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Diastolic dysfunction is a common risk factor for cognitive decline
a new study suggests. “We found people with worsening diastolic dysfunction have more white matter hyperintensities on brain imaging and greater difficulty with executive functioning, suggesting that diastolic dysfunction is a common modifiable risk factor for cognitive impairment,” said lead author Alicia S. Parker, MD. Dr. Parker is assistant professor of cognitive and behavioral neurology at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio.
“This is an entirely new finding. While there have been some small studies suggesting a link between diastolic dysfunction and a reduction in working memory, this is by far the largest dataset on this topic and the first study that has included brain imaging and neuropsychological measures,” she said.
“Diastolic dysfunction is very common in the older population, and we need to do more to find it and treat it to help prevent or reduce cognitive decline,” Dr. Parker added.
This research is being presented online as part of the 2020 American Academy of Neurology Science Highlights.
Dr. Parker explained that systolic dysfunction is known to have a major effect on cardiovascular outcomes and has been found to be associated with cognitive decline. Proposed mechanisms for cognitive decline in patients with systolic dysfunction include low cardiac output, embolic infarctions, and hypoxic changes, among others.
“There is increasing interest in analyzing the influence of diastolic dysfunction on cardiovascular outcomes, and the effects of diastolic dysfunction on cognition are not currently well delineated, which this study seeks to address,” she added.
“While these results are new, they are not surprising. In general, we are finding more and more that heart health is connected to brain health,” she commented.
Dr. Parker and her colleagues started the current research after noticing in clinic that among patients with significant diastolic dysfunction, there were often changes on brain MRI imaging, and the patients often had trouble with executive function. “The effect of diastolic dysfunction on cognition has not been well characterized, so we wanted to look at this,” she said.
The investigators analyzed data from the Framingham Heart Study Offspring Cohort at examination 8, collected between 2005 and 2008. The study sample included 1,438 individuals older than 55 years who had undergone neuropsychological assessment and echocardiographic diastolic measurement. Systolic measurements were normal for the participants, and they did not currently have dementia, stroke, or other neurologic illness.
Results showed that increasing E/E’ ratio (the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity) indicated increasing diastolic dysfunction and was associated with an increase in the incidence of mild cognitive impairment (hazard ratio, 1.29; 95% confidence interval, 1.01-1.66; P < .043).
An increased E/E’ ratio was associated with increased executive function impairment in the “similarities” (beta, –0.29; P < .002) and “phonemic fluency” (–1.28; P < .001) tasks.
Participants with moderate to severe diastolic dysfunction were more impaired with respect to both similarities (–0.62; P < .046) and phonemic fluency (–2.60; P < .023).
Data from 1,217 participants showed that among those with mild diastolic dysfunction, there was a trend toward an increase in white matter hyperintensities (0.11; P < .105). For participants with moderate to severe diastolic dysfunction, white matter hyperintensities were increased (0.30; P < 0.001).
The results were unchanged after the researchers adjusted for many other predictors of cognitive decline affecting diastolic function.
The researchers conclude: “As cerebral small vessel disease clinically presents with executive dysfunction, these results align well.” They add that replication in additional cohorts and analyses of cognition in treatment trials of diastolic dysfunction are warranted.
Earlier interventions
Commenting on the study, Marco R. Di Tullio, MD, professor of medicine and Columbia University Medical Center, New York City, who is also studying the relationship between subclinical cardiac abnormalities and cognition, said: “This is a promising area of research, as it might allow us to uncover novel risk factors for cognitive decline at an early stage, before the development of clinically manifest cardiac disease, which might allow earlier interventions to decrease or delay the onset of cognitive decline.”
Dr. Di Tullio added that he would like to know more about the interaction between diastolic dysfunction, MRI abnormalities, and cognitive impairment risk. “In this study, MRI abnormalities and cognitive impairment are treated as separate outcomes, with diastolic dysfunction being the exposure for each of them. An additional analysis of the association between diastolic dysfunction and cognitive impairment stratified by presence or absence of brain MRI findings would have been interesting.”
Dr. Parker responded that this is an area of investigation. “We suspect that our cognitive findings would not be explained by any one MRI measure, though a comprehensive examination of MRI findings would be of benefit. The thought that there may be a reversible cardiac abnormality that does not have a structural brain imaging correlate on MRI is an interesting possibility,” she said.
Dr. Di Tullio also pointed out that at present, there is no specific treatment for diastolic dysfunction other than to address some the conditions that predispose to it, such as hypertension and atrial fibrillation.
“We completely agree that specific treatments are an area of investigation and that treatment is therefore targeted at associated modifiable conditions,” Dr. Parker replied.
With regard to more specific estimates of the prevalence of diastolic dysfunction, Dr. Parker cites another Framingham analysis that involved 2,355 persons without any prevalent cardiovascular conditions. That study found that diastolic dysfunction was rare until 50 years of age and then gradually increased with age.
About 5% of people in their 50s had mild diastolic dysfunction, and about 3% had moderate to severe diastolic dysfunction. Among persons in their 60s, about 18% had mild and 5% had severe diastolic dysfunction. Among persons in their 70s, mild diastolic dysfunction occurred in 35%, and moderate to severe disease was present in 18%; and in persons older than 80 years, nearly half had mild and about 20% had moderate to severe diastolic dysfunction.
Dr. Parker has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
a new study suggests. “We found people with worsening diastolic dysfunction have more white matter hyperintensities on brain imaging and greater difficulty with executive functioning, suggesting that diastolic dysfunction is a common modifiable risk factor for cognitive impairment,” said lead author Alicia S. Parker, MD. Dr. Parker is assistant professor of cognitive and behavioral neurology at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio.
“This is an entirely new finding. While there have been some small studies suggesting a link between diastolic dysfunction and a reduction in working memory, this is by far the largest dataset on this topic and the first study that has included brain imaging and neuropsychological measures,” she said.
“Diastolic dysfunction is very common in the older population, and we need to do more to find it and treat it to help prevent or reduce cognitive decline,” Dr. Parker added.
This research is being presented online as part of the 2020 American Academy of Neurology Science Highlights.
Dr. Parker explained that systolic dysfunction is known to have a major effect on cardiovascular outcomes and has been found to be associated with cognitive decline. Proposed mechanisms for cognitive decline in patients with systolic dysfunction include low cardiac output, embolic infarctions, and hypoxic changes, among others.
“There is increasing interest in analyzing the influence of diastolic dysfunction on cardiovascular outcomes, and the effects of diastolic dysfunction on cognition are not currently well delineated, which this study seeks to address,” she added.
“While these results are new, they are not surprising. In general, we are finding more and more that heart health is connected to brain health,” she commented.
Dr. Parker and her colleagues started the current research after noticing in clinic that among patients with significant diastolic dysfunction, there were often changes on brain MRI imaging, and the patients often had trouble with executive function. “The effect of diastolic dysfunction on cognition has not been well characterized, so we wanted to look at this,” she said.
The investigators analyzed data from the Framingham Heart Study Offspring Cohort at examination 8, collected between 2005 and 2008. The study sample included 1,438 individuals older than 55 years who had undergone neuropsychological assessment and echocardiographic diastolic measurement. Systolic measurements were normal for the participants, and they did not currently have dementia, stroke, or other neurologic illness.
Results showed that increasing E/E’ ratio (the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity) indicated increasing diastolic dysfunction and was associated with an increase in the incidence of mild cognitive impairment (hazard ratio, 1.29; 95% confidence interval, 1.01-1.66; P < .043).
An increased E/E’ ratio was associated with increased executive function impairment in the “similarities” (beta, –0.29; P < .002) and “phonemic fluency” (–1.28; P < .001) tasks.
Participants with moderate to severe diastolic dysfunction were more impaired with respect to both similarities (–0.62; P < .046) and phonemic fluency (–2.60; P < .023).
Data from 1,217 participants showed that among those with mild diastolic dysfunction, there was a trend toward an increase in white matter hyperintensities (0.11; P < .105). For participants with moderate to severe diastolic dysfunction, white matter hyperintensities were increased (0.30; P < 0.001).
The results were unchanged after the researchers adjusted for many other predictors of cognitive decline affecting diastolic function.
The researchers conclude: “As cerebral small vessel disease clinically presents with executive dysfunction, these results align well.” They add that replication in additional cohorts and analyses of cognition in treatment trials of diastolic dysfunction are warranted.
Earlier interventions
Commenting on the study, Marco R. Di Tullio, MD, professor of medicine and Columbia University Medical Center, New York City, who is also studying the relationship between subclinical cardiac abnormalities and cognition, said: “This is a promising area of research, as it might allow us to uncover novel risk factors for cognitive decline at an early stage, before the development of clinically manifest cardiac disease, which might allow earlier interventions to decrease or delay the onset of cognitive decline.”
Dr. Di Tullio added that he would like to know more about the interaction between diastolic dysfunction, MRI abnormalities, and cognitive impairment risk. “In this study, MRI abnormalities and cognitive impairment are treated as separate outcomes, with diastolic dysfunction being the exposure for each of them. An additional analysis of the association between diastolic dysfunction and cognitive impairment stratified by presence or absence of brain MRI findings would have been interesting.”
Dr. Parker responded that this is an area of investigation. “We suspect that our cognitive findings would not be explained by any one MRI measure, though a comprehensive examination of MRI findings would be of benefit. The thought that there may be a reversible cardiac abnormality that does not have a structural brain imaging correlate on MRI is an interesting possibility,” she said.
Dr. Di Tullio also pointed out that at present, there is no specific treatment for diastolic dysfunction other than to address some the conditions that predispose to it, such as hypertension and atrial fibrillation.
“We completely agree that specific treatments are an area of investigation and that treatment is therefore targeted at associated modifiable conditions,” Dr. Parker replied.
With regard to more specific estimates of the prevalence of diastolic dysfunction, Dr. Parker cites another Framingham analysis that involved 2,355 persons without any prevalent cardiovascular conditions. That study found that diastolic dysfunction was rare until 50 years of age and then gradually increased with age.
About 5% of people in their 50s had mild diastolic dysfunction, and about 3% had moderate to severe diastolic dysfunction. Among persons in their 60s, about 18% had mild and 5% had severe diastolic dysfunction. Among persons in their 70s, mild diastolic dysfunction occurred in 35%, and moderate to severe disease was present in 18%; and in persons older than 80 years, nearly half had mild and about 20% had moderate to severe diastolic dysfunction.
Dr. Parker has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
a new study suggests. “We found people with worsening diastolic dysfunction have more white matter hyperintensities on brain imaging and greater difficulty with executive functioning, suggesting that diastolic dysfunction is a common modifiable risk factor for cognitive impairment,” said lead author Alicia S. Parker, MD. Dr. Parker is assistant professor of cognitive and behavioral neurology at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio.
“This is an entirely new finding. While there have been some small studies suggesting a link between diastolic dysfunction and a reduction in working memory, this is by far the largest dataset on this topic and the first study that has included brain imaging and neuropsychological measures,” she said.
“Diastolic dysfunction is very common in the older population, and we need to do more to find it and treat it to help prevent or reduce cognitive decline,” Dr. Parker added.
This research is being presented online as part of the 2020 American Academy of Neurology Science Highlights.
Dr. Parker explained that systolic dysfunction is known to have a major effect on cardiovascular outcomes and has been found to be associated with cognitive decline. Proposed mechanisms for cognitive decline in patients with systolic dysfunction include low cardiac output, embolic infarctions, and hypoxic changes, among others.
“There is increasing interest in analyzing the influence of diastolic dysfunction on cardiovascular outcomes, and the effects of diastolic dysfunction on cognition are not currently well delineated, which this study seeks to address,” she added.
“While these results are new, they are not surprising. In general, we are finding more and more that heart health is connected to brain health,” she commented.
Dr. Parker and her colleagues started the current research after noticing in clinic that among patients with significant diastolic dysfunction, there were often changes on brain MRI imaging, and the patients often had trouble with executive function. “The effect of diastolic dysfunction on cognition has not been well characterized, so we wanted to look at this,” she said.
The investigators analyzed data from the Framingham Heart Study Offspring Cohort at examination 8, collected between 2005 and 2008. The study sample included 1,438 individuals older than 55 years who had undergone neuropsychological assessment and echocardiographic diastolic measurement. Systolic measurements were normal for the participants, and they did not currently have dementia, stroke, or other neurologic illness.
Results showed that increasing E/E’ ratio (the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity) indicated increasing diastolic dysfunction and was associated with an increase in the incidence of mild cognitive impairment (hazard ratio, 1.29; 95% confidence interval, 1.01-1.66; P < .043).
An increased E/E’ ratio was associated with increased executive function impairment in the “similarities” (beta, –0.29; P < .002) and “phonemic fluency” (–1.28; P < .001) tasks.
Participants with moderate to severe diastolic dysfunction were more impaired with respect to both similarities (–0.62; P < .046) and phonemic fluency (–2.60; P < .023).
Data from 1,217 participants showed that among those with mild diastolic dysfunction, there was a trend toward an increase in white matter hyperintensities (0.11; P < .105). For participants with moderate to severe diastolic dysfunction, white matter hyperintensities were increased (0.30; P < 0.001).
The results were unchanged after the researchers adjusted for many other predictors of cognitive decline affecting diastolic function.
The researchers conclude: “As cerebral small vessel disease clinically presents with executive dysfunction, these results align well.” They add that replication in additional cohorts and analyses of cognition in treatment trials of diastolic dysfunction are warranted.
Earlier interventions
Commenting on the study, Marco R. Di Tullio, MD, professor of medicine and Columbia University Medical Center, New York City, who is also studying the relationship between subclinical cardiac abnormalities and cognition, said: “This is a promising area of research, as it might allow us to uncover novel risk factors for cognitive decline at an early stage, before the development of clinically manifest cardiac disease, which might allow earlier interventions to decrease or delay the onset of cognitive decline.”
Dr. Di Tullio added that he would like to know more about the interaction between diastolic dysfunction, MRI abnormalities, and cognitive impairment risk. “In this study, MRI abnormalities and cognitive impairment are treated as separate outcomes, with diastolic dysfunction being the exposure for each of them. An additional analysis of the association between diastolic dysfunction and cognitive impairment stratified by presence or absence of brain MRI findings would have been interesting.”
Dr. Parker responded that this is an area of investigation. “We suspect that our cognitive findings would not be explained by any one MRI measure, though a comprehensive examination of MRI findings would be of benefit. The thought that there may be a reversible cardiac abnormality that does not have a structural brain imaging correlate on MRI is an interesting possibility,” she said.
Dr. Di Tullio also pointed out that at present, there is no specific treatment for diastolic dysfunction other than to address some the conditions that predispose to it, such as hypertension and atrial fibrillation.
“We completely agree that specific treatments are an area of investigation and that treatment is therefore targeted at associated modifiable conditions,” Dr. Parker replied.
With regard to more specific estimates of the prevalence of diastolic dysfunction, Dr. Parker cites another Framingham analysis that involved 2,355 persons without any prevalent cardiovascular conditions. That study found that diastolic dysfunction was rare until 50 years of age and then gradually increased with age.
About 5% of people in their 50s had mild diastolic dysfunction, and about 3% had moderate to severe diastolic dysfunction. Among persons in their 60s, about 18% had mild and 5% had severe diastolic dysfunction. Among persons in their 70s, mild diastolic dysfunction occurred in 35%, and moderate to severe disease was present in 18%; and in persons older than 80 years, nearly half had mild and about 20% had moderate to severe diastolic dysfunction.
Dr. Parker has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Reporting for duty at the front lines of COVID-19: From your editor in chief
I am writing this in mid-April, in time for our May issue. These are unusual times. During unusual times, people rise up and do unusual and exemplary things. I firmly believe in the ability of humans to rise to the occasion and step out of their boundaries and boxes when needed. And the current COVID-19 pandemic is no exception. Our patients need us. The medical community needs us, and hematologists around the world have stepped up to help in any ways they can.
Since the beginning of the year with rumblings of the emergence of a novel SARs-CoV-2 virus in patients with influenza-like illness, the hematology community has banded together to figure out what this will mean for our patients battling malignant and nonmalignant blood disorders.
With very little published literature to go on, we have had to glean from our experience with the H1N1 influenza pandemic to develop a strategy to support hematology patients who may develop COVID-19 infection. With more questions than answers, institutions around the country and globally began to collaborate and communicate furiously with each other to learn from those who had experienced the effects of the virus before we had. We have been learning to anticipate blood supply changes, treatment modifications, and therapeutic needs for those who will inevitably get the virus.
Concern rose not just for the patients but also for the providers and clinical team who care for the hematology patients. How do we preserve and protect our workforce? A pandemic does not prevent new-diagnosis leukemia or myelodysplastic syndrome blast crisis from presenting as usual at 3 p.m. on a Friday afternoon. Who is at highest risk among the staff? If we practice social distancing what does that look like in a hematology clinic, in an infusion room? Or on the stem cell transplant in-patient unit? So many questions with minimal scientific evidence to guide our decisions.
As a sickle cell disease (SCD) specialist, I had some unique concerns. Roughly 10%-15% of the sickle cell population in the United States are supported by monthly red blood cell exchange transfusions, a lifesaving therapy to prevent recurrent stroke and to manage severe end organ damage. The vast majority of patients are on some disease-modifying therapy that requires ongoing lifelong monitoring of hematologic parameters, as well as renal and hepatic function. Most SCD patients also are members of racial minorities, live in densely populated parts of the city, and have significant social determinants of health that make adherence to social distancing mandates near impossible.
Frequent exposure to acute care for painful exacerbations of their disease, preexisting comorbidities involving the lung, heart, and kidney, and their underlying cellular and humoral immune dysfunction also put our patients at heightened risk of contracting COVID-19 infection.
So how have we handled the COVID-19 pandemic thus far? We have engaged various partners, collaborators, and colleagues to figure things out. Our institutions have established incident command operations to supervise and guide bed management, staff deployment/redeployment, and the supply chain, particularly as regards personal protective equipment; and to support physician and staff wellness. Our administrative leaders have partnered seamlessly with clinical leaders to rapidly roll out robust telemedicine strategies so that we can continue to provide ongoing medical care as best we can.
We have worked tirelessly across disciplines to develop guidance documents that are specialty specific with ways to support disease populations working with the hospitalist and acute care units to define testing, treatment, and admission and discharge criteria. We have engaged communications teams that have developed health-literate public messaging for the patients and the community about coronavirus as well as the rapidly changing public health guidelines to help #flattenthecurve.
As providers, we have reviewed our patient panels to determine who can tolerate appointment delays and who has to come in to be seen with minimal impact to health outcomes. We have read more articles in the past month than perhaps the past year; listened to more podcasts, webinars, and virtual lectures on COVID-19 and strategies to halt spread of the virus – just trying to learn more. We have engaged in social media – following COVID-19 public and private groups – to get and to offer support, as well as keep a finger on the pulse of the health community around this pandemic.
For my SCD population, I have had to decide who can tolerate simple rather than exchange transfusions for the next 3-6 months and what is the minimum number of red cell units we can safely use per red cell exchange procedure as we prepare for a possible blood supply shortage. The hematology community has worked tirelessly with national societies and numerous stakeholder groups to develop a comprehensive toolkit with regularly updated information about COVID-19 relevant to the hematology community (hematology.org/covid-19).
At a practice level, we are proactively reaching out to our hematology patients and their families to reassure them and connect them with resources and support while ensuring that they have adequate supply of their daily hematology medications with tips like using the pharmacy drive-through or home medication delivery options. The past 2 weeks in Charlotte, N.C., have been hectic with preparation. My days are long; a mixture of telemedicine visits, strategic meetings, and meetings to cascade the newest plan to the staff so that they know and are comfortable with it for the patients they take care of.
When the adrenaline from each day begins to wane, we think of our individual families; we worry about relatives far and near. We mourn the loss of loved ones or other hematologists or providers who have succumbed to the COVID-19 virus. We take a minute to think about ourselves and how this pandemic affects us individually and personally. I think about my older sister who runs a smaller hospital in the Bronx, N.Y. She is at the epicenter of the pandemic and is short-staffed in the ICU and medicine floors. Because she is an ob.gyn, she has called me for guidance on a pregnant woman with anemia and sickle cell trait. I hadn’t heard from her in 24 hours and I began to wonder – is she okay? Why didn’t she answer my call this morning? Is she sick? Did she get the information I sent to her linking her with our virtual ICU experts so she can implement a similar program for her hospital?
Next, I think of my younger sister in Long Island, N.Y., who was covering shifts as a hospitalist. She had asked me to send her some hematology tips on managing disseminated intravascular coagulopathy in COVID-19 patients as she has limited access to consultants. She sees an average of seven to nine COVID-19–positive patients and several persons under investigation per shift.
I also think of my 76-year-old mom who is upset that she cannot go to the adult center because of social distancing. So, even though I am weary, I do a FaceTime call with mom. I try to explain why it’s important for her to stay indoors. It’s only temporary, I reassure her; but I cannot say how long “temporary” is.
I pack up my bags, change out of my scrubs to head to my car thinking of my daughter who just turned 21 years old and was so excited about her college graduation in May. She had a meltdown yesterday because her university announced there will be no in-person gradation. I wonder how I can help her see the big picture and yet, why should she? She’s only 21.
Then I get a page – it’s a patient with sickle cell disease – my first COVID-19–positive patient. As I take the history and turn my computer back on to do this consult, I realize that this is what all the preparation was for. The sickle cell guidance document we had worked on over the past weeks to outline a step-by-step approach to managing a SCD patient with COVID-19 that is intentionally aligned with our institutions COVID-19 treatment protocol with specific nuances relevant to patients with red blood cell disorders, was now being put to use. I felt glad for my patient that we were prepared and had a semblance of a plan on how to approach his care.
The battle is far from over. Actually, as of my writing this, it’s just starting in my part of the country. The days will continue to be long. I continue to appreciate the beauty of the human spirit among the people we work with, the hematology community we belong to, and the patients that we serve. I am committed (as are all of you) to staying “on-duty” for as long as I can, and I’d like to take this opportunity to say to all the hematologists out there – “Thank you for your service and for reporting for duty to the front lines.”
Ifeyinwa (Ify) Osunkwo, MD, MPH, is a professor of medicine and the director of the Sickle Cell Disease Enterprise at the Levine Cancer Institute, Atrium Health, Charlotte, N.C. She is the editor in chief of Hematology News.
I am writing this in mid-April, in time for our May issue. These are unusual times. During unusual times, people rise up and do unusual and exemplary things. I firmly believe in the ability of humans to rise to the occasion and step out of their boundaries and boxes when needed. And the current COVID-19 pandemic is no exception. Our patients need us. The medical community needs us, and hematologists around the world have stepped up to help in any ways they can.
Since the beginning of the year with rumblings of the emergence of a novel SARs-CoV-2 virus in patients with influenza-like illness, the hematology community has banded together to figure out what this will mean for our patients battling malignant and nonmalignant blood disorders.
With very little published literature to go on, we have had to glean from our experience with the H1N1 influenza pandemic to develop a strategy to support hematology patients who may develop COVID-19 infection. With more questions than answers, institutions around the country and globally began to collaborate and communicate furiously with each other to learn from those who had experienced the effects of the virus before we had. We have been learning to anticipate blood supply changes, treatment modifications, and therapeutic needs for those who will inevitably get the virus.
Concern rose not just for the patients but also for the providers and clinical team who care for the hematology patients. How do we preserve and protect our workforce? A pandemic does not prevent new-diagnosis leukemia or myelodysplastic syndrome blast crisis from presenting as usual at 3 p.m. on a Friday afternoon. Who is at highest risk among the staff? If we practice social distancing what does that look like in a hematology clinic, in an infusion room? Or on the stem cell transplant in-patient unit? So many questions with minimal scientific evidence to guide our decisions.
As a sickle cell disease (SCD) specialist, I had some unique concerns. Roughly 10%-15% of the sickle cell population in the United States are supported by monthly red blood cell exchange transfusions, a lifesaving therapy to prevent recurrent stroke and to manage severe end organ damage. The vast majority of patients are on some disease-modifying therapy that requires ongoing lifelong monitoring of hematologic parameters, as well as renal and hepatic function. Most SCD patients also are members of racial minorities, live in densely populated parts of the city, and have significant social determinants of health that make adherence to social distancing mandates near impossible.
Frequent exposure to acute care for painful exacerbations of their disease, preexisting comorbidities involving the lung, heart, and kidney, and their underlying cellular and humoral immune dysfunction also put our patients at heightened risk of contracting COVID-19 infection.
So how have we handled the COVID-19 pandemic thus far? We have engaged various partners, collaborators, and colleagues to figure things out. Our institutions have established incident command operations to supervise and guide bed management, staff deployment/redeployment, and the supply chain, particularly as regards personal protective equipment; and to support physician and staff wellness. Our administrative leaders have partnered seamlessly with clinical leaders to rapidly roll out robust telemedicine strategies so that we can continue to provide ongoing medical care as best we can.
We have worked tirelessly across disciplines to develop guidance documents that are specialty specific with ways to support disease populations working with the hospitalist and acute care units to define testing, treatment, and admission and discharge criteria. We have engaged communications teams that have developed health-literate public messaging for the patients and the community about coronavirus as well as the rapidly changing public health guidelines to help #flattenthecurve.
As providers, we have reviewed our patient panels to determine who can tolerate appointment delays and who has to come in to be seen with minimal impact to health outcomes. We have read more articles in the past month than perhaps the past year; listened to more podcasts, webinars, and virtual lectures on COVID-19 and strategies to halt spread of the virus – just trying to learn more. We have engaged in social media – following COVID-19 public and private groups – to get and to offer support, as well as keep a finger on the pulse of the health community around this pandemic.
For my SCD population, I have had to decide who can tolerate simple rather than exchange transfusions for the next 3-6 months and what is the minimum number of red cell units we can safely use per red cell exchange procedure as we prepare for a possible blood supply shortage. The hematology community has worked tirelessly with national societies and numerous stakeholder groups to develop a comprehensive toolkit with regularly updated information about COVID-19 relevant to the hematology community (hematology.org/covid-19).
At a practice level, we are proactively reaching out to our hematology patients and their families to reassure them and connect them with resources and support while ensuring that they have adequate supply of their daily hematology medications with tips like using the pharmacy drive-through or home medication delivery options. The past 2 weeks in Charlotte, N.C., have been hectic with preparation. My days are long; a mixture of telemedicine visits, strategic meetings, and meetings to cascade the newest plan to the staff so that they know and are comfortable with it for the patients they take care of.
When the adrenaline from each day begins to wane, we think of our individual families; we worry about relatives far and near. We mourn the loss of loved ones or other hematologists or providers who have succumbed to the COVID-19 virus. We take a minute to think about ourselves and how this pandemic affects us individually and personally. I think about my older sister who runs a smaller hospital in the Bronx, N.Y. She is at the epicenter of the pandemic and is short-staffed in the ICU and medicine floors. Because she is an ob.gyn, she has called me for guidance on a pregnant woman with anemia and sickle cell trait. I hadn’t heard from her in 24 hours and I began to wonder – is she okay? Why didn’t she answer my call this morning? Is she sick? Did she get the information I sent to her linking her with our virtual ICU experts so she can implement a similar program for her hospital?
Next, I think of my younger sister in Long Island, N.Y., who was covering shifts as a hospitalist. She had asked me to send her some hematology tips on managing disseminated intravascular coagulopathy in COVID-19 patients as she has limited access to consultants. She sees an average of seven to nine COVID-19–positive patients and several persons under investigation per shift.
I also think of my 76-year-old mom who is upset that she cannot go to the adult center because of social distancing. So, even though I am weary, I do a FaceTime call with mom. I try to explain why it’s important for her to stay indoors. It’s only temporary, I reassure her; but I cannot say how long “temporary” is.
I pack up my bags, change out of my scrubs to head to my car thinking of my daughter who just turned 21 years old and was so excited about her college graduation in May. She had a meltdown yesterday because her university announced there will be no in-person gradation. I wonder how I can help her see the big picture and yet, why should she? She’s only 21.
Then I get a page – it’s a patient with sickle cell disease – my first COVID-19–positive patient. As I take the history and turn my computer back on to do this consult, I realize that this is what all the preparation was for. The sickle cell guidance document we had worked on over the past weeks to outline a step-by-step approach to managing a SCD patient with COVID-19 that is intentionally aligned with our institutions COVID-19 treatment protocol with specific nuances relevant to patients with red blood cell disorders, was now being put to use. I felt glad for my patient that we were prepared and had a semblance of a plan on how to approach his care.
The battle is far from over. Actually, as of my writing this, it’s just starting in my part of the country. The days will continue to be long. I continue to appreciate the beauty of the human spirit among the people we work with, the hematology community we belong to, and the patients that we serve. I am committed (as are all of you) to staying “on-duty” for as long as I can, and I’d like to take this opportunity to say to all the hematologists out there – “Thank you for your service and for reporting for duty to the front lines.”
Ifeyinwa (Ify) Osunkwo, MD, MPH, is a professor of medicine and the director of the Sickle Cell Disease Enterprise at the Levine Cancer Institute, Atrium Health, Charlotte, N.C. She is the editor in chief of Hematology News.
I am writing this in mid-April, in time for our May issue. These are unusual times. During unusual times, people rise up and do unusual and exemplary things. I firmly believe in the ability of humans to rise to the occasion and step out of their boundaries and boxes when needed. And the current COVID-19 pandemic is no exception. Our patients need us. The medical community needs us, and hematologists around the world have stepped up to help in any ways they can.
Since the beginning of the year with rumblings of the emergence of a novel SARs-CoV-2 virus in patients with influenza-like illness, the hematology community has banded together to figure out what this will mean for our patients battling malignant and nonmalignant blood disorders.
With very little published literature to go on, we have had to glean from our experience with the H1N1 influenza pandemic to develop a strategy to support hematology patients who may develop COVID-19 infection. With more questions than answers, institutions around the country and globally began to collaborate and communicate furiously with each other to learn from those who had experienced the effects of the virus before we had. We have been learning to anticipate blood supply changes, treatment modifications, and therapeutic needs for those who will inevitably get the virus.
Concern rose not just for the patients but also for the providers and clinical team who care for the hematology patients. How do we preserve and protect our workforce? A pandemic does not prevent new-diagnosis leukemia or myelodysplastic syndrome blast crisis from presenting as usual at 3 p.m. on a Friday afternoon. Who is at highest risk among the staff? If we practice social distancing what does that look like in a hematology clinic, in an infusion room? Or on the stem cell transplant in-patient unit? So many questions with minimal scientific evidence to guide our decisions.
As a sickle cell disease (SCD) specialist, I had some unique concerns. Roughly 10%-15% of the sickle cell population in the United States are supported by monthly red blood cell exchange transfusions, a lifesaving therapy to prevent recurrent stroke and to manage severe end organ damage. The vast majority of patients are on some disease-modifying therapy that requires ongoing lifelong monitoring of hematologic parameters, as well as renal and hepatic function. Most SCD patients also are members of racial minorities, live in densely populated parts of the city, and have significant social determinants of health that make adherence to social distancing mandates near impossible.
Frequent exposure to acute care for painful exacerbations of their disease, preexisting comorbidities involving the lung, heart, and kidney, and their underlying cellular and humoral immune dysfunction also put our patients at heightened risk of contracting COVID-19 infection.
So how have we handled the COVID-19 pandemic thus far? We have engaged various partners, collaborators, and colleagues to figure things out. Our institutions have established incident command operations to supervise and guide bed management, staff deployment/redeployment, and the supply chain, particularly as regards personal protective equipment; and to support physician and staff wellness. Our administrative leaders have partnered seamlessly with clinical leaders to rapidly roll out robust telemedicine strategies so that we can continue to provide ongoing medical care as best we can.
We have worked tirelessly across disciplines to develop guidance documents that are specialty specific with ways to support disease populations working with the hospitalist and acute care units to define testing, treatment, and admission and discharge criteria. We have engaged communications teams that have developed health-literate public messaging for the patients and the community about coronavirus as well as the rapidly changing public health guidelines to help #flattenthecurve.
As providers, we have reviewed our patient panels to determine who can tolerate appointment delays and who has to come in to be seen with minimal impact to health outcomes. We have read more articles in the past month than perhaps the past year; listened to more podcasts, webinars, and virtual lectures on COVID-19 and strategies to halt spread of the virus – just trying to learn more. We have engaged in social media – following COVID-19 public and private groups – to get and to offer support, as well as keep a finger on the pulse of the health community around this pandemic.
For my SCD population, I have had to decide who can tolerate simple rather than exchange transfusions for the next 3-6 months and what is the minimum number of red cell units we can safely use per red cell exchange procedure as we prepare for a possible blood supply shortage. The hematology community has worked tirelessly with national societies and numerous stakeholder groups to develop a comprehensive toolkit with regularly updated information about COVID-19 relevant to the hematology community (hematology.org/covid-19).
At a practice level, we are proactively reaching out to our hematology patients and their families to reassure them and connect them with resources and support while ensuring that they have adequate supply of their daily hematology medications with tips like using the pharmacy drive-through or home medication delivery options. The past 2 weeks in Charlotte, N.C., have been hectic with preparation. My days are long; a mixture of telemedicine visits, strategic meetings, and meetings to cascade the newest plan to the staff so that they know and are comfortable with it for the patients they take care of.
When the adrenaline from each day begins to wane, we think of our individual families; we worry about relatives far and near. We mourn the loss of loved ones or other hematologists or providers who have succumbed to the COVID-19 virus. We take a minute to think about ourselves and how this pandemic affects us individually and personally. I think about my older sister who runs a smaller hospital in the Bronx, N.Y. She is at the epicenter of the pandemic and is short-staffed in the ICU and medicine floors. Because she is an ob.gyn, she has called me for guidance on a pregnant woman with anemia and sickle cell trait. I hadn’t heard from her in 24 hours and I began to wonder – is she okay? Why didn’t she answer my call this morning? Is she sick? Did she get the information I sent to her linking her with our virtual ICU experts so she can implement a similar program for her hospital?
Next, I think of my younger sister in Long Island, N.Y., who was covering shifts as a hospitalist. She had asked me to send her some hematology tips on managing disseminated intravascular coagulopathy in COVID-19 patients as she has limited access to consultants. She sees an average of seven to nine COVID-19–positive patients and several persons under investigation per shift.
I also think of my 76-year-old mom who is upset that she cannot go to the adult center because of social distancing. So, even though I am weary, I do a FaceTime call with mom. I try to explain why it’s important for her to stay indoors. It’s only temporary, I reassure her; but I cannot say how long “temporary” is.
I pack up my bags, change out of my scrubs to head to my car thinking of my daughter who just turned 21 years old and was so excited about her college graduation in May. She had a meltdown yesterday because her university announced there will be no in-person gradation. I wonder how I can help her see the big picture and yet, why should she? She’s only 21.
Then I get a page – it’s a patient with sickle cell disease – my first COVID-19–positive patient. As I take the history and turn my computer back on to do this consult, I realize that this is what all the preparation was for. The sickle cell guidance document we had worked on over the past weeks to outline a step-by-step approach to managing a SCD patient with COVID-19 that is intentionally aligned with our institutions COVID-19 treatment protocol with specific nuances relevant to patients with red blood cell disorders, was now being put to use. I felt glad for my patient that we were prepared and had a semblance of a plan on how to approach his care.
The battle is far from over. Actually, as of my writing this, it’s just starting in my part of the country. The days will continue to be long. I continue to appreciate the beauty of the human spirit among the people we work with, the hematology community we belong to, and the patients that we serve. I am committed (as are all of you) to staying “on-duty” for as long as I can, and I’d like to take this opportunity to say to all the hematologists out there – “Thank you for your service and for reporting for duty to the front lines.”
Ifeyinwa (Ify) Osunkwo, MD, MPH, is a professor of medicine and the director of the Sickle Cell Disease Enterprise at the Levine Cancer Institute, Atrium Health, Charlotte, N.C. She is the editor in chief of Hematology News.
Three months of COVID-19 may mean 80,000 missed cancer diagnoses
, according to a report by the IQVIA Institute for Human Data Science looking at trends in the United States.
Screening and monitoring tests for breast, prostate, colorectal, cervical, and lung cancer were down 39%-90% in early April, compared with the baseline month of February, according to report authors Murray Aitken and Michael Kleinrock, both of IQVIA.
These findings are based on data from IQVIA’s medical claims database, which includes more than 205 million patients, over 1.7 billion claims, and 3 billion service records obtained annually.
The data suggest that, at current positivity rates, there could be 36,000 missed or delayed diagnoses of breast cancer during the 3-month period from early March through early June. Estimates for missed diagnoses of the four other cancers analyzed include 450 for lung cancer, 2,500 for cervical cancer, 18,800 for colorectal cancer, and 22,600 for prostate cancer.
The authors project a total of 22 million canceled or delayed tests for the five cancers over the 3-month period ending June 5, based on a comparison of claims data for early April with the February baseline. Catching up on this backlog will be problematic, according to the authors.
“Current excess health care capacity ... would require providers to shift priorities to make time and space in schedules and facilities as well as the cooperation of patients to return to health care providers,” the authors wrote. “Both of these could be further disrupted by economic factors or reintroduction of social distancing in a reemergence of the outbreak.”
The report was produced by the IQVIA Institute for Human Data Science without industry or government funding.
SOURCE: Murray A and Kleinrock M. Shifts in healthcare demand, delivery and care during the COVID-19 era. IQVIA Institute for Human Data Science. April 2020.
, according to a report by the IQVIA Institute for Human Data Science looking at trends in the United States.
Screening and monitoring tests for breast, prostate, colorectal, cervical, and lung cancer were down 39%-90% in early April, compared with the baseline month of February, according to report authors Murray Aitken and Michael Kleinrock, both of IQVIA.
These findings are based on data from IQVIA’s medical claims database, which includes more than 205 million patients, over 1.7 billion claims, and 3 billion service records obtained annually.
The data suggest that, at current positivity rates, there could be 36,000 missed or delayed diagnoses of breast cancer during the 3-month period from early March through early June. Estimates for missed diagnoses of the four other cancers analyzed include 450 for lung cancer, 2,500 for cervical cancer, 18,800 for colorectal cancer, and 22,600 for prostate cancer.
The authors project a total of 22 million canceled or delayed tests for the five cancers over the 3-month period ending June 5, based on a comparison of claims data for early April with the February baseline. Catching up on this backlog will be problematic, according to the authors.
“Current excess health care capacity ... would require providers to shift priorities to make time and space in schedules and facilities as well as the cooperation of patients to return to health care providers,” the authors wrote. “Both of these could be further disrupted by economic factors or reintroduction of social distancing in a reemergence of the outbreak.”
The report was produced by the IQVIA Institute for Human Data Science without industry or government funding.
SOURCE: Murray A and Kleinrock M. Shifts in healthcare demand, delivery and care during the COVID-19 era. IQVIA Institute for Human Data Science. April 2020.
, according to a report by the IQVIA Institute for Human Data Science looking at trends in the United States.
Screening and monitoring tests for breast, prostate, colorectal, cervical, and lung cancer were down 39%-90% in early April, compared with the baseline month of February, according to report authors Murray Aitken and Michael Kleinrock, both of IQVIA.
These findings are based on data from IQVIA’s medical claims database, which includes more than 205 million patients, over 1.7 billion claims, and 3 billion service records obtained annually.
The data suggest that, at current positivity rates, there could be 36,000 missed or delayed diagnoses of breast cancer during the 3-month period from early March through early June. Estimates for missed diagnoses of the four other cancers analyzed include 450 for lung cancer, 2,500 for cervical cancer, 18,800 for colorectal cancer, and 22,600 for prostate cancer.
The authors project a total of 22 million canceled or delayed tests for the five cancers over the 3-month period ending June 5, based on a comparison of claims data for early April with the February baseline. Catching up on this backlog will be problematic, according to the authors.
“Current excess health care capacity ... would require providers to shift priorities to make time and space in schedules and facilities as well as the cooperation of patients to return to health care providers,” the authors wrote. “Both of these could be further disrupted by economic factors or reintroduction of social distancing in a reemergence of the outbreak.”
The report was produced by the IQVIA Institute for Human Data Science without industry or government funding.
SOURCE: Murray A and Kleinrock M. Shifts in healthcare demand, delivery and care during the COVID-19 era. IQVIA Institute for Human Data Science. April 2020.
Cancer screening, monitoring down during pandemic
according to a report by the IQVIA Institute for Human Data Science.
There were 90% fewer colonoscopies ordered during the week ending April 10, compared with the weekly average for Feb. 1-28, based on claims data analyzed by IQVIA.
IQVIA’s medical claims database includes more than 205 million patients, over 1.7 billion claims, and 3 billion service records obtained annually.
The data also showed an 87% reduction in mammograms and an 83% reduction in Pap smears during the week ending April 10. Prostate-specific antigen tests for prostate cancer decreased by 60%, and CT scans for lung cancer decreased by 39%.
The smaller decrease in CT scans for lung cancer “may reflect the generally more serious nature of those tumors or be due to concerns about ruling out COVID-related issues in some patients,” according to report authors Murray Aitken and Michael Kleinrock, both of IQVIA.
The report also showed that overall patient interactions with oncologists were down by 20% through April 3, based on medical and pharmacy claims processed since February, but there was variation by tumor type.
The authors noted “little or no disruption” in oncologist visits in March for patients with aggressive tumors or those diagnosed at advanced stages, compared with February. However, for patients with skin cancer or prostate cancer, visit rates were down by 20%-50% in March.
“This may reflect that oncologists who are providing care across multiple tumor types are prioritizing their time and efforts to those patients with more advanced or aggressive tumors,” the authors wrote.
This report was produced by the IQVIA Institute for Human Data Science without industry or government funding.
SOURCE: Murray A and Kleinrock M. Shifts in healthcare demand, delivery and care during the COVID-19 era. IQVIA Institute for Human Data Science. April 2020.
according to a report by the IQVIA Institute for Human Data Science.
There were 90% fewer colonoscopies ordered during the week ending April 10, compared with the weekly average for Feb. 1-28, based on claims data analyzed by IQVIA.
IQVIA’s medical claims database includes more than 205 million patients, over 1.7 billion claims, and 3 billion service records obtained annually.
The data also showed an 87% reduction in mammograms and an 83% reduction in Pap smears during the week ending April 10. Prostate-specific antigen tests for prostate cancer decreased by 60%, and CT scans for lung cancer decreased by 39%.
The smaller decrease in CT scans for lung cancer “may reflect the generally more serious nature of those tumors or be due to concerns about ruling out COVID-related issues in some patients,” according to report authors Murray Aitken and Michael Kleinrock, both of IQVIA.
The report also showed that overall patient interactions with oncologists were down by 20% through April 3, based on medical and pharmacy claims processed since February, but there was variation by tumor type.
The authors noted “little or no disruption” in oncologist visits in March for patients with aggressive tumors or those diagnosed at advanced stages, compared with February. However, for patients with skin cancer or prostate cancer, visit rates were down by 20%-50% in March.
“This may reflect that oncologists who are providing care across multiple tumor types are prioritizing their time and efforts to those patients with more advanced or aggressive tumors,” the authors wrote.
This report was produced by the IQVIA Institute for Human Data Science without industry or government funding.
SOURCE: Murray A and Kleinrock M. Shifts in healthcare demand, delivery and care during the COVID-19 era. IQVIA Institute for Human Data Science. April 2020.
according to a report by the IQVIA Institute for Human Data Science.
There were 90% fewer colonoscopies ordered during the week ending April 10, compared with the weekly average for Feb. 1-28, based on claims data analyzed by IQVIA.
IQVIA’s medical claims database includes more than 205 million patients, over 1.7 billion claims, and 3 billion service records obtained annually.
The data also showed an 87% reduction in mammograms and an 83% reduction in Pap smears during the week ending April 10. Prostate-specific antigen tests for prostate cancer decreased by 60%, and CT scans for lung cancer decreased by 39%.
The smaller decrease in CT scans for lung cancer “may reflect the generally more serious nature of those tumors or be due to concerns about ruling out COVID-related issues in some patients,” according to report authors Murray Aitken and Michael Kleinrock, both of IQVIA.
The report also showed that overall patient interactions with oncologists were down by 20% through April 3, based on medical and pharmacy claims processed since February, but there was variation by tumor type.
The authors noted “little or no disruption” in oncologist visits in March for patients with aggressive tumors or those diagnosed at advanced stages, compared with February. However, for patients with skin cancer or prostate cancer, visit rates were down by 20%-50% in March.
“This may reflect that oncologists who are providing care across multiple tumor types are prioritizing their time and efforts to those patients with more advanced or aggressive tumors,” the authors wrote.
This report was produced by the IQVIA Institute for Human Data Science without industry or government funding.
SOURCE: Murray A and Kleinrock M. Shifts in healthcare demand, delivery and care during the COVID-19 era. IQVIA Institute for Human Data Science. April 2020.
FDA tightens requirements for COVID-19 antibody tests
The U.S. Food and Drug Administration is tightening requirements for companies that develop COVID-19 antibody tests in an effort to combat fraud and better regulate the frenzy of tests coming to market.
The updated policy, announced May 4, requires commercial antibody test developers to apply for Emergency Use Authorization (EUA) from the FDA under a tight time frame and also provides specific performance threshold recommendations for test specificity and sensitivity. The revised requirements follow a March 16 policy that allowed developers to validate their own tests and bring them to market without an agency review. More than 100 coronavirus antibody tests have since entered the market, fueling a congressional investigation into the accuracy of tests.
When the March policy was issued, FDA Commissioner Stephen M. Hahn, MD, said it was critical for the FDA to provide regulatory flexibility for serology test developers, given the nature of the COVID-19 public health emergency and an understanding that the tests were not meant to be used as the sole basis for COVID-19 diagnosis.
“As FDA has authorized more antibody tests and validation data has become available, including through the capability at [the National Cancer Institute] the careful balancing of risks and benefits has shifted to the approach we have outlined today and our policy update,” Dr. Hahn said during a May 4 press conference.
The new approach requires all commercial manufacturers to submit EUA requests with their validation data within 10 business days from the date they notified the FDA of their validation testing or from the date of the May 4 policy, whichever is later. Additionally, the FDA has provided specific performance threshold recommendations for specificity and sensitivity for all serology test developers.
In a statement released May 4, FDA leaders acknowledged the widespread fraud that is occurring in connection to antibody tests entering the market.
“We unfortunately see unscrupulous actors marketing fraudulent test kits and using the pandemic as an opportunity to take advantage of Americans’ anxiety,” wrote Anand Shah, MD, FDA deputy commissioner for medical and scientific affairs in a joint statement with Jeff E. Shuren, MD, director for the FDA’s Center for Devices and Radiological Health. “Some test developers have falsely claimed their serological tests are FDA approved or authorized. Others have falsely claimed that their tests can diagnose COVID-19 or that they are for at-home testing, which would fall outside of the policies outlined in our March 16 guidance, as well as the updated guidance.”
At the same time, FDA officials said they are aware of a “concerning number” of commercial serology tests that are being inappropriately marketed, including for diagnostic use, or that are performing poorly based on an independent evaluation by the National Institutes of Health, according to the May 4 statement.
In addition to tightening its requirements for test developers, the FDA also is introducing a more streamlined process to support EUA submissions and review. Two voluntary EUA templates for antibody tests are now available – one for commercial manufacturers and one for Clinical Laboratory Improvement Amendments-certified high-complexity labs seeking FDA authorization. The templates will facilitate the preparation and submission of EUA requests and can be used by any interested developer, according to the FDA.
To date, 12 antibody tests have been authorized under an individual EUA, and more than 200 antibody tests are currently the subject of a pre-EUA or EUA review, according to the FDA.
Many unknowns remain about antibody tests and how they might help researchers and clinicians understand and/or potentially treat COVID-19. Antibody tests may be able to provide information on disease prevalence and frequency of asymptomatic infection, as well as identify potential donors of “convalescent plasma,” an approach in which blood plasma containing antibodies from a recovered individual serves as a therapy for an infected patient with severe disease, Dr. Shah wrote in the May 4 statement.
“There are a lot of unanswered questions about this particular issue,” Dr. Hahn said during the press conference. “We need the data because we need to understand this particular aspect of the disease and put it as part of the puzzle around COVID-19.”
The U.S. Food and Drug Administration is tightening requirements for companies that develop COVID-19 antibody tests in an effort to combat fraud and better regulate the frenzy of tests coming to market.
The updated policy, announced May 4, requires commercial antibody test developers to apply for Emergency Use Authorization (EUA) from the FDA under a tight time frame and also provides specific performance threshold recommendations for test specificity and sensitivity. The revised requirements follow a March 16 policy that allowed developers to validate their own tests and bring them to market without an agency review. More than 100 coronavirus antibody tests have since entered the market, fueling a congressional investigation into the accuracy of tests.
When the March policy was issued, FDA Commissioner Stephen M. Hahn, MD, said it was critical for the FDA to provide regulatory flexibility for serology test developers, given the nature of the COVID-19 public health emergency and an understanding that the tests were not meant to be used as the sole basis for COVID-19 diagnosis.
“As FDA has authorized more antibody tests and validation data has become available, including through the capability at [the National Cancer Institute] the careful balancing of risks and benefits has shifted to the approach we have outlined today and our policy update,” Dr. Hahn said during a May 4 press conference.
The new approach requires all commercial manufacturers to submit EUA requests with their validation data within 10 business days from the date they notified the FDA of their validation testing or from the date of the May 4 policy, whichever is later. Additionally, the FDA has provided specific performance threshold recommendations for specificity and sensitivity for all serology test developers.
In a statement released May 4, FDA leaders acknowledged the widespread fraud that is occurring in connection to antibody tests entering the market.
“We unfortunately see unscrupulous actors marketing fraudulent test kits and using the pandemic as an opportunity to take advantage of Americans’ anxiety,” wrote Anand Shah, MD, FDA deputy commissioner for medical and scientific affairs in a joint statement with Jeff E. Shuren, MD, director for the FDA’s Center for Devices and Radiological Health. “Some test developers have falsely claimed their serological tests are FDA approved or authorized. Others have falsely claimed that their tests can diagnose COVID-19 or that they are for at-home testing, which would fall outside of the policies outlined in our March 16 guidance, as well as the updated guidance.”
At the same time, FDA officials said they are aware of a “concerning number” of commercial serology tests that are being inappropriately marketed, including for diagnostic use, or that are performing poorly based on an independent evaluation by the National Institutes of Health, according to the May 4 statement.
In addition to tightening its requirements for test developers, the FDA also is introducing a more streamlined process to support EUA submissions and review. Two voluntary EUA templates for antibody tests are now available – one for commercial manufacturers and one for Clinical Laboratory Improvement Amendments-certified high-complexity labs seeking FDA authorization. The templates will facilitate the preparation and submission of EUA requests and can be used by any interested developer, according to the FDA.
To date, 12 antibody tests have been authorized under an individual EUA, and more than 200 antibody tests are currently the subject of a pre-EUA or EUA review, according to the FDA.
Many unknowns remain about antibody tests and how they might help researchers and clinicians understand and/or potentially treat COVID-19. Antibody tests may be able to provide information on disease prevalence and frequency of asymptomatic infection, as well as identify potential donors of “convalescent plasma,” an approach in which blood plasma containing antibodies from a recovered individual serves as a therapy for an infected patient with severe disease, Dr. Shah wrote in the May 4 statement.
“There are a lot of unanswered questions about this particular issue,” Dr. Hahn said during the press conference. “We need the data because we need to understand this particular aspect of the disease and put it as part of the puzzle around COVID-19.”
The U.S. Food and Drug Administration is tightening requirements for companies that develop COVID-19 antibody tests in an effort to combat fraud and better regulate the frenzy of tests coming to market.
The updated policy, announced May 4, requires commercial antibody test developers to apply for Emergency Use Authorization (EUA) from the FDA under a tight time frame and also provides specific performance threshold recommendations for test specificity and sensitivity. The revised requirements follow a March 16 policy that allowed developers to validate their own tests and bring them to market without an agency review. More than 100 coronavirus antibody tests have since entered the market, fueling a congressional investigation into the accuracy of tests.
When the March policy was issued, FDA Commissioner Stephen M. Hahn, MD, said it was critical for the FDA to provide regulatory flexibility for serology test developers, given the nature of the COVID-19 public health emergency and an understanding that the tests were not meant to be used as the sole basis for COVID-19 diagnosis.
“As FDA has authorized more antibody tests and validation data has become available, including through the capability at [the National Cancer Institute] the careful balancing of risks and benefits has shifted to the approach we have outlined today and our policy update,” Dr. Hahn said during a May 4 press conference.
The new approach requires all commercial manufacturers to submit EUA requests with their validation data within 10 business days from the date they notified the FDA of their validation testing or from the date of the May 4 policy, whichever is later. Additionally, the FDA has provided specific performance threshold recommendations for specificity and sensitivity for all serology test developers.
In a statement released May 4, FDA leaders acknowledged the widespread fraud that is occurring in connection to antibody tests entering the market.
“We unfortunately see unscrupulous actors marketing fraudulent test kits and using the pandemic as an opportunity to take advantage of Americans’ anxiety,” wrote Anand Shah, MD, FDA deputy commissioner for medical and scientific affairs in a joint statement with Jeff E. Shuren, MD, director for the FDA’s Center for Devices and Radiological Health. “Some test developers have falsely claimed their serological tests are FDA approved or authorized. Others have falsely claimed that their tests can diagnose COVID-19 or that they are for at-home testing, which would fall outside of the policies outlined in our March 16 guidance, as well as the updated guidance.”
At the same time, FDA officials said they are aware of a “concerning number” of commercial serology tests that are being inappropriately marketed, including for diagnostic use, or that are performing poorly based on an independent evaluation by the National Institutes of Health, according to the May 4 statement.
In addition to tightening its requirements for test developers, the FDA also is introducing a more streamlined process to support EUA submissions and review. Two voluntary EUA templates for antibody tests are now available – one for commercial manufacturers and one for Clinical Laboratory Improvement Amendments-certified high-complexity labs seeking FDA authorization. The templates will facilitate the preparation and submission of EUA requests and can be used by any interested developer, according to the FDA.
To date, 12 antibody tests have been authorized under an individual EUA, and more than 200 antibody tests are currently the subject of a pre-EUA or EUA review, according to the FDA.
Many unknowns remain about antibody tests and how they might help researchers and clinicians understand and/or potentially treat COVID-19. Antibody tests may be able to provide information on disease prevalence and frequency of asymptomatic infection, as well as identify potential donors of “convalescent plasma,” an approach in which blood plasma containing antibodies from a recovered individual serves as a therapy for an infected patient with severe disease, Dr. Shah wrote in the May 4 statement.
“There are a lot of unanswered questions about this particular issue,” Dr. Hahn said during the press conference. “We need the data because we need to understand this particular aspect of the disease and put it as part of the puzzle around COVID-19.”
Multiple atopic dermatitis therapies completed or close to completing phase 3 studies
Major , Jonathan I. Silverberg, MD, PhD, said during a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled due to the COVID-19 pandemic.
“In the next 2-3 years, we may have nine new treatments approved for atopic dermatitis,” said Dr. Silverberg, director of clinical research and contact dermatitis at the University.
All nine medications he discussed are either in ongoing pivotal phase 3 randomized controlled trials or have completed their phase 3 developmental programs. “This is not theoretical; these are things you’re going to be using in your toolbox imminently,” he stressed.
Oral JAK inhibitors
The Janus kinase (JAK) pathway is the intracellular signaling mediator that interacts with extracellular inflammatory cytokines, including interleukin-4, -13, and -31, which are familiar to dermatologists because they’re targeted by potent biologic monoclonal antibody therapies. For example, IL-4 goes through JAK1 and 3, while IL-31 signals through JAK1 and 2.
“You really need to know the key JAK and STAT pathways involved in atopic dermatitis because it will help you determine the selectivity of the agents you’re going to be using,” the dermatologist advised.
Three oral, once-daily JAK inhibitors – abrocitinib, upadacitinib, and baricitinib – are in an advanced stage of development.
“Upadacitinib and abrocitinib may be the two most potent options coming to market soon for us to be thinking about,” Dr. Silverberg said.
Abrocitinib: Three positive phase 3 studies featuring this selective JAK1 inhibitor have been completed in adults with moderate to severe atopic dermatitis (AD). The most recent, JADE COMPARE, featured a head-to-head randomized comparison of abrocitinib and the injectable IL-4/IL-13 inhibitor dupilumab. The results of this 837-patient study haven’t yet been formally presented at a conference because of the COVID-19 pandemic. However, Pfizer recently announced that abrocitinib at 200 mg/day achieved significantly greater improvements than dupilumab (Dupixent) in the coprimary endpoints of skin clearance as reflected in an Investigator’s Global Assessment (IGA) score of 0 or 1 (that is, clear or almost clear) and disease extent based upon 75% reduction from baseline in Eczema Area and Severity Index (EASI 75) at 12 weeks. The same was true at 16 weeks.
Also, a significantly larger proportion of abrocitinib-treated patients achieved at least a 4-point reduction in itch severity as measured using the Peak Pruritus Numerical Rating Scale at week 2. The company plans to file for regulatory approval later this year.
The JADE COMPARE data are exciting because of a pressing unmet need for treatment options that are even more powerful than dupilumab, Dr. Silverberg said.
Upadacitinib: This is selective JAK1 inhibitor is not as far along in the developmental pipeline as abrocitinib, but the efficacy appears to be comparable. In a phase 2 study of 126 adults with moderate to severe AD, upadacitinib at the top dose of 30 mg/day achieved efficacy results Dr. Silverberg deemed “quite extraordinary,” with a rate of IGA score of 0 or 1 of 50% at 16 weeks and an EASI 75 response rate of 69%. Those findings numerically eclipsed results seen in an earlier phase 3 pivotal trial for dupilumab, in which the IGA 0/1 rate was 37% and EASI 75 was 48%, albeit with the caveat that cross-trial comparisons must be taken with a large grain of salt.
Baricitinib: Multiple phase 3 studies of this JAK 1/2 inhibitor have reported positive results. At the top dose of 4 mg/day, baricitinib appears to be less effective than dupilumab in its earlier pivotal trials.
“This may be a good oral option for our patients. It could be similar to the Otezla [apremilast] story in psoriasis: It’s perhaps not as effective as a lot of the biologics, but patients often prefer an oral option,” Dr. Silverberg said.
Of note, in one large, placebo-controlled, phase 3 study of baricitinib on top of background low- or medium-potency topical steroids, the IGA 0/1 rate at 16 weeks with placebo plus topical steroids was a modest 14.7%, which underscores that this long-time workhorse topical therapy is objectively less effective than most physicians think. In contrast, the IGA 0/1 rate with baricitinib at 4 mg/day plus topical steroids was a more respectable 30.6%.
All three oral JAK inhibitors have rapid onset of efficacy, a key advantage over the biologic agents.
“The issue you have to keep in mind is safety. The safety in the atopic dermatitis population was overall quite good for all three drugs. However, safety concerns have come up with JAK inhibitors in rheumatoid arthritis. I think that’s the part we watch the most in this. The efficacy has become clear. Now the question is where does the safety take us,” he said.
Novel injectable biologics
Nemolizumab: This humanized monoclonal antibody inhibits IL-31 receptor alpha. Mounting evidence implicates IL-31 as both a proinflammatory and immunomodulatory cytokine linking the immune and neural systems.
Early on, most researchers pigeonholed IL-31 as being a key player only in the itch factor in AD. Not so. Indeed, Dr. Silverberg was the lead investigator in a recent phase 2b study of nemolizumab that demonstrated the biologic is also effective at rapidly clearing AD lesions. The study, which evaluated three different doses in 226 adults with moderate to severe AD and severe pruritus who were on background topical corticosteroids, showed that nemolizumab at 30 mg every 4 weeks trounced placebo in terms of itch reduction: The 69% drop from baseline in Peak Pruritus Numeric Rating Scale at week 16 was twice that in controls, with a significant difference apparent even at week 1.
But in addition, the 33% IGA 0/1 rate at the same time point bested the 12% rate in controls. The EASI 75 response rate was significantly higher as well – 49% versus 19% – as was the EASI 90 response of 33%, compared with 9% in controls. Moreover, nemolizumab-treated patients used close to 40% less topical steroids during the study (J Allergy Clin Immunol. 2020 Jan;145[1]:173-82).
“This is something that’s fascinating. The study gets into the idea that a subset of atopic dermatitis patients have the itch that rashes, and perhaps if you break the itch/scratch cycle you can modify the lesions. Or the effect may even be due to the direct anti-inflammatory action of IL-31 blockade,” Dr. Silverberg observed.
It appeared that a plateau hadn’t been reached for some endpoints out at week 24, when the study ended. Japanese phase 3 studies have been completed, with what he called “great results,” and others are ongoing in the United States.
Tralokinumab: This fully human monoclonal antibody binds to IL-13, but unlike dupilumab, it doesn’t also inhibit IL-4. Tralokinumab met all primary and secondary endpoints in three pivotal phase 3 clinical trials, known as ECZTRA 1-3, that assessed it as treatment for moderate to severe AD in adults and showed an overall adverse event rate comparable with placebo. Leo Pharma, the Danish company developing the biologic, has announced it will file for marketing approval before the end of 2020. Phase 3 data would have been presented at the annual meeting of the American Academy of Dermatology in Denver, had it not been canceled. Dr. Silverberg said that, based upon phase 2 results, it appears tralokinumab may not be quite as effective as dupilumab in the overall AD population, but he predicted the newcomer will still play a useful role.
“The complexities of the immune system are such that some patients will respond better to one drug than another. I think we still have a lot to learn about who the patients are for these novel assets,” he said.
Lebrikizumab: This is another selective IL-13 inhibitor, but this one binds to IL-13 in a slightly different way than tralokinumab. The Food and Drug Administration granted it Fast Track status in December 2019. Twin placebo-controlled phase 3 studies of lebrikizumab as monotherapy for moderate to severe AD are ongoing, and another phase 3 trial of the biologic in combination with topical steroids is planned. Based upon the results of a phase 2b study, the highest dose studied – 250 mg every 2 weeks – appears to be at least as effective as dupilumab.
Nonsteroidal topical agents
These three late-stage topical creams – ruxolitinib, delgocitinib, and tapinarof – have previously received considerable coverage in Dermatology News. Ruxolitinib, a selective JAK1/2 inhibitor, has completed a positive phase 3 trial in adolescents and adults with mild to moderate AD. Delgocitinib, a pan-JAK1/2/3 and Tyrosine kinase 2 inhibitor, is already approved in an ointment formulation in Japan, and the cream formulation is in phase 2 studies in the United States and Europe. Tapinarof has a unique mechanism of action – it’s an aryl hydrocarbon receptor modulator – and is now in phase 3 in adolescents and adults with moderate to severe AD.
These three drugs appear to offer efficacy that’s comparable to or even better than medium-potency topical steroids, and without the notorious steroidal side effects that have caused widespread parental steroid-phobia. Potential applications for other inflammatory diseases, including vitiligo and psoriasis, are under study.
Dr. Silverberg reported receiving research grants from Galderma and GlaxoSmithKline and serving as a consultant to those pharmaceutical companies and more than a dozen others.
Major , Jonathan I. Silverberg, MD, PhD, said during a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled due to the COVID-19 pandemic.
“In the next 2-3 years, we may have nine new treatments approved for atopic dermatitis,” said Dr. Silverberg, director of clinical research and contact dermatitis at the University.
All nine medications he discussed are either in ongoing pivotal phase 3 randomized controlled trials or have completed their phase 3 developmental programs. “This is not theoretical; these are things you’re going to be using in your toolbox imminently,” he stressed.
Oral JAK inhibitors
The Janus kinase (JAK) pathway is the intracellular signaling mediator that interacts with extracellular inflammatory cytokines, including interleukin-4, -13, and -31, which are familiar to dermatologists because they’re targeted by potent biologic monoclonal antibody therapies. For example, IL-4 goes through JAK1 and 3, while IL-31 signals through JAK1 and 2.
“You really need to know the key JAK and STAT pathways involved in atopic dermatitis because it will help you determine the selectivity of the agents you’re going to be using,” the dermatologist advised.
Three oral, once-daily JAK inhibitors – abrocitinib, upadacitinib, and baricitinib – are in an advanced stage of development.
“Upadacitinib and abrocitinib may be the two most potent options coming to market soon for us to be thinking about,” Dr. Silverberg said.
Abrocitinib: Three positive phase 3 studies featuring this selective JAK1 inhibitor have been completed in adults with moderate to severe atopic dermatitis (AD). The most recent, JADE COMPARE, featured a head-to-head randomized comparison of abrocitinib and the injectable IL-4/IL-13 inhibitor dupilumab. The results of this 837-patient study haven’t yet been formally presented at a conference because of the COVID-19 pandemic. However, Pfizer recently announced that abrocitinib at 200 mg/day achieved significantly greater improvements than dupilumab (Dupixent) in the coprimary endpoints of skin clearance as reflected in an Investigator’s Global Assessment (IGA) score of 0 or 1 (that is, clear or almost clear) and disease extent based upon 75% reduction from baseline in Eczema Area and Severity Index (EASI 75) at 12 weeks. The same was true at 16 weeks.
Also, a significantly larger proportion of abrocitinib-treated patients achieved at least a 4-point reduction in itch severity as measured using the Peak Pruritus Numerical Rating Scale at week 2. The company plans to file for regulatory approval later this year.
The JADE COMPARE data are exciting because of a pressing unmet need for treatment options that are even more powerful than dupilumab, Dr. Silverberg said.
Upadacitinib: This is selective JAK1 inhibitor is not as far along in the developmental pipeline as abrocitinib, but the efficacy appears to be comparable. In a phase 2 study of 126 adults with moderate to severe AD, upadacitinib at the top dose of 30 mg/day achieved efficacy results Dr. Silverberg deemed “quite extraordinary,” with a rate of IGA score of 0 or 1 of 50% at 16 weeks and an EASI 75 response rate of 69%. Those findings numerically eclipsed results seen in an earlier phase 3 pivotal trial for dupilumab, in which the IGA 0/1 rate was 37% and EASI 75 was 48%, albeit with the caveat that cross-trial comparisons must be taken with a large grain of salt.
Baricitinib: Multiple phase 3 studies of this JAK 1/2 inhibitor have reported positive results. At the top dose of 4 mg/day, baricitinib appears to be less effective than dupilumab in its earlier pivotal trials.
“This may be a good oral option for our patients. It could be similar to the Otezla [apremilast] story in psoriasis: It’s perhaps not as effective as a lot of the biologics, but patients often prefer an oral option,” Dr. Silverberg said.
Of note, in one large, placebo-controlled, phase 3 study of baricitinib on top of background low- or medium-potency topical steroids, the IGA 0/1 rate at 16 weeks with placebo plus topical steroids was a modest 14.7%, which underscores that this long-time workhorse topical therapy is objectively less effective than most physicians think. In contrast, the IGA 0/1 rate with baricitinib at 4 mg/day plus topical steroids was a more respectable 30.6%.
All three oral JAK inhibitors have rapid onset of efficacy, a key advantage over the biologic agents.
“The issue you have to keep in mind is safety. The safety in the atopic dermatitis population was overall quite good for all three drugs. However, safety concerns have come up with JAK inhibitors in rheumatoid arthritis. I think that’s the part we watch the most in this. The efficacy has become clear. Now the question is where does the safety take us,” he said.
Novel injectable biologics
Nemolizumab: This humanized monoclonal antibody inhibits IL-31 receptor alpha. Mounting evidence implicates IL-31 as both a proinflammatory and immunomodulatory cytokine linking the immune and neural systems.
Early on, most researchers pigeonholed IL-31 as being a key player only in the itch factor in AD. Not so. Indeed, Dr. Silverberg was the lead investigator in a recent phase 2b study of nemolizumab that demonstrated the biologic is also effective at rapidly clearing AD lesions. The study, which evaluated three different doses in 226 adults with moderate to severe AD and severe pruritus who were on background topical corticosteroids, showed that nemolizumab at 30 mg every 4 weeks trounced placebo in terms of itch reduction: The 69% drop from baseline in Peak Pruritus Numeric Rating Scale at week 16 was twice that in controls, with a significant difference apparent even at week 1.
But in addition, the 33% IGA 0/1 rate at the same time point bested the 12% rate in controls. The EASI 75 response rate was significantly higher as well – 49% versus 19% – as was the EASI 90 response of 33%, compared with 9% in controls. Moreover, nemolizumab-treated patients used close to 40% less topical steroids during the study (J Allergy Clin Immunol. 2020 Jan;145[1]:173-82).
“This is something that’s fascinating. The study gets into the idea that a subset of atopic dermatitis patients have the itch that rashes, and perhaps if you break the itch/scratch cycle you can modify the lesions. Or the effect may even be due to the direct anti-inflammatory action of IL-31 blockade,” Dr. Silverberg observed.
It appeared that a plateau hadn’t been reached for some endpoints out at week 24, when the study ended. Japanese phase 3 studies have been completed, with what he called “great results,” and others are ongoing in the United States.
Tralokinumab: This fully human monoclonal antibody binds to IL-13, but unlike dupilumab, it doesn’t also inhibit IL-4. Tralokinumab met all primary and secondary endpoints in three pivotal phase 3 clinical trials, known as ECZTRA 1-3, that assessed it as treatment for moderate to severe AD in adults and showed an overall adverse event rate comparable with placebo. Leo Pharma, the Danish company developing the biologic, has announced it will file for marketing approval before the end of 2020. Phase 3 data would have been presented at the annual meeting of the American Academy of Dermatology in Denver, had it not been canceled. Dr. Silverberg said that, based upon phase 2 results, it appears tralokinumab may not be quite as effective as dupilumab in the overall AD population, but he predicted the newcomer will still play a useful role.
“The complexities of the immune system are such that some patients will respond better to one drug than another. I think we still have a lot to learn about who the patients are for these novel assets,” he said.
Lebrikizumab: This is another selective IL-13 inhibitor, but this one binds to IL-13 in a slightly different way than tralokinumab. The Food and Drug Administration granted it Fast Track status in December 2019. Twin placebo-controlled phase 3 studies of lebrikizumab as monotherapy for moderate to severe AD are ongoing, and another phase 3 trial of the biologic in combination with topical steroids is planned. Based upon the results of a phase 2b study, the highest dose studied – 250 mg every 2 weeks – appears to be at least as effective as dupilumab.
Nonsteroidal topical agents
These three late-stage topical creams – ruxolitinib, delgocitinib, and tapinarof – have previously received considerable coverage in Dermatology News. Ruxolitinib, a selective JAK1/2 inhibitor, has completed a positive phase 3 trial in adolescents and adults with mild to moderate AD. Delgocitinib, a pan-JAK1/2/3 and Tyrosine kinase 2 inhibitor, is already approved in an ointment formulation in Japan, and the cream formulation is in phase 2 studies in the United States and Europe. Tapinarof has a unique mechanism of action – it’s an aryl hydrocarbon receptor modulator – and is now in phase 3 in adolescents and adults with moderate to severe AD.
These three drugs appear to offer efficacy that’s comparable to or even better than medium-potency topical steroids, and without the notorious steroidal side effects that have caused widespread parental steroid-phobia. Potential applications for other inflammatory diseases, including vitiligo and psoriasis, are under study.
Dr. Silverberg reported receiving research grants from Galderma and GlaxoSmithKline and serving as a consultant to those pharmaceutical companies and more than a dozen others.
Major , Jonathan I. Silverberg, MD, PhD, said during a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled due to the COVID-19 pandemic.
“In the next 2-3 years, we may have nine new treatments approved for atopic dermatitis,” said Dr. Silverberg, director of clinical research and contact dermatitis at the University.
All nine medications he discussed are either in ongoing pivotal phase 3 randomized controlled trials or have completed their phase 3 developmental programs. “This is not theoretical; these are things you’re going to be using in your toolbox imminently,” he stressed.
Oral JAK inhibitors
The Janus kinase (JAK) pathway is the intracellular signaling mediator that interacts with extracellular inflammatory cytokines, including interleukin-4, -13, and -31, which are familiar to dermatologists because they’re targeted by potent biologic monoclonal antibody therapies. For example, IL-4 goes through JAK1 and 3, while IL-31 signals through JAK1 and 2.
“You really need to know the key JAK and STAT pathways involved in atopic dermatitis because it will help you determine the selectivity of the agents you’re going to be using,” the dermatologist advised.
Three oral, once-daily JAK inhibitors – abrocitinib, upadacitinib, and baricitinib – are in an advanced stage of development.
“Upadacitinib and abrocitinib may be the two most potent options coming to market soon for us to be thinking about,” Dr. Silverberg said.
Abrocitinib: Three positive phase 3 studies featuring this selective JAK1 inhibitor have been completed in adults with moderate to severe atopic dermatitis (AD). The most recent, JADE COMPARE, featured a head-to-head randomized comparison of abrocitinib and the injectable IL-4/IL-13 inhibitor dupilumab. The results of this 837-patient study haven’t yet been formally presented at a conference because of the COVID-19 pandemic. However, Pfizer recently announced that abrocitinib at 200 mg/day achieved significantly greater improvements than dupilumab (Dupixent) in the coprimary endpoints of skin clearance as reflected in an Investigator’s Global Assessment (IGA) score of 0 or 1 (that is, clear or almost clear) and disease extent based upon 75% reduction from baseline in Eczema Area and Severity Index (EASI 75) at 12 weeks. The same was true at 16 weeks.
Also, a significantly larger proportion of abrocitinib-treated patients achieved at least a 4-point reduction in itch severity as measured using the Peak Pruritus Numerical Rating Scale at week 2. The company plans to file for regulatory approval later this year.
The JADE COMPARE data are exciting because of a pressing unmet need for treatment options that are even more powerful than dupilumab, Dr. Silverberg said.
Upadacitinib: This is selective JAK1 inhibitor is not as far along in the developmental pipeline as abrocitinib, but the efficacy appears to be comparable. In a phase 2 study of 126 adults with moderate to severe AD, upadacitinib at the top dose of 30 mg/day achieved efficacy results Dr. Silverberg deemed “quite extraordinary,” with a rate of IGA score of 0 or 1 of 50% at 16 weeks and an EASI 75 response rate of 69%. Those findings numerically eclipsed results seen in an earlier phase 3 pivotal trial for dupilumab, in which the IGA 0/1 rate was 37% and EASI 75 was 48%, albeit with the caveat that cross-trial comparisons must be taken with a large grain of salt.
Baricitinib: Multiple phase 3 studies of this JAK 1/2 inhibitor have reported positive results. At the top dose of 4 mg/day, baricitinib appears to be less effective than dupilumab in its earlier pivotal trials.
“This may be a good oral option for our patients. It could be similar to the Otezla [apremilast] story in psoriasis: It’s perhaps not as effective as a lot of the biologics, but patients often prefer an oral option,” Dr. Silverberg said.
Of note, in one large, placebo-controlled, phase 3 study of baricitinib on top of background low- or medium-potency topical steroids, the IGA 0/1 rate at 16 weeks with placebo plus topical steroids was a modest 14.7%, which underscores that this long-time workhorse topical therapy is objectively less effective than most physicians think. In contrast, the IGA 0/1 rate with baricitinib at 4 mg/day plus topical steroids was a more respectable 30.6%.
All three oral JAK inhibitors have rapid onset of efficacy, a key advantage over the biologic agents.
“The issue you have to keep in mind is safety. The safety in the atopic dermatitis population was overall quite good for all three drugs. However, safety concerns have come up with JAK inhibitors in rheumatoid arthritis. I think that’s the part we watch the most in this. The efficacy has become clear. Now the question is where does the safety take us,” he said.
Novel injectable biologics
Nemolizumab: This humanized monoclonal antibody inhibits IL-31 receptor alpha. Mounting evidence implicates IL-31 as both a proinflammatory and immunomodulatory cytokine linking the immune and neural systems.
Early on, most researchers pigeonholed IL-31 as being a key player only in the itch factor in AD. Not so. Indeed, Dr. Silverberg was the lead investigator in a recent phase 2b study of nemolizumab that demonstrated the biologic is also effective at rapidly clearing AD lesions. The study, which evaluated three different doses in 226 adults with moderate to severe AD and severe pruritus who were on background topical corticosteroids, showed that nemolizumab at 30 mg every 4 weeks trounced placebo in terms of itch reduction: The 69% drop from baseline in Peak Pruritus Numeric Rating Scale at week 16 was twice that in controls, with a significant difference apparent even at week 1.
But in addition, the 33% IGA 0/1 rate at the same time point bested the 12% rate in controls. The EASI 75 response rate was significantly higher as well – 49% versus 19% – as was the EASI 90 response of 33%, compared with 9% in controls. Moreover, nemolizumab-treated patients used close to 40% less topical steroids during the study (J Allergy Clin Immunol. 2020 Jan;145[1]:173-82).
“This is something that’s fascinating. The study gets into the idea that a subset of atopic dermatitis patients have the itch that rashes, and perhaps if you break the itch/scratch cycle you can modify the lesions. Or the effect may even be due to the direct anti-inflammatory action of IL-31 blockade,” Dr. Silverberg observed.
It appeared that a plateau hadn’t been reached for some endpoints out at week 24, when the study ended. Japanese phase 3 studies have been completed, with what he called “great results,” and others are ongoing in the United States.
Tralokinumab: This fully human monoclonal antibody binds to IL-13, but unlike dupilumab, it doesn’t also inhibit IL-4. Tralokinumab met all primary and secondary endpoints in three pivotal phase 3 clinical trials, known as ECZTRA 1-3, that assessed it as treatment for moderate to severe AD in adults and showed an overall adverse event rate comparable with placebo. Leo Pharma, the Danish company developing the biologic, has announced it will file for marketing approval before the end of 2020. Phase 3 data would have been presented at the annual meeting of the American Academy of Dermatology in Denver, had it not been canceled. Dr. Silverberg said that, based upon phase 2 results, it appears tralokinumab may not be quite as effective as dupilumab in the overall AD population, but he predicted the newcomer will still play a useful role.
“The complexities of the immune system are such that some patients will respond better to one drug than another. I think we still have a lot to learn about who the patients are for these novel assets,” he said.
Lebrikizumab: This is another selective IL-13 inhibitor, but this one binds to IL-13 in a slightly different way than tralokinumab. The Food and Drug Administration granted it Fast Track status in December 2019. Twin placebo-controlled phase 3 studies of lebrikizumab as monotherapy for moderate to severe AD are ongoing, and another phase 3 trial of the biologic in combination with topical steroids is planned. Based upon the results of a phase 2b study, the highest dose studied – 250 mg every 2 weeks – appears to be at least as effective as dupilumab.
Nonsteroidal topical agents
These three late-stage topical creams – ruxolitinib, delgocitinib, and tapinarof – have previously received considerable coverage in Dermatology News. Ruxolitinib, a selective JAK1/2 inhibitor, has completed a positive phase 3 trial in adolescents and adults with mild to moderate AD. Delgocitinib, a pan-JAK1/2/3 and Tyrosine kinase 2 inhibitor, is already approved in an ointment formulation in Japan, and the cream formulation is in phase 2 studies in the United States and Europe. Tapinarof has a unique mechanism of action – it’s an aryl hydrocarbon receptor modulator – and is now in phase 3 in adolescents and adults with moderate to severe AD.
These three drugs appear to offer efficacy that’s comparable to or even better than medium-potency topical steroids, and without the notorious steroidal side effects that have caused widespread parental steroid-phobia. Potential applications for other inflammatory diseases, including vitiligo and psoriasis, are under study.
Dr. Silverberg reported receiving research grants from Galderma and GlaxoSmithKline and serving as a consultant to those pharmaceutical companies and more than a dozen others.
Adding mechanical to pharma prophylaxis does not cut DVT incidence
Background: Critically ill patients have a high risk of venous thromboembolism (VTE) during their hospitalizations, and it is standard of care to prophylax against this complication by either pharmacological or mechanical means.
Study design: Prospective, randomized, controlled trial (Pneumatic Compression for Preventing Venous Thromboembolism [PREVENT]).
Setting: Multicenter study involving 20 ICUs in Saudi Arabia, Canada, Australia, and India.
Synopsis: The study monitored 2,003 medical and surgical ICU patients on pharmacological thromboprophylaxis (unfractionated or low-molecular-weight heparin) after receiving either adjunctive pneumatic compression or pharmacological thromboprophylaxis alone. The primary outcome was incident (newly diagnosed) proximal lower-limb DVT detected by twice-weekly venous ultrasonography until ICU discharge, death, attainment of full mobility, or trial day 28, whichever occurred first. Key secondary outcomes included the occurrence of any lower-limb DVTs and pulmonary embolism. Intermittent pneumatic compression was used a median of 22 hours daily. The incidence of proximal lower limb DVT did not differ in the two groups and was relatively low (4%) in the control group. There were also no differences in the groups in the composite VTE, death at 28 days, or any other secondary outcomes studied.
The main limitation of the study was the low incidence of primary outcomes in the control group, which reduced the power of the study.
Bottom line: Based on the PREVENT trial, adjunctive intermittent pneumatic compression provided no additional benefit to pharmacological prophylaxis in the prevention of incident proximal lower-limb DVT.
Citation: Arabi Y et al. Adjunctive intermittent pneumatic compression for venous thromboprophylaxis. N Eng J Med. 2019 Feb 18. doi: 10.1056/NEJMoa1816150.
Dr. Sekaran is a hospitalist at Massachusetts General Hospital.
Background: Critically ill patients have a high risk of venous thromboembolism (VTE) during their hospitalizations, and it is standard of care to prophylax against this complication by either pharmacological or mechanical means.
Study design: Prospective, randomized, controlled trial (Pneumatic Compression for Preventing Venous Thromboembolism [PREVENT]).
Setting: Multicenter study involving 20 ICUs in Saudi Arabia, Canada, Australia, and India.
Synopsis: The study monitored 2,003 medical and surgical ICU patients on pharmacological thromboprophylaxis (unfractionated or low-molecular-weight heparin) after receiving either adjunctive pneumatic compression or pharmacological thromboprophylaxis alone. The primary outcome was incident (newly diagnosed) proximal lower-limb DVT detected by twice-weekly venous ultrasonography until ICU discharge, death, attainment of full mobility, or trial day 28, whichever occurred first. Key secondary outcomes included the occurrence of any lower-limb DVTs and pulmonary embolism. Intermittent pneumatic compression was used a median of 22 hours daily. The incidence of proximal lower limb DVT did not differ in the two groups and was relatively low (4%) in the control group. There were also no differences in the groups in the composite VTE, death at 28 days, or any other secondary outcomes studied.
The main limitation of the study was the low incidence of primary outcomes in the control group, which reduced the power of the study.
Bottom line: Based on the PREVENT trial, adjunctive intermittent pneumatic compression provided no additional benefit to pharmacological prophylaxis in the prevention of incident proximal lower-limb DVT.
Citation: Arabi Y et al. Adjunctive intermittent pneumatic compression for venous thromboprophylaxis. N Eng J Med. 2019 Feb 18. doi: 10.1056/NEJMoa1816150.
Dr. Sekaran is a hospitalist at Massachusetts General Hospital.
Background: Critically ill patients have a high risk of venous thromboembolism (VTE) during their hospitalizations, and it is standard of care to prophylax against this complication by either pharmacological or mechanical means.
Study design: Prospective, randomized, controlled trial (Pneumatic Compression for Preventing Venous Thromboembolism [PREVENT]).
Setting: Multicenter study involving 20 ICUs in Saudi Arabia, Canada, Australia, and India.
Synopsis: The study monitored 2,003 medical and surgical ICU patients on pharmacological thromboprophylaxis (unfractionated or low-molecular-weight heparin) after receiving either adjunctive pneumatic compression or pharmacological thromboprophylaxis alone. The primary outcome was incident (newly diagnosed) proximal lower-limb DVT detected by twice-weekly venous ultrasonography until ICU discharge, death, attainment of full mobility, or trial day 28, whichever occurred first. Key secondary outcomes included the occurrence of any lower-limb DVTs and pulmonary embolism. Intermittent pneumatic compression was used a median of 22 hours daily. The incidence of proximal lower limb DVT did not differ in the two groups and was relatively low (4%) in the control group. There were also no differences in the groups in the composite VTE, death at 28 days, or any other secondary outcomes studied.
The main limitation of the study was the low incidence of primary outcomes in the control group, which reduced the power of the study.
Bottom line: Based on the PREVENT trial, adjunctive intermittent pneumatic compression provided no additional benefit to pharmacological prophylaxis in the prevention of incident proximal lower-limb DVT.
Citation: Arabi Y et al. Adjunctive intermittent pneumatic compression for venous thromboprophylaxis. N Eng J Med. 2019 Feb 18. doi: 10.1056/NEJMoa1816150.
Dr. Sekaran is a hospitalist at Massachusetts General Hospital.
FOURIER: Evolocumab follow-up shows no cognitive adverse effects
Treatment with a PCSK9 inhibitor, as well as achieving dramatically lowered cholesterol levels, did not mess with patients’ minds. Results from a cognition self-assessment completed by more than 22,000 patients when they finished participation in the FOURIER pivotal outcomes trial for evolocumab showed no signal of mental harm from either treatment with this PCSK9 inhibitor or from reaching a serum level of low-density lipoprotein cholesterol (LDL-C) of less than 20 mg/dL.
“We observed that patients treated with evolocumab, as well as those who achieved progressively very low LDL-C at 4 weeks in the FOURIER trial, had similar self-reported cognition in comparison with those receiving placebo and those with higher achieved LDL-C levels,” wrote a team of researchers from the trial in an article published online on May 4 (J Am Coll Cardiol. 2020 May 12;75[18]: 2283-93). “These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while reducing recurrent CV [cardiovascular] events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients.”
The findings added to prior results documenting the cognitive safety of evolocumab (Repatha) from a much smaller FOURIER substudy that involved more intensive testing, the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study with 1,204 patients drawn from the broader study and tested after a median 19 months on treatment (N Engl J Med. 2017 Aug 17;377[17]: 633-43), as well as reports of neurocognitive safety for the other U.S. approved PCSK9 (proprotein convertase subtilisin kexin 9) inhibitor, alirocumab (Praluent) (N Engl J Med. 2015 Apr 16;372[16]:1489-99), various statins (J Gen Intern Med. 2015 Mar;30[3]: 348-58), and a third type of LDL-C–lowering agent, ezetimibe (JAMA Cardiol. 2017 May;2[5]:547-55).
Despite this evidence from across several drug classes that all cut LDL-C a long-standing but unsubstantiated belief persists among some that lipid lowering, especially by statins, blunts mental function, misinformation that’s easy to find on the Internet. “I estimate that about 20% of patients prescribed a statin won’t take it because of something they’ve heard” including that statins make you stupid. “It’s hard to undo that,” said Robert P. Giugliano, MD, a cardiologist at Brigham and Women’s Hospital in Boston and senior author for the new FOURIER study as well as for EBBINGHAUS. The same stigma has not gained nearly as much traction for PCSK9 inhibitors, however, and Dr. Giugliano said he has also recently sensed what may be a downtrend in statin apprehension.
“The information added by this study is very important,” commented Massimo R. Mannarino, MD, an atherosclerotic disease researcher at the University of Perugia (Italy). “The prejudice and misinformation regarding possible side effects of statins among patients and also some physicians unfortunately remains very strong today,” he said in an interview. “My impression is that PCSK9 inhibitors are less affected by this negative bias and are seen as a safer alternative to statins.” Concerns about PCSK9 inhibitors have especially focused on “the possible risks from very low cholesterol levels on the brain.” The evidence from both studies and clinical experience “allows for a very positive opinion about the efficacy and safety of PCSK9 inhibitors, although the long-term effects still require a few more years of observation,” said Dr. Mannarino, who led a review of the evidence that clears this class from links to neurocognitive loss (J Clin Lipid. 2018 Sep 1;12[5]:1123-32).
FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27,564 patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol despite maximally tolerated standard treatment. Treatment with evolocumab for a median of 2.2 years resulted in a statistically significant 15% reduction in the study’s primary efficacy endpoint, compared with placebo (N Engl J Med. 2017 May 4;376[18]:1713-22), and led to the drug receiving an indication for lowering rates of MI, stroke, and symptom-driven coronary revascularization.
The prespecified substudy reported by Dr. Giugliano and his associates focused on a 23-question, validated, self-assessment survey of cognitive function completed by 22,655 of the FOURIER patients (82%). The more than 4,900 other patients in the study who did not complete the survey had modestly higher prevalence rates of various comorbidities at baseline, and also higher rates of adverse outcomes during follow-up, and in many cases these adverse outcome may have contributed to these patients not being able to complete their end-of-study cognitive assessment. For example, almost a quarter of the patients who did not complete their end-of-study cognitive assessment failed to do so because they had already died.
Overall, the prevalence of patients indicating a cognitive decline was virtually identical among 11,363 patients who had been maintained on evolocumab, with a 3.7% rate, and the 11,292 patients in the placebo group, with a 3.6% rate. When analyzed by achieved level of LDL-C after 4 weeks on treatment, the 2,338 patients with a level below 20 mg/dL had a 3.8% rate of self-reported cognitive loss, compared with a 4.5% rate among 3,613 patients who had an LDL-C level of at least 100 mg/dL when measured 4 weeks into the study.
One of the strengths of the new cognitive analysis is that, although it did not use the more sophisticated assessment tests employed on fewer patients in the EBBINGHAUS substudy, it used the Everyday Cognition scale (Neuropsychiatry. 2008 Jul;22[4]: 531-44). “We asked patients what they have experienced, and in the end that is what’s important, so this adds to the neurocognitive testing,” run in EBBINGHAUS, Dr. Giugliano said in an interview.
“The neurocognitive results in the present study were self-reported, and that might be a limitation, as it is less specific and objective, but it is also a strength, as it could be more sensitive” especially for a “nocebo effect common to all lipid-lowering drugs linked to the bad reputation historically attributed to statins,” Dr. Mannarino said.
Should the new FOURIER data “be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 monoclonal antibodies has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats,” Jennifer G. Robinson, MD, a professor of epidemiology at the University of Iowa College of Public Health in Iowa City, said in an editorial that accompanied the new report (J Am Coll Cardiol. 2020 May 12;75[18]:2294-6). Her three caveats are the missing 18% of patients who never took the end-of-study assessment, the relative paucity of patients at very advanced age in FOURIER, in which patients averaged 62.5 years old, and the exclusion from FOURIER of patients with a history of hemorrhagic stroke. Dr. Robinson also cited the 2.2 year median follow-up as leaving unsettled the potential cognitive impact of longer treatment.
In response, Dr. Giugliano noted that the very large size of FOURIER and the 22,655 patients who completed their survey provided substantial numbers of patients to address some of these concerns in robust subgroup analyses. For example, the new report showed no signal of excess cognitive complaints with evolocumab treatment among 1,999 patients who were at least 75 years old when entering the study, or in more than 5,000 patients with a history of cerebrovascular disease at baseline, or in 1,990 patients with a history of a nonstroke neurologic disease. In addition, while he conceded that the 18% of patients not accounted for in the new study placed some limits on generalizability of the findings, he also maintained that this unavoidable failure to collect data from a modest percentage of patients doesn’t scuttle the overarching signal of cognitive safety for most patients. And regarding the duration of treatment monitored, he noted that 5-year follow-up cognitive assessments are planned.
FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has received personal fees and research support from Amgen and from several other companies. Dr. Mannarino had no disclosures. Dr. Robinson has been a consultant to The Medicines Company, Novartis, and Pfizer, and she has received research funding to her institution from Amgen and several other companies.
SOURCE: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Correction: Dr. Giugliano's name was misspelled in an earlier version of this article.
Treatment with a PCSK9 inhibitor, as well as achieving dramatically lowered cholesterol levels, did not mess with patients’ minds. Results from a cognition self-assessment completed by more than 22,000 patients when they finished participation in the FOURIER pivotal outcomes trial for evolocumab showed no signal of mental harm from either treatment with this PCSK9 inhibitor or from reaching a serum level of low-density lipoprotein cholesterol (LDL-C) of less than 20 mg/dL.
“We observed that patients treated with evolocumab, as well as those who achieved progressively very low LDL-C at 4 weeks in the FOURIER trial, had similar self-reported cognition in comparison with those receiving placebo and those with higher achieved LDL-C levels,” wrote a team of researchers from the trial in an article published online on May 4 (J Am Coll Cardiol. 2020 May 12;75[18]: 2283-93). “These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while reducing recurrent CV [cardiovascular] events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients.”
The findings added to prior results documenting the cognitive safety of evolocumab (Repatha) from a much smaller FOURIER substudy that involved more intensive testing, the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study with 1,204 patients drawn from the broader study and tested after a median 19 months on treatment (N Engl J Med. 2017 Aug 17;377[17]: 633-43), as well as reports of neurocognitive safety for the other U.S. approved PCSK9 (proprotein convertase subtilisin kexin 9) inhibitor, alirocumab (Praluent) (N Engl J Med. 2015 Apr 16;372[16]:1489-99), various statins (J Gen Intern Med. 2015 Mar;30[3]: 348-58), and a third type of LDL-C–lowering agent, ezetimibe (JAMA Cardiol. 2017 May;2[5]:547-55).
Despite this evidence from across several drug classes that all cut LDL-C a long-standing but unsubstantiated belief persists among some that lipid lowering, especially by statins, blunts mental function, misinformation that’s easy to find on the Internet. “I estimate that about 20% of patients prescribed a statin won’t take it because of something they’ve heard” including that statins make you stupid. “It’s hard to undo that,” said Robert P. Giugliano, MD, a cardiologist at Brigham and Women’s Hospital in Boston and senior author for the new FOURIER study as well as for EBBINGHAUS. The same stigma has not gained nearly as much traction for PCSK9 inhibitors, however, and Dr. Giugliano said he has also recently sensed what may be a downtrend in statin apprehension.
“The information added by this study is very important,” commented Massimo R. Mannarino, MD, an atherosclerotic disease researcher at the University of Perugia (Italy). “The prejudice and misinformation regarding possible side effects of statins among patients and also some physicians unfortunately remains very strong today,” he said in an interview. “My impression is that PCSK9 inhibitors are less affected by this negative bias and are seen as a safer alternative to statins.” Concerns about PCSK9 inhibitors have especially focused on “the possible risks from very low cholesterol levels on the brain.” The evidence from both studies and clinical experience “allows for a very positive opinion about the efficacy and safety of PCSK9 inhibitors, although the long-term effects still require a few more years of observation,” said Dr. Mannarino, who led a review of the evidence that clears this class from links to neurocognitive loss (J Clin Lipid. 2018 Sep 1;12[5]:1123-32).
FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27,564 patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol despite maximally tolerated standard treatment. Treatment with evolocumab for a median of 2.2 years resulted in a statistically significant 15% reduction in the study’s primary efficacy endpoint, compared with placebo (N Engl J Med. 2017 May 4;376[18]:1713-22), and led to the drug receiving an indication for lowering rates of MI, stroke, and symptom-driven coronary revascularization.
The prespecified substudy reported by Dr. Giugliano and his associates focused on a 23-question, validated, self-assessment survey of cognitive function completed by 22,655 of the FOURIER patients (82%). The more than 4,900 other patients in the study who did not complete the survey had modestly higher prevalence rates of various comorbidities at baseline, and also higher rates of adverse outcomes during follow-up, and in many cases these adverse outcome may have contributed to these patients not being able to complete their end-of-study cognitive assessment. For example, almost a quarter of the patients who did not complete their end-of-study cognitive assessment failed to do so because they had already died.
Overall, the prevalence of patients indicating a cognitive decline was virtually identical among 11,363 patients who had been maintained on evolocumab, with a 3.7% rate, and the 11,292 patients in the placebo group, with a 3.6% rate. When analyzed by achieved level of LDL-C after 4 weeks on treatment, the 2,338 patients with a level below 20 mg/dL had a 3.8% rate of self-reported cognitive loss, compared with a 4.5% rate among 3,613 patients who had an LDL-C level of at least 100 mg/dL when measured 4 weeks into the study.
One of the strengths of the new cognitive analysis is that, although it did not use the more sophisticated assessment tests employed on fewer patients in the EBBINGHAUS substudy, it used the Everyday Cognition scale (Neuropsychiatry. 2008 Jul;22[4]: 531-44). “We asked patients what they have experienced, and in the end that is what’s important, so this adds to the neurocognitive testing,” run in EBBINGHAUS, Dr. Giugliano said in an interview.
“The neurocognitive results in the present study were self-reported, and that might be a limitation, as it is less specific and objective, but it is also a strength, as it could be more sensitive” especially for a “nocebo effect common to all lipid-lowering drugs linked to the bad reputation historically attributed to statins,” Dr. Mannarino said.
Should the new FOURIER data “be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 monoclonal antibodies has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats,” Jennifer G. Robinson, MD, a professor of epidemiology at the University of Iowa College of Public Health in Iowa City, said in an editorial that accompanied the new report (J Am Coll Cardiol. 2020 May 12;75[18]:2294-6). Her three caveats are the missing 18% of patients who never took the end-of-study assessment, the relative paucity of patients at very advanced age in FOURIER, in which patients averaged 62.5 years old, and the exclusion from FOURIER of patients with a history of hemorrhagic stroke. Dr. Robinson also cited the 2.2 year median follow-up as leaving unsettled the potential cognitive impact of longer treatment.
In response, Dr. Giugliano noted that the very large size of FOURIER and the 22,655 patients who completed their survey provided substantial numbers of patients to address some of these concerns in robust subgroup analyses. For example, the new report showed no signal of excess cognitive complaints with evolocumab treatment among 1,999 patients who were at least 75 years old when entering the study, or in more than 5,000 patients with a history of cerebrovascular disease at baseline, or in 1,990 patients with a history of a nonstroke neurologic disease. In addition, while he conceded that the 18% of patients not accounted for in the new study placed some limits on generalizability of the findings, he also maintained that this unavoidable failure to collect data from a modest percentage of patients doesn’t scuttle the overarching signal of cognitive safety for most patients. And regarding the duration of treatment monitored, he noted that 5-year follow-up cognitive assessments are planned.
FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has received personal fees and research support from Amgen and from several other companies. Dr. Mannarino had no disclosures. Dr. Robinson has been a consultant to The Medicines Company, Novartis, and Pfizer, and she has received research funding to her institution from Amgen and several other companies.
SOURCE: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Correction: Dr. Giugliano's name was misspelled in an earlier version of this article.
Treatment with a PCSK9 inhibitor, as well as achieving dramatically lowered cholesterol levels, did not mess with patients’ minds. Results from a cognition self-assessment completed by more than 22,000 patients when they finished participation in the FOURIER pivotal outcomes trial for evolocumab showed no signal of mental harm from either treatment with this PCSK9 inhibitor or from reaching a serum level of low-density lipoprotein cholesterol (LDL-C) of less than 20 mg/dL.
“We observed that patients treated with evolocumab, as well as those who achieved progressively very low LDL-C at 4 weeks in the FOURIER trial, had similar self-reported cognition in comparison with those receiving placebo and those with higher achieved LDL-C levels,” wrote a team of researchers from the trial in an article published online on May 4 (J Am Coll Cardiol. 2020 May 12;75[18]: 2283-93). “These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while reducing recurrent CV [cardiovascular] events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients.”
The findings added to prior results documenting the cognitive safety of evolocumab (Repatha) from a much smaller FOURIER substudy that involved more intensive testing, the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study with 1,204 patients drawn from the broader study and tested after a median 19 months on treatment (N Engl J Med. 2017 Aug 17;377[17]: 633-43), as well as reports of neurocognitive safety for the other U.S. approved PCSK9 (proprotein convertase subtilisin kexin 9) inhibitor, alirocumab (Praluent) (N Engl J Med. 2015 Apr 16;372[16]:1489-99), various statins (J Gen Intern Med. 2015 Mar;30[3]: 348-58), and a third type of LDL-C–lowering agent, ezetimibe (JAMA Cardiol. 2017 May;2[5]:547-55).
Despite this evidence from across several drug classes that all cut LDL-C a long-standing but unsubstantiated belief persists among some that lipid lowering, especially by statins, blunts mental function, misinformation that’s easy to find on the Internet. “I estimate that about 20% of patients prescribed a statin won’t take it because of something they’ve heard” including that statins make you stupid. “It’s hard to undo that,” said Robert P. Giugliano, MD, a cardiologist at Brigham and Women’s Hospital in Boston and senior author for the new FOURIER study as well as for EBBINGHAUS. The same stigma has not gained nearly as much traction for PCSK9 inhibitors, however, and Dr. Giugliano said he has also recently sensed what may be a downtrend in statin apprehension.
“The information added by this study is very important,” commented Massimo R. Mannarino, MD, an atherosclerotic disease researcher at the University of Perugia (Italy). “The prejudice and misinformation regarding possible side effects of statins among patients and also some physicians unfortunately remains very strong today,” he said in an interview. “My impression is that PCSK9 inhibitors are less affected by this negative bias and are seen as a safer alternative to statins.” Concerns about PCSK9 inhibitors have especially focused on “the possible risks from very low cholesterol levels on the brain.” The evidence from both studies and clinical experience “allows for a very positive opinion about the efficacy and safety of PCSK9 inhibitors, although the long-term effects still require a few more years of observation,” said Dr. Mannarino, who led a review of the evidence that clears this class from links to neurocognitive loss (J Clin Lipid. 2018 Sep 1;12[5]:1123-32).
FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27,564 patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol despite maximally tolerated standard treatment. Treatment with evolocumab for a median of 2.2 years resulted in a statistically significant 15% reduction in the study’s primary efficacy endpoint, compared with placebo (N Engl J Med. 2017 May 4;376[18]:1713-22), and led to the drug receiving an indication for lowering rates of MI, stroke, and symptom-driven coronary revascularization.
The prespecified substudy reported by Dr. Giugliano and his associates focused on a 23-question, validated, self-assessment survey of cognitive function completed by 22,655 of the FOURIER patients (82%). The more than 4,900 other patients in the study who did not complete the survey had modestly higher prevalence rates of various comorbidities at baseline, and also higher rates of adverse outcomes during follow-up, and in many cases these adverse outcome may have contributed to these patients not being able to complete their end-of-study cognitive assessment. For example, almost a quarter of the patients who did not complete their end-of-study cognitive assessment failed to do so because they had already died.
Overall, the prevalence of patients indicating a cognitive decline was virtually identical among 11,363 patients who had been maintained on evolocumab, with a 3.7% rate, and the 11,292 patients in the placebo group, with a 3.6% rate. When analyzed by achieved level of LDL-C after 4 weeks on treatment, the 2,338 patients with a level below 20 mg/dL had a 3.8% rate of self-reported cognitive loss, compared with a 4.5% rate among 3,613 patients who had an LDL-C level of at least 100 mg/dL when measured 4 weeks into the study.
One of the strengths of the new cognitive analysis is that, although it did not use the more sophisticated assessment tests employed on fewer patients in the EBBINGHAUS substudy, it used the Everyday Cognition scale (Neuropsychiatry. 2008 Jul;22[4]: 531-44). “We asked patients what they have experienced, and in the end that is what’s important, so this adds to the neurocognitive testing,” run in EBBINGHAUS, Dr. Giugliano said in an interview.
“The neurocognitive results in the present study were self-reported, and that might be a limitation, as it is less specific and objective, but it is also a strength, as it could be more sensitive” especially for a “nocebo effect common to all lipid-lowering drugs linked to the bad reputation historically attributed to statins,” Dr. Mannarino said.
Should the new FOURIER data “be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 monoclonal antibodies has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats,” Jennifer G. Robinson, MD, a professor of epidemiology at the University of Iowa College of Public Health in Iowa City, said in an editorial that accompanied the new report (J Am Coll Cardiol. 2020 May 12;75[18]:2294-6). Her three caveats are the missing 18% of patients who never took the end-of-study assessment, the relative paucity of patients at very advanced age in FOURIER, in which patients averaged 62.5 years old, and the exclusion from FOURIER of patients with a history of hemorrhagic stroke. Dr. Robinson also cited the 2.2 year median follow-up as leaving unsettled the potential cognitive impact of longer treatment.
In response, Dr. Giugliano noted that the very large size of FOURIER and the 22,655 patients who completed their survey provided substantial numbers of patients to address some of these concerns in robust subgroup analyses. For example, the new report showed no signal of excess cognitive complaints with evolocumab treatment among 1,999 patients who were at least 75 years old when entering the study, or in more than 5,000 patients with a history of cerebrovascular disease at baseline, or in 1,990 patients with a history of a nonstroke neurologic disease. In addition, while he conceded that the 18% of patients not accounted for in the new study placed some limits on generalizability of the findings, he also maintained that this unavoidable failure to collect data from a modest percentage of patients doesn’t scuttle the overarching signal of cognitive safety for most patients. And regarding the duration of treatment monitored, he noted that 5-year follow-up cognitive assessments are planned.
FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has received personal fees and research support from Amgen and from several other companies. Dr. Mannarino had no disclosures. Dr. Robinson has been a consultant to The Medicines Company, Novartis, and Pfizer, and she has received research funding to her institution from Amgen and several other companies.
SOURCE: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Correction: Dr. Giugliano's name was misspelled in an earlier version of this article.
FROM JACC
Key clinical point: A cognition survey of a large number of trial participants showed no signal of adverse effects from evolocumab treatment.
Major finding: Survey results showed cognitive compromise in 3.7% of patients on evolocumab and in 3.6% control patients on placebo.
Study details:
Disclosures: FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Guigliano has received personal fees and research support from Amgen and from several other companies.
Source: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Hydroxychloroquine-triggered QTc-interval prolongations mount in COVID-19 patients
The potential for serious arrhythmias from hydroxychloroquine treatment of COVID-19 patients received further documentation from a pair of studies released on May 1, casting further doubt on whether the uncertain benefit from this or related drugs to infected patients is worth the clear risks the agents pose.
A report from 90 confirmed COVID-19 patients treated with hydroxychloroquine at one Boston hospital during March-April 2020 identified a significantly prolonged, corrected QT (QTc) interval of at least 500 msec in 18 patients (20%), which included 10 patients whose QTc rose by at least 60 msec above baseline, and a total of 21 patients (23%) having a notable prolongation (JAMA Cardiol. 2020 May 4. doi: 10.1001/jamacardio.2020.1834). This series included one patient who developed torsades de pointes following treatment with hydroxychloroquine and azithromycin, “which to our knowledge has yet to be reported elsewhere in the literature,” the report said.
The second report, from a single center in Lyon, France, included 40 confirmed COVID-19 patients treated with hydroxychloroquine during 2 weeks in late March, and found that 37 (93%) had some increase in the QTc interval, including 14 patients (36%) with an increase of at least 60 msec, and 7 patients (18%) whose QTc rose to at least 500 msec (JAMA Cardiol. 2020 May. doi: 10.1001/jamacardio.2020.1787). However, none of the 40 patients in this series developed an identified ventricular arrhythmia. All patients in both studies received hydroxychloroquine for at least 1 day, and roughly half the patients in each series also received concurrent azithromycin, another drug that can prolong the QTc interval and that has been frequently used in combination with hydroxychloroquine as an unproven COVID-19 treatment cocktail.
These two reports, as well as prior report from Brazil on COVID-19 patients treated with chloroquine diphosphate (JAMA Netw Open. 2020;3[4]:e208857), “underscore the potential risk associated with widespread use of hydroxychloroquine and the combination of hydroxychloroquine and azithromycin in ambulatory patients with known or suspected COVID-19. Understanding whether this risk is worth taking in the absence of evidence of therapeutic efficacy creates a knowledge gap that needs to be addressed,” wrote Robert O. Bonow, MD, a professor of medicine at Northwestern University in Chicago, and coauthors in an editorial that accompanied the two reports (JAMA Cardiol. 2020 May 4;doi: 10.1001/jamacardio.2020.1782). The editorial cited two recently-begun prospective trials, ORCHID and RECOVERY, that are more systematically assessing the safety and efficacy of hydroxychloroquine treatment in COVID-19 patients.
The findings lend further support to a Safety Communication from the U.S. Food and Drug Administration on April 24 that reminded clinicians that the Emergency Use Authorization for hydroxychloroquine and chloroquine in COVID-19 patients that the FDA issued on March 28 applied to only certain hospitalized patients or those enrolled in clinical trials. The Safety Communication also said that agency was aware of reports of adverse arrhythmia events when COVID-19 patients received these drugs outside a hospital setting as well as uninfected people who had received one of these drugs for preventing infection.
In addition, leaders of the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society on April 10 issued a summary of considerations when using hydroxychloroquine and azithromycin to treat COVID-19 patients, and noted that a way to minimized the risk from these drugs is to withhold them from patients with a QTc interval of 500 msec or greater at baseline (J Am Coll Cardiol. 2020 Apr 10. doi: 10.1016/j.jacc.2020.04.016). The summary also highlighted the need for regular ECG monitoring of COVID-19 patients who receive drugs that can prolong the QTc interval, and recommended withdrawing treatment from patients when their QTc exceeds the 500 msec threshold.
None of the authors of the two reports and editorial had relevant commercial disclosures.
The potential for serious arrhythmias from hydroxychloroquine treatment of COVID-19 patients received further documentation from a pair of studies released on May 1, casting further doubt on whether the uncertain benefit from this or related drugs to infected patients is worth the clear risks the agents pose.
A report from 90 confirmed COVID-19 patients treated with hydroxychloroquine at one Boston hospital during March-April 2020 identified a significantly prolonged, corrected QT (QTc) interval of at least 500 msec in 18 patients (20%), which included 10 patients whose QTc rose by at least 60 msec above baseline, and a total of 21 patients (23%) having a notable prolongation (JAMA Cardiol. 2020 May 4. doi: 10.1001/jamacardio.2020.1834). This series included one patient who developed torsades de pointes following treatment with hydroxychloroquine and azithromycin, “which to our knowledge has yet to be reported elsewhere in the literature,” the report said.
The second report, from a single center in Lyon, France, included 40 confirmed COVID-19 patients treated with hydroxychloroquine during 2 weeks in late March, and found that 37 (93%) had some increase in the QTc interval, including 14 patients (36%) with an increase of at least 60 msec, and 7 patients (18%) whose QTc rose to at least 500 msec (JAMA Cardiol. 2020 May. doi: 10.1001/jamacardio.2020.1787). However, none of the 40 patients in this series developed an identified ventricular arrhythmia. All patients in both studies received hydroxychloroquine for at least 1 day, and roughly half the patients in each series also received concurrent azithromycin, another drug that can prolong the QTc interval and that has been frequently used in combination with hydroxychloroquine as an unproven COVID-19 treatment cocktail.
These two reports, as well as prior report from Brazil on COVID-19 patients treated with chloroquine diphosphate (JAMA Netw Open. 2020;3[4]:e208857), “underscore the potential risk associated with widespread use of hydroxychloroquine and the combination of hydroxychloroquine and azithromycin in ambulatory patients with known or suspected COVID-19. Understanding whether this risk is worth taking in the absence of evidence of therapeutic efficacy creates a knowledge gap that needs to be addressed,” wrote Robert O. Bonow, MD, a professor of medicine at Northwestern University in Chicago, and coauthors in an editorial that accompanied the two reports (JAMA Cardiol. 2020 May 4;doi: 10.1001/jamacardio.2020.1782). The editorial cited two recently-begun prospective trials, ORCHID and RECOVERY, that are more systematically assessing the safety and efficacy of hydroxychloroquine treatment in COVID-19 patients.
The findings lend further support to a Safety Communication from the U.S. Food and Drug Administration on April 24 that reminded clinicians that the Emergency Use Authorization for hydroxychloroquine and chloroquine in COVID-19 patients that the FDA issued on March 28 applied to only certain hospitalized patients or those enrolled in clinical trials. The Safety Communication also said that agency was aware of reports of adverse arrhythmia events when COVID-19 patients received these drugs outside a hospital setting as well as uninfected people who had received one of these drugs for preventing infection.
In addition, leaders of the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society on April 10 issued a summary of considerations when using hydroxychloroquine and azithromycin to treat COVID-19 patients, and noted that a way to minimized the risk from these drugs is to withhold them from patients with a QTc interval of 500 msec or greater at baseline (J Am Coll Cardiol. 2020 Apr 10. doi: 10.1016/j.jacc.2020.04.016). The summary also highlighted the need for regular ECG monitoring of COVID-19 patients who receive drugs that can prolong the QTc interval, and recommended withdrawing treatment from patients when their QTc exceeds the 500 msec threshold.
None of the authors of the two reports and editorial had relevant commercial disclosures.
The potential for serious arrhythmias from hydroxychloroquine treatment of COVID-19 patients received further documentation from a pair of studies released on May 1, casting further doubt on whether the uncertain benefit from this or related drugs to infected patients is worth the clear risks the agents pose.
A report from 90 confirmed COVID-19 patients treated with hydroxychloroquine at one Boston hospital during March-April 2020 identified a significantly prolonged, corrected QT (QTc) interval of at least 500 msec in 18 patients (20%), which included 10 patients whose QTc rose by at least 60 msec above baseline, and a total of 21 patients (23%) having a notable prolongation (JAMA Cardiol. 2020 May 4. doi: 10.1001/jamacardio.2020.1834). This series included one patient who developed torsades de pointes following treatment with hydroxychloroquine and azithromycin, “which to our knowledge has yet to be reported elsewhere in the literature,” the report said.
The second report, from a single center in Lyon, France, included 40 confirmed COVID-19 patients treated with hydroxychloroquine during 2 weeks in late March, and found that 37 (93%) had some increase in the QTc interval, including 14 patients (36%) with an increase of at least 60 msec, and 7 patients (18%) whose QTc rose to at least 500 msec (JAMA Cardiol. 2020 May. doi: 10.1001/jamacardio.2020.1787). However, none of the 40 patients in this series developed an identified ventricular arrhythmia. All patients in both studies received hydroxychloroquine for at least 1 day, and roughly half the patients in each series also received concurrent azithromycin, another drug that can prolong the QTc interval and that has been frequently used in combination with hydroxychloroquine as an unproven COVID-19 treatment cocktail.
These two reports, as well as prior report from Brazil on COVID-19 patients treated with chloroquine diphosphate (JAMA Netw Open. 2020;3[4]:e208857), “underscore the potential risk associated with widespread use of hydroxychloroquine and the combination of hydroxychloroquine and azithromycin in ambulatory patients with known or suspected COVID-19. Understanding whether this risk is worth taking in the absence of evidence of therapeutic efficacy creates a knowledge gap that needs to be addressed,” wrote Robert O. Bonow, MD, a professor of medicine at Northwestern University in Chicago, and coauthors in an editorial that accompanied the two reports (JAMA Cardiol. 2020 May 4;doi: 10.1001/jamacardio.2020.1782). The editorial cited two recently-begun prospective trials, ORCHID and RECOVERY, that are more systematically assessing the safety and efficacy of hydroxychloroquine treatment in COVID-19 patients.
The findings lend further support to a Safety Communication from the U.S. Food and Drug Administration on April 24 that reminded clinicians that the Emergency Use Authorization for hydroxychloroquine and chloroquine in COVID-19 patients that the FDA issued on March 28 applied to only certain hospitalized patients or those enrolled in clinical trials. The Safety Communication also said that agency was aware of reports of adverse arrhythmia events when COVID-19 patients received these drugs outside a hospital setting as well as uninfected people who had received one of these drugs for preventing infection.
In addition, leaders of the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society on April 10 issued a summary of considerations when using hydroxychloroquine and azithromycin to treat COVID-19 patients, and noted that a way to minimized the risk from these drugs is to withhold them from patients with a QTc interval of 500 msec or greater at baseline (J Am Coll Cardiol. 2020 Apr 10. doi: 10.1016/j.jacc.2020.04.016). The summary also highlighted the need for regular ECG monitoring of COVID-19 patients who receive drugs that can prolong the QTc interval, and recommended withdrawing treatment from patients when their QTc exceeds the 500 msec threshold.
None of the authors of the two reports and editorial had relevant commercial disclosures.
FROM JAMA CARDIOLOGY
COVID-19: Social distancing with young children
Emma just celebrated her second birthday, and she has been working on the usual things that children start to master at this age: potty training, making friends, exerting her will through both actions and words, and generally enjoying life as the center of attention for both her parents and grandparents. Like everyone else in Maryland, Emma’s life changed suddenly with the coronavirus stay-at-home order that was issued on March 30. There is no more day care and her parents work from home while caring for her. Her grandparents visit, but only outside and only from a distance – there are no more hugs and there is no more sitting in her grandfather’s lap while he reads stories.
One afternoon a few weeks ago, Emma was looking out the window when she saw her friend, Max, walk by with his parents. Before her parents could stop her, Emma bolted out the door, and she and little Max wrapped each other in a tight embrace. Their parents snapped a photo of the smiling toddlers hugging before they separated the children. The photo is adorable, but as all struggle with social distancing, the poignance of two innocent toddlers in a forbidden embrace is a bit heartbreaking.
Everyone who has ever observed children knows that social distancing is not in their nature. Children play, they hug, they wrestle and tackle and poke, and sometimes even bite. And every student of social psychology has been taught about Harry Harlow’s experiments with rhesus macaques who were separated from their mothers and given access to an inanimate object to serve as a surrogate mother. The Harlow studies, while controversial, were revolutionary in demonstrating that early interactions with both a mother and with playmates were essential in the development of normal social relationships.
Regine Galanti, PhD, is a clinical psychologist at Long Island Behavioral Psychology, Cedarhurst, N.Y., who specializes in the treatment of anxiety and behavior problems. With young children she uses parent-child interaction therapy (PCIT) to help build relationships and discipline. Dr. Galanti said: “I don’t think we’re well prepared as a field to answer questions about the long-term effects of social distancing. If you need young children to socially distance, the responsibility has to fall on the adults. It’s important to explain to children what’s going on and to be honest in a developmentally appropriate way.”
Dr. Galanti has noticed that the issues that people had before COVID-19 are exacerbated by the stress of the current situation. What we do know is that young children thrive on structure.”
Tovah P. Klein, PhD, is the author of “How Toddlers Thrive” (Touchstone, 2015) and is the director of the Barnard College Center for Toddler Development in Manhattan. “When this started, we thought we would be closed for a few weeks,” Dr. Klein said. “We wanted to maintain a connection to the children, so we made videos for the parents to show to the kids, just to say ‘We’re still here.’ But as time went on and we realized it was going to be a while, we felt it was important to provide connection, so we launched a virtual program.”
Dr. Klein said that the teachers meet with their classes of 13 2-year-olds over Zoom, and when they first started, she asked the teachers to try to meet for 10 minutes. They are now meeting for 40 minutes twice a week. The children like seeing their teachers in their homes and they like seeing each other. In addition, the teachers make videos to send home and they are currently working on one to demystify masks. “We’re working on normalizing masks and showing children that when you put the mask on, you’re still there underneath.”
The center has existed for 48 years. There have been struggles for some of the children who attend; some of the parents have been hospitalized with the virus, and some work on the front line and so parents may be living away from a child.
“We’ve seen more challenging behaviors during this time, more tantrums, toileting issues, night awakenings, and more fragility. But as the new normal takes hold, things are settling in. Parents have been good about getting new routines and it helps if parents can handle their own stress,” Dr. Klein said. She also pointed out that for parents working at home while caring for their children, this can be particularly difficult on a young child. “The child knows the parent is home, but isn’t spending time with him, and he sees it as a rejection.”
Margaret Adams, MD, is a child psychiatrist in Maryland who works with very young children and their parents. She says that some of the children are thriving with the extra attention from their parents. “I often have seen difficulties with readjustment to the routine of separations to day care after a family vacation of a week, or sometimes even a weekend, even for those young ones who seem to love the social aspects of day care. I think it is likely a big impact will come upon return, depending on the developmental stage of the child,” Dr. Adams noted.
Despite the hardships of the moment, all three experts expressed hopefulness about the future for these children.
“Young children are super-resilient and that’s the blessing of this,” Dr. Galanti said. “I think they will be okay.”
Emma is home for now with her parents, who are expecting another child soon. Her mother notes: “The days are long and balancing work is an impossible challenge, but being with Emma has been a total blessing, and when would I ever have this much time to spend with my kid? She’s at such a fun age – so curious and adventurous – it’s amazing to watch her language and skills progress. I wish we weren’t in the midst of a pandemic, but Emma is definitely the bright spot.”
Dr. Miller is coauthor with Annette Hanson, MD, of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins, both in Baltimore. Dr. Miller has no disclosures.
Emma just celebrated her second birthday, and she has been working on the usual things that children start to master at this age: potty training, making friends, exerting her will through both actions and words, and generally enjoying life as the center of attention for both her parents and grandparents. Like everyone else in Maryland, Emma’s life changed suddenly with the coronavirus stay-at-home order that was issued on March 30. There is no more day care and her parents work from home while caring for her. Her grandparents visit, but only outside and only from a distance – there are no more hugs and there is no more sitting in her grandfather’s lap while he reads stories.
One afternoon a few weeks ago, Emma was looking out the window when she saw her friend, Max, walk by with his parents. Before her parents could stop her, Emma bolted out the door, and she and little Max wrapped each other in a tight embrace. Their parents snapped a photo of the smiling toddlers hugging before they separated the children. The photo is adorable, but as all struggle with social distancing, the poignance of two innocent toddlers in a forbidden embrace is a bit heartbreaking.
Everyone who has ever observed children knows that social distancing is not in their nature. Children play, they hug, they wrestle and tackle and poke, and sometimes even bite. And every student of social psychology has been taught about Harry Harlow’s experiments with rhesus macaques who were separated from their mothers and given access to an inanimate object to serve as a surrogate mother. The Harlow studies, while controversial, were revolutionary in demonstrating that early interactions with both a mother and with playmates were essential in the development of normal social relationships.
Regine Galanti, PhD, is a clinical psychologist at Long Island Behavioral Psychology, Cedarhurst, N.Y., who specializes in the treatment of anxiety and behavior problems. With young children she uses parent-child interaction therapy (PCIT) to help build relationships and discipline. Dr. Galanti said: “I don’t think we’re well prepared as a field to answer questions about the long-term effects of social distancing. If you need young children to socially distance, the responsibility has to fall on the adults. It’s important to explain to children what’s going on and to be honest in a developmentally appropriate way.”
Dr. Galanti has noticed that the issues that people had before COVID-19 are exacerbated by the stress of the current situation. What we do know is that young children thrive on structure.”
Tovah P. Klein, PhD, is the author of “How Toddlers Thrive” (Touchstone, 2015) and is the director of the Barnard College Center for Toddler Development in Manhattan. “When this started, we thought we would be closed for a few weeks,” Dr. Klein said. “We wanted to maintain a connection to the children, so we made videos for the parents to show to the kids, just to say ‘We’re still here.’ But as time went on and we realized it was going to be a while, we felt it was important to provide connection, so we launched a virtual program.”
Dr. Klein said that the teachers meet with their classes of 13 2-year-olds over Zoom, and when they first started, she asked the teachers to try to meet for 10 minutes. They are now meeting for 40 minutes twice a week. The children like seeing their teachers in their homes and they like seeing each other. In addition, the teachers make videos to send home and they are currently working on one to demystify masks. “We’re working on normalizing masks and showing children that when you put the mask on, you’re still there underneath.”
The center has existed for 48 years. There have been struggles for some of the children who attend; some of the parents have been hospitalized with the virus, and some work on the front line and so parents may be living away from a child.
“We’ve seen more challenging behaviors during this time, more tantrums, toileting issues, night awakenings, and more fragility. But as the new normal takes hold, things are settling in. Parents have been good about getting new routines and it helps if parents can handle their own stress,” Dr. Klein said. She also pointed out that for parents working at home while caring for their children, this can be particularly difficult on a young child. “The child knows the parent is home, but isn’t spending time with him, and he sees it as a rejection.”
Margaret Adams, MD, is a child psychiatrist in Maryland who works with very young children and their parents. She says that some of the children are thriving with the extra attention from their parents. “I often have seen difficulties with readjustment to the routine of separations to day care after a family vacation of a week, or sometimes even a weekend, even for those young ones who seem to love the social aspects of day care. I think it is likely a big impact will come upon return, depending on the developmental stage of the child,” Dr. Adams noted.
Despite the hardships of the moment, all three experts expressed hopefulness about the future for these children.
“Young children are super-resilient and that’s the blessing of this,” Dr. Galanti said. “I think they will be okay.”
Emma is home for now with her parents, who are expecting another child soon. Her mother notes: “The days are long and balancing work is an impossible challenge, but being with Emma has been a total blessing, and when would I ever have this much time to spend with my kid? She’s at such a fun age – so curious and adventurous – it’s amazing to watch her language and skills progress. I wish we weren’t in the midst of a pandemic, but Emma is definitely the bright spot.”
Dr. Miller is coauthor with Annette Hanson, MD, of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins, both in Baltimore. Dr. Miller has no disclosures.
Emma just celebrated her second birthday, and she has been working on the usual things that children start to master at this age: potty training, making friends, exerting her will through both actions and words, and generally enjoying life as the center of attention for both her parents and grandparents. Like everyone else in Maryland, Emma’s life changed suddenly with the coronavirus stay-at-home order that was issued on March 30. There is no more day care and her parents work from home while caring for her. Her grandparents visit, but only outside and only from a distance – there are no more hugs and there is no more sitting in her grandfather’s lap while he reads stories.
One afternoon a few weeks ago, Emma was looking out the window when she saw her friend, Max, walk by with his parents. Before her parents could stop her, Emma bolted out the door, and she and little Max wrapped each other in a tight embrace. Their parents snapped a photo of the smiling toddlers hugging before they separated the children. The photo is adorable, but as all struggle with social distancing, the poignance of two innocent toddlers in a forbidden embrace is a bit heartbreaking.
Everyone who has ever observed children knows that social distancing is not in their nature. Children play, they hug, they wrestle and tackle and poke, and sometimes even bite. And every student of social psychology has been taught about Harry Harlow’s experiments with rhesus macaques who were separated from their mothers and given access to an inanimate object to serve as a surrogate mother. The Harlow studies, while controversial, were revolutionary in demonstrating that early interactions with both a mother and with playmates were essential in the development of normal social relationships.
Regine Galanti, PhD, is a clinical psychologist at Long Island Behavioral Psychology, Cedarhurst, N.Y., who specializes in the treatment of anxiety and behavior problems. With young children she uses parent-child interaction therapy (PCIT) to help build relationships and discipline. Dr. Galanti said: “I don’t think we’re well prepared as a field to answer questions about the long-term effects of social distancing. If you need young children to socially distance, the responsibility has to fall on the adults. It’s important to explain to children what’s going on and to be honest in a developmentally appropriate way.”
Dr. Galanti has noticed that the issues that people had before COVID-19 are exacerbated by the stress of the current situation. What we do know is that young children thrive on structure.”
Tovah P. Klein, PhD, is the author of “How Toddlers Thrive” (Touchstone, 2015) and is the director of the Barnard College Center for Toddler Development in Manhattan. “When this started, we thought we would be closed for a few weeks,” Dr. Klein said. “We wanted to maintain a connection to the children, so we made videos for the parents to show to the kids, just to say ‘We’re still here.’ But as time went on and we realized it was going to be a while, we felt it was important to provide connection, so we launched a virtual program.”
Dr. Klein said that the teachers meet with their classes of 13 2-year-olds over Zoom, and when they first started, she asked the teachers to try to meet for 10 minutes. They are now meeting for 40 minutes twice a week. The children like seeing their teachers in their homes and they like seeing each other. In addition, the teachers make videos to send home and they are currently working on one to demystify masks. “We’re working on normalizing masks and showing children that when you put the mask on, you’re still there underneath.”
The center has existed for 48 years. There have been struggles for some of the children who attend; some of the parents have been hospitalized with the virus, and some work on the front line and so parents may be living away from a child.
“We’ve seen more challenging behaviors during this time, more tantrums, toileting issues, night awakenings, and more fragility. But as the new normal takes hold, things are settling in. Parents have been good about getting new routines and it helps if parents can handle their own stress,” Dr. Klein said. She also pointed out that for parents working at home while caring for their children, this can be particularly difficult on a young child. “The child knows the parent is home, but isn’t spending time with him, and he sees it as a rejection.”
Margaret Adams, MD, is a child psychiatrist in Maryland who works with very young children and their parents. She says that some of the children are thriving with the extra attention from their parents. “I often have seen difficulties with readjustment to the routine of separations to day care after a family vacation of a week, or sometimes even a weekend, even for those young ones who seem to love the social aspects of day care. I think it is likely a big impact will come upon return, depending on the developmental stage of the child,” Dr. Adams noted.
Despite the hardships of the moment, all three experts expressed hopefulness about the future for these children.
“Young children are super-resilient and that’s the blessing of this,” Dr. Galanti said. “I think they will be okay.”
Emma is home for now with her parents, who are expecting another child soon. Her mother notes: “The days are long and balancing work is an impossible challenge, but being with Emma has been a total blessing, and when would I ever have this much time to spend with my kid? She’s at such a fun age – so curious and adventurous – it’s amazing to watch her language and skills progress. I wish we weren’t in the midst of a pandemic, but Emma is definitely the bright spot.”
Dr. Miller is coauthor with Annette Hanson, MD, of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins, both in Baltimore. Dr. Miller has no disclosures.