years while South Carolina and Tennessee consider humans aged 0-20 years to be children. Other data limitations involve Texas, which has reported age distribution for only 8% of all cases, and New York, which is not reporting the age distribution of statewide cases, the AAP/CHA report noted.

The definition of child isn’t the only thing that varies between the states. The cumulative case rate for Tennessee, the highest in the country at 1,315 per 100,000 children, is 10 times that of Vermont, which is the lowest at 131 per 100,000, the AAP and CHA said. Vermont reports child COVID-19 cases using an age range of 0-19 years.

The other states with rates over 1,000 cases per 100,000 children are Arizona (1,300), which had the highest rate a week ago; South Carolina (1,214); Louisiana (1,127); Mississippi (1,120); and Nevada (1,068). Those with rates below 200 cases per 100,000 children are Maine (150), New Hampshire (175), and Hawaii (188), according to this week’s report.

rfranki@mdedge.com

Children represented 9.3% of all U.S. COVID-19 cases as of Aug. 20, 2020 – an increase from 9.1% the previous week – but only 0.06% of all U.S. deaths reported, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

The cumulative number of pediatric cases reported up to that date was 442,785, or 9.3% of the total COVID-19 case load of more than 4.76 million among all ages. There have been only 92 pediatric deaths, however, which works out to just 0.06% of the 154,279 reported for all ages, the AAP and the CHA said Aug. 24 in their most recent update.

Child hospitalizations also were on the low side, representing 1.7% (4,062) of the cumulative total of 234,810 admissions among all ages as of Aug. 20, based on data from 21 states and New York City.

Nationally, the cumulative number of reported child cases is now up to 583 per 100,000 children, and that figure covers 49 states, Washington, D.C., Guam, New York City, and Puerto Rico.

There is some disagreement among the states, though, about the definition of “child.” Most states use an age range of 0-17, 0-18, or 0-19, but Florida and Utah go with a range of 0-14 years while South Carolina and Tennessee consider humans aged 0-20 years to be children. Other data limitations involve Texas, which has reported age distribution for only 8% of all cases, and New York, which is not reporting the age distribution of statewide cases, the AAP/CHA report noted.

The definition of child isn’t the only thing that varies between the states. The cumulative case rate for Tennessee, the highest in the country at 1,315 per 100,000 children, is 10 times that of Vermont, which is the lowest at 131 per 100,000, the AAP and CHA said. Vermont reports child COVID-19 cases using an age range of 0-19 years.

The other states with rates over 1,000 cases per 100,000 children are Arizona (1,300), which had the highest rate a week ago; South Carolina (1,214); Louisiana (1,127); Mississippi (1,120); and Nevada (1,068). Those with rates below 200 cases per 100,000 children are Maine (150), New Hampshire (175), and Hawaii (188), according to this week’s report.

rfranki@mdedge.com

Children represented 9.3% of all U.S. COVID-19 cases as of Aug. 20, 2020 – an increase from 9.1% the previous week – but only 0.06% of all U.S. deaths reported, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

The cumulative number of pediatric cases reported up to that date was 442,785, or 9.3% of the total COVID-19 case load of more than 4.76 million among all ages. There have been only 92 pediatric deaths, however, which works out to just 0.06% of the 154,279 reported for all ages, the AAP and the CHA said Aug. 24 in their most recent update.

Child hospitalizations also were on the low side, representing 1.7% (4,062) of the cumulative total of 234,810 admissions among all ages as of Aug. 20, based on data from 21 states and New York City.

Nationally, the cumulative number of reported child cases is now up to 583 per 100,000 children, and that figure covers 49 states, Washington, D.C., Guam, New York City, and Puerto Rico.

There is some disagreement among the states, though, about the definition of “child.” Most states use an age range of 0-17, 0-18, or 0-19, but Florida and Utah go with a range of 0-14 years while South Carolina and Tennessee consider humans aged 0-20 years to be children. Other data limitations involve Texas, which has reported age distribution for only 8% of all cases, and New York, which is not reporting the age distribution of statewide cases, the AAP/CHA report noted.

The definition of child isn’t the only thing that varies between the states. The cumulative case rate for Tennessee, the highest in the country at 1,315 per 100,000 children, is 10 times that of Vermont, which is the lowest at 131 per 100,000, the AAP and CHA said. Vermont reports child COVID-19 cases using an age range of 0-19 years.

The other states with rates over 1,000 cases per 100,000 children are Arizona (1,300), which had the highest rate a week ago; South Carolina (1,214); Louisiana (1,127); Mississippi (1,120); and Nevada (1,068). Those with rates below 200 cases per 100,000 children are Maine (150), New Hampshire (175), and Hawaii (188), according to this week’s report.

rfranki@mdedge.com

I wrote these poems in mid-March, when fear of COVID-19 struck and New York City locked down. Nearly a half-year later, the impact continues with uncertainty everywhere.

Before and After

Before – there were trees,

I hardly noticed them.

There were buses and newspapers.

Should I read a book or the Post?

Am I wasting time looking

out the window at crowds

milling into Central Park?

The tourists walk to Strawberry Fields,

and the bus turns to Central Park West.

I hardly noticed

because I had plans.

After – it ended, first slowly,

then abruptly. We sat together

in the shop, knitting,

only three of us

before the store shut.

After that –

In the park daffodils radiate gold

and grow in groups.

And the magnolia trees

flaunt their succulent petals.

The fragile cherry blossoms float flowers

Still – it is after

And before, there were trees

I hardly noticed.
 

War Means Nothing to Them

The birds and the trees know nothing.

They are not embarrassed.

The birds chirp, the trees flower;

War means nothing to them.

Grass grows thick and green,

welcomes the spring.

Babies too, even toddlers,

go about their infant business.

They play or coo or smile

as happy as the birds, the trees,

the grass, flush with life.

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.

I wrote these poems in mid-March, when fear of COVID-19 struck and New York City locked down. Nearly a half-year later, the impact continues with uncertainty everywhere.

Before and After

Before – there were trees,

I hardly noticed them.

There were buses and newspapers.

Should I read a book or the Post?

Am I wasting time looking

out the window at crowds

milling into Central Park?

The tourists walk to Strawberry Fields,

and the bus turns to Central Park West.

I hardly noticed

because I had plans.

After – it ended, first slowly,

then abruptly. We sat together

in the shop, knitting,

only three of us

before the store shut.

After that –

In the park daffodils radiate gold

and grow in groups.

And the magnolia trees

flaunt their succulent petals.

The fragile cherry blossoms float flowers

Still – it is after

And before, there were trees

I hardly noticed.
 

War Means Nothing to Them

The birds and the trees know nothing.

They are not embarrassed.

The birds chirp, the trees flower;

War means nothing to them.

Grass grows thick and green,

welcomes the spring.

Babies too, even toddlers,

go about their infant business.

They play or coo or smile

as happy as the birds, the trees,

the grass, flush with life.

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.

I wrote these poems in mid-March, when fear of COVID-19 struck and New York City locked down. Nearly a half-year later, the impact continues with uncertainty everywhere.

Before and After

Before – there were trees,

I hardly noticed them.

There were buses and newspapers.

Should I read a book or the Post?

Am I wasting time looking

out the window at crowds

milling into Central Park?

The tourists walk to Strawberry Fields,

and the bus turns to Central Park West.

I hardly noticed

because I had plans.

After – it ended, first slowly,

then abruptly. We sat together

in the shop, knitting,

only three of us

before the store shut.

After that –

In the park daffodils radiate gold

and grow in groups.

And the magnolia trees

flaunt their succulent petals.

The fragile cherry blossoms float flowers

Still – it is after

And before, there were trees

I hardly noticed.
 

War Means Nothing to Them

The birds and the trees know nothing.

They are not embarrassed.

The birds chirp, the trees flower;

War means nothing to them.

Grass grows thick and green,

welcomes the spring.

Babies too, even toddlers,

go about their infant business.

They play or coo or smile

as happy as the birds, the trees,

the grass, flush with life.

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.

The hypersomnias are an etiologically diverse group of disorders of wakefulness and sleep, characterized principally by excessive daytime sleepiness (EDS), often despite sufficient or even long total sleep durations. Hypersomnolence may be severely disabling and isolating for patients, is associated with decreased quality of life and economic disadvantage, and, in some cases, may pose a personal and public health danger through drowsy driving. Though historically, management of these patients has been principally supportive and aimed at reducing daytime functional impairment, new and evolving treatments are quickly changing management paradigms in this population. This brief review highlights some of the newest pharmacotherapeutic advances in this dynamic field.

Hypersomnolence is a common presenting concern primary care and sleep clinics, with an estimated prevalence of EDS in the general adult population of as high as 6%.¹ The initial diagnosis of hypersomnia is, broadly, a clinical one, with careful consideration to the patient’s report of daytime sleepiness and functional impairment, sleep/wake cycle, and any medical comorbidities. The primary hypersomnias include narcolepsy type 1 (narcolepsy with cataplexy, NT1) and narcolepsy type 2 (without cataplexy, NT2), Kleine-Levin Syndrome (KLS), and idiopathic hypersomnia. Secondary hypersomnia disorders are more commonly encountered in clinical practice and include hypersomnia attributable to another medical condition (including psychiatric and neurologic disorders), hypersomnia related to medication effects, and EDS related to behaviorally insufficient sleep. Distinguishing primary and secondary etiologies, when possible, is important as treatment pathways may vary considerably between hypersomnias.

Generally, overnight in-lab polysomnography is warranted to exclude untreated or sub-optimally treated sleep-disordered breathing or movement disorders which may undermine sleep quality. In the absence of any such findings, this is usually followed by daytime multiple sleep latency testing (MSLT). The MSLT is comprised of four to five scheduled daytime naps in the sleep lab and is designed to quantify a patient’s propensity to sleep during the day and to identify architectural sleep abnormalities which indicate narcolepsy. Specifically, narcolepsy is identified by MSLT when a patient exhibits a sleep onset latency of ≤ 8 minutes and at least two sleep-onset REM periods (SOREMPs), or, one SOREMP on MSLT with a second noted on the preceding night’s PSG. Actigraphy or sleep logs may be helpful in quantifying a patient’s total sleep time in their home environment. Adjunctive laboratory tests for narcolepsy including HLA typing and CSF hypocretin testing may sometimes be indicated.

General hypersomnia management usually consists of the use of wakefulness promoting agents, such as stimulants (eg, dexmethylphenidate) and dopamine-modulating agents (eg, modafinil, armodafinil), and adjunctive supportive strategies, including planned daytime naps and elimination of modifiable secondary causes. In those patients with hypersomnolence associated with depression or anxiety, the use of antidepressants, including SSRI, SNRI, and DNRIs, is often effective, and these medications can also improve cataplexy symptoms in narcoleptics. KLS may respond to treatment with lithium, shortening the duration of the striking hypersomnolent episodes characteristic of this rare syndrome, and there is some indication that ketamine may also be a helpful adjunctive in some cases. In treatment-refractory cases of hypersomnolence associated with GABA-A receptor potentiation, drugs such as flumazenil and clarithromycin appear to improve subjective measures of hypersomnolence.^2,3 In patients with narcolepsy, sodium oxybate (available as Xyrem and, more recently, as a generic medication) has proven to be clinically very useful, reducing EDS and the frequency and severity of cataplexy and sleep disturbance associated with this condition. In July 2020, the FDA approved a new, low-sodium formulation of sodium oxybate (Xywav) for patients 7 years of age and older with a diagnosis of narcolepsy, a helpful option in those patients with cardiovascular and renal disease.

Despite this broadening armamentarium, in many cases daytime sleepiness and functional impairment is refractory to typical pharmacotherapy. In this context, we would like to highlight two newer pharmacotherapeutic options, solriamfetol and pitolisant.


 

Solriamfetol

Solriamfetol (Sunosi) is a Schedule IV FDA-approved medication indicated for treatment of EDS in adults with narcolepsy or obstructive sleep apnea. The precise mechanism of action is unknown, but this medication is believed to inhibit both dopamine and norepinerphrine reuptake in the brain, similar to the widely-prescribed NDRI buproprion. In a 12-week RCT study on its effects on narcolepsy in adults, solriamfetol improved important measures of wakefulness and sleepiness, without associated polysomnographic evidence of significant sleep disruption.⁴ In another 12-week RCT study of solriamfetol in adult patients with EDS related to OSA, there was a dose-dependent improvement in measures of wakefulness.⁵ Some notable side-effects seen with this medication include anxiety and elevated mood, as well as increases in blood pressure. A subsequent study of this medication found that it was efficacious at maintenance of improvements at 6 months.⁶ Given the theorized mechanism of action as an NDRI, future observation and studies could provide insights on its effect on depression, as well.

Pitolisant

Histaminergic neurons within the CNS play an important role in the promotion of wakefulness. Pitolisant (Wakix) is an interesting wakefulness-promoting agent for adult patients with narcolepsy. It acts as an inverse agonist and antagonist of histamine H3 receptors, resulting in a reduction of the usual feedback inhibition effected through the H3 receptor, thereby enhancing CNS release of histamine and other neurotransmitters. This medication was approved by the FDA in August 2019 and is currently indicated for adult patients with narcolepsy. The HARMONY I trial comparing pitolisant with both placebo and modafinil in adults with narcolepsy and EDS demonstrated improvement in measures of sleepiness and maintenance of wakefulness over placebo, and noninferiority to modafinil.⁷ In addition, pitolisant had a favorable side-effect profile compared with modafinil. Subsequent studies have reaffirmed the safety profile of pitolisant, including its minimal abuse potential. In one recent placebo-controlled trial of the use of pitolisant in a population of 268 adults with positive airway pressure (PAP) non-adherence, pitolisant was found to improve measures of EDS and related patient-reported measurements in patients with OSA who were CPAP nonadherent.⁸ Though generally well-tolerated by patients, in initial clinical trials pitolisant was associated with increased headache, insomnia, and nausea relative to placebo, among other less commonly reported adverse effects. Pitolisant is QT interval-prolonging, so caution must be taken when using this medication in combination other medications which may induce QT interval prolongation, including SSRIs.

Future directions

Greater awareness of the hypersomnias and their management has led to improved outcomes and access to care for these patients, yet these disorders remain burdensome and the treatments imperfect. Looking forward, novel pharmacotherapies that target underlying mechanisms rather than symptom palliation will allow for more precise treatments. Ongoing investigations of hypocretin receptor agonists seek to target one critical central mediator of wakefulness. Recent studies have highlighted the association of dysautonomia with hypersomnia, offering interesting insight into possible future targets to improve the function and quality of life of these patients.⁹ Similarly, understanding of the interplay between psychiatric disorders and primary and secondary hypersomnias may offer new therapeutic pathways.

As treatment plans targeting hypersomnia become more comprehensive and holistic, with an increased emphasis on self-care, sleep hygiene, and mental health awareness, in addition to mechanism-specific treatments, we hope they will ultimately provide improved symptom and burden relief for our patients.
 

Dr. Shih Yee-Marie Tan Gipson is a psychiatrist and Dr. Kevin Gipson is a sleep medicine specialist, both with Massachusetts General Hospital, Boston.

References

¹ Dauvilliers, et al. Hypersomnia. Dialogues Clin Neurosci. 2005;7(4):347-356.

² Trotti, et al. Clarithromycin in gamma-aminobutyric acid-related hypersomnolence: A randomized, crossover trial. Ann Neurol. 2015;78(3):454-465. doi: 10.1002/ana.24459.

³ Trotti, et al. Flumazenil for the treatment of refractory hypersomnolence: Clinical experience with 153 patients. J Clin Sleep Med. 2016;12(10):1389-1394. doi: 10.5664/jcsm.6196.

⁴ Thorpy, et al. A randomized study of solriamfetol for excessive sleepiness in narcolepsy. Ann Neurol. 2019; 85(3):359-370. doi: 10.1002/ana.25423.

⁵ Schweitzer, et al. Solriamfetol for excessive sleepiness in obstructive sleep apnea (TONES 3): A randomized controlled trial. Am J Respir Crit Care Med. 2019;199(11):1421-1431. doi: 10.1164/rccm.201806-1100OC.

⁶ Malhotra, et al. Long-term study of the safety and maintenance of efficacy of solriamfetol (JZP-110) in the treatment of excessive sleepiness in participants with narcolepsy or obstructive sleep apnea. Sleep. 2020; 43(2): doi: 10.1093/sleep/zsz220.

⁷ Dauvilliers, et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013;12(11):1068-1075. doi: 10.1016/S1474-4422(13)70225-4.

⁸ Dauvilliers, et al. Pitolisant for daytime sleepiness in obstructive sleep apnea patients refusing CPAP: A randomized trial. Am J Respir Crit Care Med. 2020. doi: 10.1164/rccm.201907-1284OC.

⁹ Miglis, et al. Frequency and severity of autonomic symptoms in idiopathic hypersomnia. J Clin Sleep Med. 2020; 16(5):749-756. doi: 10.5664/jcsm.8344.
 

The hypersomnias are an etiologically diverse group of disorders of wakefulness and sleep, characterized principally by excessive daytime sleepiness (EDS), often despite sufficient or even long total sleep durations. Hypersomnolence may be severely disabling and isolating for patients, is associated with decreased quality of life and economic disadvantage, and, in some cases, may pose a personal and public health danger through drowsy driving. Though historically, management of these patients has been principally supportive and aimed at reducing daytime functional impairment, new and evolving treatments are quickly changing management paradigms in this population. This brief review highlights some of the newest pharmacotherapeutic advances in this dynamic field.

Hypersomnolence is a common presenting concern primary care and sleep clinics, with an estimated prevalence of EDS in the general adult population of as high as 6%.¹ The initial diagnosis of hypersomnia is, broadly, a clinical one, with careful consideration to the patient’s report of daytime sleepiness and functional impairment, sleep/wake cycle, and any medical comorbidities. The primary hypersomnias include narcolepsy type 1 (narcolepsy with cataplexy, NT1) and narcolepsy type 2 (without cataplexy, NT2), Kleine-Levin Syndrome (KLS), and idiopathic hypersomnia. Secondary hypersomnia disorders are more commonly encountered in clinical practice and include hypersomnia attributable to another medical condition (including psychiatric and neurologic disorders), hypersomnia related to medication effects, and EDS related to behaviorally insufficient sleep. Distinguishing primary and secondary etiologies, when possible, is important as treatment pathways may vary considerably between hypersomnias.

Generally, overnight in-lab polysomnography is warranted to exclude untreated or sub-optimally treated sleep-disordered breathing or movement disorders which may undermine sleep quality. In the absence of any such findings, this is usually followed by daytime multiple sleep latency testing (MSLT). The MSLT is comprised of four to five scheduled daytime naps in the sleep lab and is designed to quantify a patient’s propensity to sleep during the day and to identify architectural sleep abnormalities which indicate narcolepsy. Specifically, narcolepsy is identified by MSLT when a patient exhibits a sleep onset latency of ≤ 8 minutes and at least two sleep-onset REM periods (SOREMPs), or, one SOREMP on MSLT with a second noted on the preceding night’s PSG. Actigraphy or sleep logs may be helpful in quantifying a patient’s total sleep time in their home environment. Adjunctive laboratory tests for narcolepsy including HLA typing and CSF hypocretin testing may sometimes be indicated.

General hypersomnia management usually consists of the use of wakefulness promoting agents, such as stimulants (eg, dexmethylphenidate) and dopamine-modulating agents (eg, modafinil, armodafinil), and adjunctive supportive strategies, including planned daytime naps and elimination of modifiable secondary causes. In those patients with hypersomnolence associated with depression or anxiety, the use of antidepressants, including SSRI, SNRI, and DNRIs, is often effective, and these medications can also improve cataplexy symptoms in narcoleptics. KLS may respond to treatment with lithium, shortening the duration of the striking hypersomnolent episodes characteristic of this rare syndrome, and there is some indication that ketamine may also be a helpful adjunctive in some cases. In treatment-refractory cases of hypersomnolence associated with GABA-A receptor potentiation, drugs such as flumazenil and clarithromycin appear to improve subjective measures of hypersomnolence.^2,3 In patients with narcolepsy, sodium oxybate (available as Xyrem and, more recently, as a generic medication) has proven to be clinically very useful, reducing EDS and the frequency and severity of cataplexy and sleep disturbance associated with this condition. In July 2020, the FDA approved a new, low-sodium formulation of sodium oxybate (Xywav) for patients 7 years of age and older with a diagnosis of narcolepsy, a helpful option in those patients with cardiovascular and renal disease.

Despite this broadening armamentarium, in many cases daytime sleepiness and functional impairment is refractory to typical pharmacotherapy. In this context, we would like to highlight two newer pharmacotherapeutic options, solriamfetol and pitolisant.


 

Solriamfetol

Solriamfetol (Sunosi) is a Schedule IV FDA-approved medication indicated for treatment of EDS in adults with narcolepsy or obstructive sleep apnea. The precise mechanism of action is unknown, but this medication is believed to inhibit both dopamine and norepinerphrine reuptake in the brain, similar to the widely-prescribed NDRI buproprion. In a 12-week RCT study on its effects on narcolepsy in adults, solriamfetol improved important measures of wakefulness and sleepiness, without associated polysomnographic evidence of significant sleep disruption.⁴ In another 12-week RCT study of solriamfetol in adult patients with EDS related to OSA, there was a dose-dependent improvement in measures of wakefulness.⁵ Some notable side-effects seen with this medication include anxiety and elevated mood, as well as increases in blood pressure. A subsequent study of this medication found that it was efficacious at maintenance of improvements at 6 months.⁶ Given the theorized mechanism of action as an NDRI, future observation and studies could provide insights on its effect on depression, as well.

Pitolisant

Histaminergic neurons within the CNS play an important role in the promotion of wakefulness. Pitolisant (Wakix) is an interesting wakefulness-promoting agent for adult patients with narcolepsy. It acts as an inverse agonist and antagonist of histamine H3 receptors, resulting in a reduction of the usual feedback inhibition effected through the H3 receptor, thereby enhancing CNS release of histamine and other neurotransmitters. This medication was approved by the FDA in August 2019 and is currently indicated for adult patients with narcolepsy. The HARMONY I trial comparing pitolisant with both placebo and modafinil in adults with narcolepsy and EDS demonstrated improvement in measures of sleepiness and maintenance of wakefulness over placebo, and noninferiority to modafinil.⁷ In addition, pitolisant had a favorable side-effect profile compared with modafinil. Subsequent studies have reaffirmed the safety profile of pitolisant, including its minimal abuse potential. In one recent placebo-controlled trial of the use of pitolisant in a population of 268 adults with positive airway pressure (PAP) non-adherence, pitolisant was found to improve measures of EDS and related patient-reported measurements in patients with OSA who were CPAP nonadherent.⁸ Though generally well-tolerated by patients, in initial clinical trials pitolisant was associated with increased headache, insomnia, and nausea relative to placebo, among other less commonly reported adverse effects. Pitolisant is QT interval-prolonging, so caution must be taken when using this medication in combination other medications which may induce QT interval prolongation, including SSRIs.

Future directions

Greater awareness of the hypersomnias and their management has led to improved outcomes and access to care for these patients, yet these disorders remain burdensome and the treatments imperfect. Looking forward, novel pharmacotherapies that target underlying mechanisms rather than symptom palliation will allow for more precise treatments. Ongoing investigations of hypocretin receptor agonists seek to target one critical central mediator of wakefulness. Recent studies have highlighted the association of dysautonomia with hypersomnia, offering interesting insight into possible future targets to improve the function and quality of life of these patients.⁹ Similarly, understanding of the interplay between psychiatric disorders and primary and secondary hypersomnias may offer new therapeutic pathways.

As treatment plans targeting hypersomnia become more comprehensive and holistic, with an increased emphasis on self-care, sleep hygiene, and mental health awareness, in addition to mechanism-specific treatments, we hope they will ultimately provide improved symptom and burden relief for our patients.
 

Dr. Shih Yee-Marie Tan Gipson is a psychiatrist and Dr. Kevin Gipson is a sleep medicine specialist, both with Massachusetts General Hospital, Boston.

References

¹ Dauvilliers, et al. Hypersomnia. Dialogues Clin Neurosci. 2005;7(4):347-356.

² Trotti, et al. Clarithromycin in gamma-aminobutyric acid-related hypersomnolence: A randomized, crossover trial. Ann Neurol. 2015;78(3):454-465. doi: 10.1002/ana.24459.

³ Trotti, et al. Flumazenil for the treatment of refractory hypersomnolence: Clinical experience with 153 patients. J Clin Sleep Med. 2016;12(10):1389-1394. doi: 10.5664/jcsm.6196.

⁴ Thorpy, et al. A randomized study of solriamfetol for excessive sleepiness in narcolepsy. Ann Neurol. 2019; 85(3):359-370. doi: 10.1002/ana.25423.

⁵ Schweitzer, et al. Solriamfetol for excessive sleepiness in obstructive sleep apnea (TONES 3): A randomized controlled trial. Am J Respir Crit Care Med. 2019;199(11):1421-1431. doi: 10.1164/rccm.201806-1100OC.

⁶ Malhotra, et al. Long-term study of the safety and maintenance of efficacy of solriamfetol (JZP-110) in the treatment of excessive sleepiness in participants with narcolepsy or obstructive sleep apnea. Sleep. 2020; 43(2): doi: 10.1093/sleep/zsz220.

⁷ Dauvilliers, et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013;12(11):1068-1075. doi: 10.1016/S1474-4422(13)70225-4.

⁸ Dauvilliers, et al. Pitolisant for daytime sleepiness in obstructive sleep apnea patients refusing CPAP: A randomized trial. Am J Respir Crit Care Med. 2020. doi: 10.1164/rccm.201907-1284OC.

⁹ Miglis, et al. Frequency and severity of autonomic symptoms in idiopathic hypersomnia. J Clin Sleep Med. 2020; 16(5):749-756. doi: 10.5664/jcsm.8344.
 

The hypersomnias are an etiologically diverse group of disorders of wakefulness and sleep, characterized principally by excessive daytime sleepiness (EDS), often despite sufficient or even long total sleep durations. Hypersomnolence may be severely disabling and isolating for patients, is associated with decreased quality of life and economic disadvantage, and, in some cases, may pose a personal and public health danger through drowsy driving. Though historically, management of these patients has been principally supportive and aimed at reducing daytime functional impairment, new and evolving treatments are quickly changing management paradigms in this population. This brief review highlights some of the newest pharmacotherapeutic advances in this dynamic field.

Hypersomnolence is a common presenting concern primary care and sleep clinics, with an estimated prevalence of EDS in the general adult population of as high as 6%.¹ The initial diagnosis of hypersomnia is, broadly, a clinical one, with careful consideration to the patient’s report of daytime sleepiness and functional impairment, sleep/wake cycle, and any medical comorbidities. The primary hypersomnias include narcolepsy type 1 (narcolepsy with cataplexy, NT1) and narcolepsy type 2 (without cataplexy, NT2), Kleine-Levin Syndrome (KLS), and idiopathic hypersomnia. Secondary hypersomnia disorders are more commonly encountered in clinical practice and include hypersomnia attributable to another medical condition (including psychiatric and neurologic disorders), hypersomnia related to medication effects, and EDS related to behaviorally insufficient sleep. Distinguishing primary and secondary etiologies, when possible, is important as treatment pathways may vary considerably between hypersomnias.

Generally, overnight in-lab polysomnography is warranted to exclude untreated or sub-optimally treated sleep-disordered breathing or movement disorders which may undermine sleep quality. In the absence of any such findings, this is usually followed by daytime multiple sleep latency testing (MSLT). The MSLT is comprised of four to five scheduled daytime naps in the sleep lab and is designed to quantify a patient’s propensity to sleep during the day and to identify architectural sleep abnormalities which indicate narcolepsy. Specifically, narcolepsy is identified by MSLT when a patient exhibits a sleep onset latency of ≤ 8 minutes and at least two sleep-onset REM periods (SOREMPs), or, one SOREMP on MSLT with a second noted on the preceding night’s PSG. Actigraphy or sleep logs may be helpful in quantifying a patient’s total sleep time in their home environment. Adjunctive laboratory tests for narcolepsy including HLA typing and CSF hypocretin testing may sometimes be indicated.

General hypersomnia management usually consists of the use of wakefulness promoting agents, such as stimulants (eg, dexmethylphenidate) and dopamine-modulating agents (eg, modafinil, armodafinil), and adjunctive supportive strategies, including planned daytime naps and elimination of modifiable secondary causes. In those patients with hypersomnolence associated with depression or anxiety, the use of antidepressants, including SSRI, SNRI, and DNRIs, is often effective, and these medications can also improve cataplexy symptoms in narcoleptics. KLS may respond to treatment with lithium, shortening the duration of the striking hypersomnolent episodes characteristic of this rare syndrome, and there is some indication that ketamine may also be a helpful adjunctive in some cases. In treatment-refractory cases of hypersomnolence associated with GABA-A receptor potentiation, drugs such as flumazenil and clarithromycin appear to improve subjective measures of hypersomnolence.^2,3 In patients with narcolepsy, sodium oxybate (available as Xyrem and, more recently, as a generic medication) has proven to be clinically very useful, reducing EDS and the frequency and severity of cataplexy and sleep disturbance associated with this condition. In July 2020, the FDA approved a new, low-sodium formulation of sodium oxybate (Xywav) for patients 7 years of age and older with a diagnosis of narcolepsy, a helpful option in those patients with cardiovascular and renal disease.

Despite this broadening armamentarium, in many cases daytime sleepiness and functional impairment is refractory to typical pharmacotherapy. In this context, we would like to highlight two newer pharmacotherapeutic options, solriamfetol and pitolisant.


 

Solriamfetol

Solriamfetol (Sunosi) is a Schedule IV FDA-approved medication indicated for treatment of EDS in adults with narcolepsy or obstructive sleep apnea. The precise mechanism of action is unknown, but this medication is believed to inhibit both dopamine and norepinerphrine reuptake in the brain, similar to the widely-prescribed NDRI buproprion. In a 12-week RCT study on its effects on narcolepsy in adults, solriamfetol improved important measures of wakefulness and sleepiness, without associated polysomnographic evidence of significant sleep disruption.⁴ In another 12-week RCT study of solriamfetol in adult patients with EDS related to OSA, there was a dose-dependent improvement in measures of wakefulness.⁵ Some notable side-effects seen with this medication include anxiety and elevated mood, as well as increases in blood pressure. A subsequent study of this medication found that it was efficacious at maintenance of improvements at 6 months.⁶ Given the theorized mechanism of action as an NDRI, future observation and studies could provide insights on its effect on depression, as well.

Pitolisant

Histaminergic neurons within the CNS play an important role in the promotion of wakefulness. Pitolisant (Wakix) is an interesting wakefulness-promoting agent for adult patients with narcolepsy. It acts as an inverse agonist and antagonist of histamine H3 receptors, resulting in a reduction of the usual feedback inhibition effected through the H3 receptor, thereby enhancing CNS release of histamine and other neurotransmitters. This medication was approved by the FDA in August 2019 and is currently indicated for adult patients with narcolepsy. The HARMONY I trial comparing pitolisant with both placebo and modafinil in adults with narcolepsy and EDS demonstrated improvement in measures of sleepiness and maintenance of wakefulness over placebo, and noninferiority to modafinil.⁷ In addition, pitolisant had a favorable side-effect profile compared with modafinil. Subsequent studies have reaffirmed the safety profile of pitolisant, including its minimal abuse potential. In one recent placebo-controlled trial of the use of pitolisant in a population of 268 adults with positive airway pressure (PAP) non-adherence, pitolisant was found to improve measures of EDS and related patient-reported measurements in patients with OSA who were CPAP nonadherent.⁸ Though generally well-tolerated by patients, in initial clinical trials pitolisant was associated with increased headache, insomnia, and nausea relative to placebo, among other less commonly reported adverse effects. Pitolisant is QT interval-prolonging, so caution must be taken when using this medication in combination other medications which may induce QT interval prolongation, including SSRIs.

Future directions

Greater awareness of the hypersomnias and their management has led to improved outcomes and access to care for these patients, yet these disorders remain burdensome and the treatments imperfect. Looking forward, novel pharmacotherapies that target underlying mechanisms rather than symptom palliation will allow for more precise treatments. Ongoing investigations of hypocretin receptor agonists seek to target one critical central mediator of wakefulness. Recent studies have highlighted the association of dysautonomia with hypersomnia, offering interesting insight into possible future targets to improve the function and quality of life of these patients.⁹ Similarly, understanding of the interplay between psychiatric disorders and primary and secondary hypersomnias may offer new therapeutic pathways.

As treatment plans targeting hypersomnia become more comprehensive and holistic, with an increased emphasis on self-care, sleep hygiene, and mental health awareness, in addition to mechanism-specific treatments, we hope they will ultimately provide improved symptom and burden relief for our patients.
 

Dr. Shih Yee-Marie Tan Gipson is a psychiatrist and Dr. Kevin Gipson is a sleep medicine specialist, both with Massachusetts General Hospital, Boston.

References

¹ Dauvilliers, et al. Hypersomnia. Dialogues Clin Neurosci. 2005;7(4):347-356.

² Trotti, et al. Clarithromycin in gamma-aminobutyric acid-related hypersomnolence: A randomized, crossover trial. Ann Neurol. 2015;78(3):454-465. doi: 10.1002/ana.24459.

³ Trotti, et al. Flumazenil for the treatment of refractory hypersomnolence: Clinical experience with 153 patients. J Clin Sleep Med. 2016;12(10):1389-1394. doi: 10.5664/jcsm.6196.

⁴ Thorpy, et al. A randomized study of solriamfetol for excessive sleepiness in narcolepsy. Ann Neurol. 2019; 85(3):359-370. doi: 10.1002/ana.25423.

⁵ Schweitzer, et al. Solriamfetol for excessive sleepiness in obstructive sleep apnea (TONES 3): A randomized controlled trial. Am J Respir Crit Care Med. 2019;199(11):1421-1431. doi: 10.1164/rccm.201806-1100OC.

⁶ Malhotra, et al. Long-term study of the safety and maintenance of efficacy of solriamfetol (JZP-110) in the treatment of excessive sleepiness in participants with narcolepsy or obstructive sleep apnea. Sleep. 2020; 43(2): doi: 10.1093/sleep/zsz220.

⁷ Dauvilliers, et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013;12(11):1068-1075. doi: 10.1016/S1474-4422(13)70225-4.

⁸ Dauvilliers, et al. Pitolisant for daytime sleepiness in obstructive sleep apnea patients refusing CPAP: A randomized trial. Am J Respir Crit Care Med. 2020. doi: 10.1164/rccm.201907-1284OC.

⁹ Miglis, et al. Frequency and severity of autonomic symptoms in idiopathic hypersomnia. J Clin Sleep Med. 2020; 16(5):749-756. doi: 10.5664/jcsm.8344.
 

Researchers are beginning to make some headway in identifying the role of secondary infections in the course and outcomes of COVID-19.

CDC/ Dr. William Kaplan

Patients who are on ventilatory support for severe COVID-19 infections appear to be at high risk for invasive pulmonary aspergillosis, which in a small prospective study was associated with a more than threefold risk for 30-day mortality. The findings were published online in Clinical Infectious Diseases.

Among 108 patients with COVID-19 on mechanical ventilation in one of three intensive care units, 30 (27.7%) were diagnosed with coronavirus-associated pulmonary aspergillosis (CAPA) based on consensus definitions similar to those used to diagnose influenza-associated pulmonary aspergillosis (IAPA).

Of the patients with CAPA, 44% died within 30 days of ICU admission, compared with 19% of patients who did not meet the criteria for aspergillosis (P = .002). This difference translated into an odds ratio (OR) for death with CAPA of 3.55 (P = .014), reported Michele Bartoletti, MD, PhD, of the infectious diseases unit at Sant’Orsola Malpighi Hospital in Bologna, Italy, and colleagues.

When the investigators applied a proposed definition of putative invasive pulmonary aspergillosis, or “PIPA” to the same patients, the 30-day mortality rate jumped to 74% vs. 26% for patients without PIPA (P < .001), with an OR of 11.60 (P < .001). “We found a high incidence of CAPA among critically ill COVID-19 patients and that its occurrence seems to change the natural history of disease,” they wrote.

“[T]he study from Bartoletti et al. alerts the clinical audience to be aware of CAPA and take appropriate (and where needed repetitive) actions that fits their clinical setting,” Roger J. Brüggemann, PharmD, of the department of pharmacy, Radboud University Medical Center, Nijmegen, the Netherlands, and colleagues wrote in an editorial accompanying the study.
 

Diagnosis challenging

At the best of times, the diagnosis of pulmonary aspergillosis is difficult, subject to both false-positive and false-negative results, said a critical care specialist who was not involved in the study.

“Critically ill patients are susceptible to having aspergillus, so in reading the article, my only concerns are that I don’t know how accurate the testing is, and I don’t know if their population is truly different from a general population of patients in the ICU,” Daniel R. Ouellette, MD, FCCP, associate director of medical critical care at Henry Ford Hospital in Detroit, said in an interview.

As seen in ICU patients with severe influenza or other viral infections, patients with severe COVID-19 disease are susceptible to secondary infections, he said, making it difficult to know whether the worse outcomes seen in patients with COVID-19 and presumed aspergillosis are a reflection of their being more critically ill or whether the secondary infections themselves account for the difference in mortality.
 

Three ICUs

Dr. Bartoletti and colleagues conducted a study on all adult patients with microbiologically confirmed COVID-19 receiving mechanical ventilation in three ICUs in Bologna.

All patients included in the study were screened for invasive pulmonary aspergillosis with bronchoalveolar lavage and galactomannan detection and cultures. The lavage was performed on ICU admission, one day from the first day of mechanical ventilation, and if patients had evidence of clinical disease progression.

Samples that tested positive for galactomannan, a component of the aspergillus cell wall, were stored and later analyzed with a commercial quantitative real-time polymerase chain reaction assay for aspergillus; these results were not reported to clinicians on the patient floors.

The investigators defined invasive pulmonary aspergillosis according to a recently proposed definition for CAPA. This definition applies to COVID-19–positive patients admitted to an ICU with pulmonary infiltrates and at least one of the following:

• A serum galactomannan > 0.5.
• Bronchoalveolar lavage galactomannan > 1.0.
• Positive aspergillus bronchoalveolar lavage culture or cavitating infiltrate not attributed to another cause in the area of the pulmonary infiltrate.

They compared the CAPA diagnostic criteria with those of PIPA criteria as described by Stijn J. Blot, PhD, and colleagues in study published in the American Journal of Respiratory and Critical Care Medicine (2012 Jul 1;186(1):56-64).

A total of 108 patients were screened for aspergillosis, with a median age of 64. The majority of patients (78%) were male. The median age-adjusted Charlson Comorbidity Index was 2.5 (range 1-4). The median Sequential Organ Failure Assessment (SOFA) score at ICU admission was 4 (range 3-5).

As noted, probable aspergillosis by CAPA criteria was diagnosed in 30 patients (27.7%), with the diagnosis made after a median of 4 days after intubation and a median of 14 days from onset of COVID-19 symptoms.

The incidence rate of probable CAPA was 38.83 per 10,000 ICU patient days.

A comparison of clinical characteristics of patients with and without probable CAPA showed that only chronic steroid therapy at ≥ 16 mg/day prednisone for at least 15 days was significantly associated with risk for CAPA (P = .02).

At a median follow-up of 31 days, 54 patients (50%) had been discharged, 44 (41%) had died, and the remaining patients were still on follow-up.

As noted before, the mortality rate with 30 days of ICU admission was 44% for patients with probable CAPA vs. 19% for patients without. Among patients deemed to have PIPA, 74% died within 30 days of admission, compared with 26% without PIPA.

In a logistic regression model, the association of CAPA with increased risk for 30-day mortality remained even after adjustment for the need for renal replacement therapy (OR 3.02, P = .015) and SOFA score at ICU admission (OR 1.38, P = .004).

In a logistic regression using the PIPA rather than CAPA definition, the OR for 30-day mortality was 11.60 (P = .001).
 

Prognostic marker

The investigators noted that bronchoalveolar lavage galactomannan index appeared to be predictive of death. Each 1-point increase in the index was associated with 1.41-fold increase in the risk for 30-day mortality (P = .0070), a relationship that held up after adjustment for age, need for renal replacement therapy, and SOFA score.

Sixteen patients who met the CAPA definition received antifungal therapy, primarily voriconazole. The use of voriconazole was associated with a nonsignificant trend toward lower mortality.

They noted that the heavy use of immunomodulating agents in the patients in their study may have contributed to the high prevalence of CAPA.

Dr. Ouellette agreed that many of the therapies used to treat COVID-19 in the ICU are experimental, and that agents used to suppress the cytokine storm that is believed to contribute to disease severity may increase risk for secondary infections such as invasive aspergillosis.

“Many of our treatments may be associated with adverse consequences,” he said. “There is a trend toward treating patients with COVID-19 pneumonia with corticosteroids, and certainly that could have an immunosuppressant effect and predispose patients to secondary infections.”

He noted that the World Health Organization recommendations current in March 2020, when the pandemic began in earnest in the United States, advised against the use of corticosteroids, likely because of a lack of evidence of efficacy and concerns about risk for secondary infections.

“Regardless of the strategic choice made, all efforts should be put into improving our ability to reliably identify patients that may benefit from therapeutic interventions, which include host and risk factors, clinical factors and CAPA disease markers,” Dr. Brüggemann and colleagues wrote in their editorial.

The study was performed without external funding. The authors and Dr. Ouellette reported no conflicts of interest. Dr. Brüggemann and coauthors report grants and/or personal fees from various companies outside the submitted work.

SOURCE: Bartoletti M et al. Clin Infect Dis. 2020 Jul 28. doi: 10.1093/cid/ciaa1065.

Researchers are beginning to make some headway in identifying the role of secondary infections in the course and outcomes of COVID-19.

CDC/ Dr. William Kaplan

Patients who are on ventilatory support for severe COVID-19 infections appear to be at high risk for invasive pulmonary aspergillosis, which in a small prospective study was associated with a more than threefold risk for 30-day mortality. The findings were published online in Clinical Infectious Diseases.

Among 108 patients with COVID-19 on mechanical ventilation in one of three intensive care units, 30 (27.7%) were diagnosed with coronavirus-associated pulmonary aspergillosis (CAPA) based on consensus definitions similar to those used to diagnose influenza-associated pulmonary aspergillosis (IAPA).

Of the patients with CAPA, 44% died within 30 days of ICU admission, compared with 19% of patients who did not meet the criteria for aspergillosis (P = .002). This difference translated into an odds ratio (OR) for death with CAPA of 3.55 (P = .014), reported Michele Bartoletti, MD, PhD, of the infectious diseases unit at Sant’Orsola Malpighi Hospital in Bologna, Italy, and colleagues.

When the investigators applied a proposed definition of putative invasive pulmonary aspergillosis, or “PIPA” to the same patients, the 30-day mortality rate jumped to 74% vs. 26% for patients without PIPA (P < .001), with an OR of 11.60 (P < .001). “We found a high incidence of CAPA among critically ill COVID-19 patients and that its occurrence seems to change the natural history of disease,” they wrote.

“[T]he study from Bartoletti et al. alerts the clinical audience to be aware of CAPA and take appropriate (and where needed repetitive) actions that fits their clinical setting,” Roger J. Brüggemann, PharmD, of the department of pharmacy, Radboud University Medical Center, Nijmegen, the Netherlands, and colleagues wrote in an editorial accompanying the study.
 

Diagnosis challenging

At the best of times, the diagnosis of pulmonary aspergillosis is difficult, subject to both false-positive and false-negative results, said a critical care specialist who was not involved in the study.

“Critically ill patients are susceptible to having aspergillus, so in reading the article, my only concerns are that I don’t know how accurate the testing is, and I don’t know if their population is truly different from a general population of patients in the ICU,” Daniel R. Ouellette, MD, FCCP, associate director of medical critical care at Henry Ford Hospital in Detroit, said in an interview.

As seen in ICU patients with severe influenza or other viral infections, patients with severe COVID-19 disease are susceptible to secondary infections, he said, making it difficult to know whether the worse outcomes seen in patients with COVID-19 and presumed aspergillosis are a reflection of their being more critically ill or whether the secondary infections themselves account for the difference in mortality.
 

Three ICUs

Dr. Bartoletti and colleagues conducted a study on all adult patients with microbiologically confirmed COVID-19 receiving mechanical ventilation in three ICUs in Bologna.

All patients included in the study were screened for invasive pulmonary aspergillosis with bronchoalveolar lavage and galactomannan detection and cultures. The lavage was performed on ICU admission, one day from the first day of mechanical ventilation, and if patients had evidence of clinical disease progression.

Samples that tested positive for galactomannan, a component of the aspergillus cell wall, were stored and later analyzed with a commercial quantitative real-time polymerase chain reaction assay for aspergillus; these results were not reported to clinicians on the patient floors.

The investigators defined invasive pulmonary aspergillosis according to a recently proposed definition for CAPA. This definition applies to COVID-19–positive patients admitted to an ICU with pulmonary infiltrates and at least one of the following:

• A serum galactomannan > 0.5.
• Bronchoalveolar lavage galactomannan > 1.0.
• Positive aspergillus bronchoalveolar lavage culture or cavitating infiltrate not attributed to another cause in the area of the pulmonary infiltrate.

They compared the CAPA diagnostic criteria with those of PIPA criteria as described by Stijn J. Blot, PhD, and colleagues in study published in the American Journal of Respiratory and Critical Care Medicine (2012 Jul 1;186(1):56-64).

A total of 108 patients were screened for aspergillosis, with a median age of 64. The majority of patients (78%) were male. The median age-adjusted Charlson Comorbidity Index was 2.5 (range 1-4). The median Sequential Organ Failure Assessment (SOFA) score at ICU admission was 4 (range 3-5).

As noted, probable aspergillosis by CAPA criteria was diagnosed in 30 patients (27.7%), with the diagnosis made after a median of 4 days after intubation and a median of 14 days from onset of COVID-19 symptoms.

The incidence rate of probable CAPA was 38.83 per 10,000 ICU patient days.

A comparison of clinical characteristics of patients with and without probable CAPA showed that only chronic steroid therapy at ≥ 16 mg/day prednisone for at least 15 days was significantly associated with risk for CAPA (P = .02).

At a median follow-up of 31 days, 54 patients (50%) had been discharged, 44 (41%) had died, and the remaining patients were still on follow-up.

As noted before, the mortality rate with 30 days of ICU admission was 44% for patients with probable CAPA vs. 19% for patients without. Among patients deemed to have PIPA, 74% died within 30 days of admission, compared with 26% without PIPA.

In a logistic regression model, the association of CAPA with increased risk for 30-day mortality remained even after adjustment for the need for renal replacement therapy (OR 3.02, P = .015) and SOFA score at ICU admission (OR 1.38, P = .004).

In a logistic regression using the PIPA rather than CAPA definition, the OR for 30-day mortality was 11.60 (P = .001).
 

Prognostic marker

The investigators noted that bronchoalveolar lavage galactomannan index appeared to be predictive of death. Each 1-point increase in the index was associated with 1.41-fold increase in the risk for 30-day mortality (P = .0070), a relationship that held up after adjustment for age, need for renal replacement therapy, and SOFA score.

Sixteen patients who met the CAPA definition received antifungal therapy, primarily voriconazole. The use of voriconazole was associated with a nonsignificant trend toward lower mortality.

They noted that the heavy use of immunomodulating agents in the patients in their study may have contributed to the high prevalence of CAPA.

Dr. Ouellette agreed that many of the therapies used to treat COVID-19 in the ICU are experimental, and that agents used to suppress the cytokine storm that is believed to contribute to disease severity may increase risk for secondary infections such as invasive aspergillosis.

“Many of our treatments may be associated with adverse consequences,” he said. “There is a trend toward treating patients with COVID-19 pneumonia with corticosteroids, and certainly that could have an immunosuppressant effect and predispose patients to secondary infections.”

He noted that the World Health Organization recommendations current in March 2020, when the pandemic began in earnest in the United States, advised against the use of corticosteroids, likely because of a lack of evidence of efficacy and concerns about risk for secondary infections.

“Regardless of the strategic choice made, all efforts should be put into improving our ability to reliably identify patients that may benefit from therapeutic interventions, which include host and risk factors, clinical factors and CAPA disease markers,” Dr. Brüggemann and colleagues wrote in their editorial.

The study was performed without external funding. The authors and Dr. Ouellette reported no conflicts of interest. Dr. Brüggemann and coauthors report grants and/or personal fees from various companies outside the submitted work.

SOURCE: Bartoletti M et al. Clin Infect Dis. 2020 Jul 28. doi: 10.1093/cid/ciaa1065.

Researchers are beginning to make some headway in identifying the role of secondary infections in the course and outcomes of COVID-19.

CDC/ Dr. William Kaplan

Patients who are on ventilatory support for severe COVID-19 infections appear to be at high risk for invasive pulmonary aspergillosis, which in a small prospective study was associated with a more than threefold risk for 30-day mortality. The findings were published online in Clinical Infectious Diseases.

Among 108 patients with COVID-19 on mechanical ventilation in one of three intensive care units, 30 (27.7%) were diagnosed with coronavirus-associated pulmonary aspergillosis (CAPA) based on consensus definitions similar to those used to diagnose influenza-associated pulmonary aspergillosis (IAPA).

Of the patients with CAPA, 44% died within 30 days of ICU admission, compared with 19% of patients who did not meet the criteria for aspergillosis (P = .002). This difference translated into an odds ratio (OR) for death with CAPA of 3.55 (P = .014), reported Michele Bartoletti, MD, PhD, of the infectious diseases unit at Sant’Orsola Malpighi Hospital in Bologna, Italy, and colleagues.

When the investigators applied a proposed definition of putative invasive pulmonary aspergillosis, or “PIPA” to the same patients, the 30-day mortality rate jumped to 74% vs. 26% for patients without PIPA (P < .001), with an OR of 11.60 (P < .001). “We found a high incidence of CAPA among critically ill COVID-19 patients and that its occurrence seems to change the natural history of disease,” they wrote.

“[T]he study from Bartoletti et al. alerts the clinical audience to be aware of CAPA and take appropriate (and where needed repetitive) actions that fits their clinical setting,” Roger J. Brüggemann, PharmD, of the department of pharmacy, Radboud University Medical Center, Nijmegen, the Netherlands, and colleagues wrote in an editorial accompanying the study.
 

Diagnosis challenging

At the best of times, the diagnosis of pulmonary aspergillosis is difficult, subject to both false-positive and false-negative results, said a critical care specialist who was not involved in the study.

“Critically ill patients are susceptible to having aspergillus, so in reading the article, my only concerns are that I don’t know how accurate the testing is, and I don’t know if their population is truly different from a general population of patients in the ICU,” Daniel R. Ouellette, MD, FCCP, associate director of medical critical care at Henry Ford Hospital in Detroit, said in an interview.

As seen in ICU patients with severe influenza or other viral infections, patients with severe COVID-19 disease are susceptible to secondary infections, he said, making it difficult to know whether the worse outcomes seen in patients with COVID-19 and presumed aspergillosis are a reflection of their being more critically ill or whether the secondary infections themselves account for the difference in mortality.
 

Three ICUs

Dr. Bartoletti and colleagues conducted a study on all adult patients with microbiologically confirmed COVID-19 receiving mechanical ventilation in three ICUs in Bologna.

All patients included in the study were screened for invasive pulmonary aspergillosis with bronchoalveolar lavage and galactomannan detection and cultures. The lavage was performed on ICU admission, one day from the first day of mechanical ventilation, and if patients had evidence of clinical disease progression.

Samples that tested positive for galactomannan, a component of the aspergillus cell wall, were stored and later analyzed with a commercial quantitative real-time polymerase chain reaction assay for aspergillus; these results were not reported to clinicians on the patient floors.

The investigators defined invasive pulmonary aspergillosis according to a recently proposed definition for CAPA. This definition applies to COVID-19–positive patients admitted to an ICU with pulmonary infiltrates and at least one of the following:

• A serum galactomannan > 0.5.
• Bronchoalveolar lavage galactomannan > 1.0.
• Positive aspergillus bronchoalveolar lavage culture or cavitating infiltrate not attributed to another cause in the area of the pulmonary infiltrate.

They compared the CAPA diagnostic criteria with those of PIPA criteria as described by Stijn J. Blot, PhD, and colleagues in study published in the American Journal of Respiratory and Critical Care Medicine (2012 Jul 1;186(1):56-64).

A total of 108 patients were screened for aspergillosis, with a median age of 64. The majority of patients (78%) were male. The median age-adjusted Charlson Comorbidity Index was 2.5 (range 1-4). The median Sequential Organ Failure Assessment (SOFA) score at ICU admission was 4 (range 3-5).

As noted, probable aspergillosis by CAPA criteria was diagnosed in 30 patients (27.7%), with the diagnosis made after a median of 4 days after intubation and a median of 14 days from onset of COVID-19 symptoms.

The incidence rate of probable CAPA was 38.83 per 10,000 ICU patient days.

A comparison of clinical characteristics of patients with and without probable CAPA showed that only chronic steroid therapy at ≥ 16 mg/day prednisone for at least 15 days was significantly associated with risk for CAPA (P = .02).

At a median follow-up of 31 days, 54 patients (50%) had been discharged, 44 (41%) had died, and the remaining patients were still on follow-up.

As noted before, the mortality rate with 30 days of ICU admission was 44% for patients with probable CAPA vs. 19% for patients without. Among patients deemed to have PIPA, 74% died within 30 days of admission, compared with 26% without PIPA.

In a logistic regression model, the association of CAPA with increased risk for 30-day mortality remained even after adjustment for the need for renal replacement therapy (OR 3.02, P = .015) and SOFA score at ICU admission (OR 1.38, P = .004).

In a logistic regression using the PIPA rather than CAPA definition, the OR for 30-day mortality was 11.60 (P = .001).
 

Prognostic marker

The investigators noted that bronchoalveolar lavage galactomannan index appeared to be predictive of death. Each 1-point increase in the index was associated with 1.41-fold increase in the risk for 30-day mortality (P = .0070), a relationship that held up after adjustment for age, need for renal replacement therapy, and SOFA score.

Sixteen patients who met the CAPA definition received antifungal therapy, primarily voriconazole. The use of voriconazole was associated with a nonsignificant trend toward lower mortality.

They noted that the heavy use of immunomodulating agents in the patients in their study may have contributed to the high prevalence of CAPA.

Dr. Ouellette agreed that many of the therapies used to treat COVID-19 in the ICU are experimental, and that agents used to suppress the cytokine storm that is believed to contribute to disease severity may increase risk for secondary infections such as invasive aspergillosis.

“Many of our treatments may be associated with adverse consequences,” he said. “There is a trend toward treating patients with COVID-19 pneumonia with corticosteroids, and certainly that could have an immunosuppressant effect and predispose patients to secondary infections.”

He noted that the World Health Organization recommendations current in March 2020, when the pandemic began in earnest in the United States, advised against the use of corticosteroids, likely because of a lack of evidence of efficacy and concerns about risk for secondary infections.

“Regardless of the strategic choice made, all efforts should be put into improving our ability to reliably identify patients that may benefit from therapeutic interventions, which include host and risk factors, clinical factors and CAPA disease markers,” Dr. Brüggemann and colleagues wrote in their editorial.

The study was performed without external funding. The authors and Dr. Ouellette reported no conflicts of interest. Dr. Brüggemann and coauthors report grants and/or personal fees from various companies outside the submitted work.

SOURCE: Bartoletti M et al. Clin Infect Dis. 2020 Jul 28. doi: 10.1093/cid/ciaa1065.