Federal Practitioner

The standard intradermal route of delivery for Bacille Calmette–Guérin (BCG) does not necessarily generate a strong enough response from lung T-cells, the researchers say. They hypothesized that administering BCG by IV or aerosol might be more effective.

They gave a group of rhesus macaques the BGC vaccine by intradermal, aerosol, or IV routes, then assessed immune responses in blood and fluid drawn from the lungs over a 24-week follow-up. Six months after vaccination, the researchers injected the vaccinated animals with a virulent strain of Mycobacterium tuberculosis (M tuberculosis) and tracked infection and disease development over 3 months.

The IV vaccination resulted in the highest durable levels of T-cells in blood and lungs. Nine of 10 animals vaccinated via IV were highly protected; 6 showed no detectable infection in any tissue tested and 3 had only very low counts of M tuberculosis in lung tissue. All unvaccinated animals and those immunized via intradermal or aerosol routes showed signs of significantly greater infection.

Upping the dose did not improve protection. The IV BCG group showed 90% protection at a threshold as low as 50 colony-forming units (the standard human ID dose is 5 x 10⁵ CFUs).

The researchers say several unique quantitative and qualitative differences in the immune responses may underlie protection. Perhaps most noteworthy, they say, was the large population of T- cells in the tissue across all lung parenchyma lobes.

The study provides a “paradigm shift,” the researchers conclude, adding that the IV route may also improve the protective capacity of other vaccines.

The standard intradermal route of delivery for Bacille Calmette–Guérin (BCG) does not necessarily generate a strong enough response from lung T-cells, the researchers say. They hypothesized that administering BCG by IV or aerosol might be more effective.

They gave a group of rhesus macaques the BGC vaccine by intradermal, aerosol, or IV routes, then assessed immune responses in blood and fluid drawn from the lungs over a 24-week follow-up. Six months after vaccination, the researchers injected the vaccinated animals with a virulent strain of Mycobacterium tuberculosis (M tuberculosis) and tracked infection and disease development over 3 months.

The IV vaccination resulted in the highest durable levels of T-cells in blood and lungs. Nine of 10 animals vaccinated via IV were highly protected; 6 showed no detectable infection in any tissue tested and 3 had only very low counts of M tuberculosis in lung tissue. All unvaccinated animals and those immunized via intradermal or aerosol routes showed signs of significantly greater infection.

Upping the dose did not improve protection. The IV BCG group showed 90% protection at a threshold as low as 50 colony-forming units (the standard human ID dose is 5 x 10⁵ CFUs).

The researchers say several unique quantitative and qualitative differences in the immune responses may underlie protection. Perhaps most noteworthy, they say, was the large population of T- cells in the tissue across all lung parenchyma lobes.

The study provides a “paradigm shift,” the researchers conclude, adding that the IV route may also improve the protective capacity of other vaccines.

The standard intradermal route of delivery for Bacille Calmette–Guérin (BCG) does not necessarily generate a strong enough response from lung T-cells, the researchers say. They hypothesized that administering BCG by IV or aerosol might be more effective.

They gave a group of rhesus macaques the BGC vaccine by intradermal, aerosol, or IV routes, then assessed immune responses in blood and fluid drawn from the lungs over a 24-week follow-up. Six months after vaccination, the researchers injected the vaccinated animals with a virulent strain of Mycobacterium tuberculosis (M tuberculosis) and tracked infection and disease development over 3 months.

The IV vaccination resulted in the highest durable levels of T-cells in blood and lungs. Nine of 10 animals vaccinated via IV were highly protected; 6 showed no detectable infection in any tissue tested and 3 had only very low counts of M tuberculosis in lung tissue. All unvaccinated animals and those immunized via intradermal or aerosol routes showed signs of significantly greater infection.

Upping the dose did not improve protection. The IV BCG group showed 90% protection at a threshold as low as 50 colony-forming units (the standard human ID dose is 5 x 10⁵ CFUs).

The researchers say several unique quantitative and qualitative differences in the immune responses may underlie protection. Perhaps most noteworthy, they say, was the large population of T- cells in the tissue across all lung parenchyma lobes.

The study provides a “paradigm shift,” the researchers conclude, adding that the IV route may also improve the protective capacity of other vaccines.

Psychiatrists do better compared with those in most specialties in finding happiness at work, according to Medscape’s 2020 Lifestyle, Happiness, and Burnout Report.

About 32% of psychiatrists reported being happy at work, according to the Medscape survey, though they lagged well behind dermatologists, who were the most satisfied with their work lives. In terms of happiness outside the office, psychiatrists were in the middle of the pack with 51% reporting that they were happy.

Somewhat fewer psychiatrists reported being burned out, compared with physicians overall, at 37% versus 41%. The biggest contributing factors to psychiatrist burnout were an overabundance of bureaucratic tasks (63%), increased time devoted to EHRs (34%), and a lack of respect from colleagues in the workplace (32%).

Psychiatrists most commonly dealt with burnout by isolating themselves from others (57%), sleeping (43%), and talking with family/friends (42%). Just under half of psychiatrists took 3-4 weeks’ vacation, compared with 44% of all physicians, and 33% took less than 3 weeks’ vacation.

More than three-quarters of psychiatrists reported that they had never felt suicidal, but 17% said that they had contemplated suicide and 1% reported that they had attempted suicide. About 45% said that they were currently seeking professional help, planning to seek help, or had used help in the past to deal with burnout or depression; 48% said that they were not planning to seek help and had not done so in the past.

In an interview, Carol A. Bernstein, MD, said it is challenging to find the meaning in these survey results.

“The challenge with surveys that measure burnout is that the drivers may be somewhat different in different specialties. I am less interested in looking at ‘who has it worse’ than I am at trying to address those systemic factors that are important for all physicians, regardless of specialty,” said Dr. Bernstein of Montefiore Medical Center/Albert Einstein College of Medicine, New York.

“The survey noted some of these factors: the increased burden of regulation and bureaucratic tasks, an EHR that was designed for billing and scheduling – not for taking care of patients – and challenges of professionalism in the workplace. These are issues that we must address for the benefit of all health care providers and patients.”

Dr. Bernstein, a past president of the American Psychiatric Association, is vice chair for faculty development and well-being at Montefiore/Albert Einstein. She is a professor in the departments of psychiatry and behavioral sciences, and obstetrics/gynecology & women’s health.

The Medscape survey was conducted from June 25 to Sept. 19, 2019, and involved 15,181 physicians.

[email protected]

Psychiatrists do better compared with those in most specialties in finding happiness at work, according to Medscape’s 2020 Lifestyle, Happiness, and Burnout Report.

About 32% of psychiatrists reported being happy at work, according to the Medscape survey, though they lagged well behind dermatologists, who were the most satisfied with their work lives. In terms of happiness outside the office, psychiatrists were in the middle of the pack with 51% reporting that they were happy.

Somewhat fewer psychiatrists reported being burned out, compared with physicians overall, at 37% versus 41%. The biggest contributing factors to psychiatrist burnout were an overabundance of bureaucratic tasks (63%), increased time devoted to EHRs (34%), and a lack of respect from colleagues in the workplace (32%).

Psychiatrists most commonly dealt with burnout by isolating themselves from others (57%), sleeping (43%), and talking with family/friends (42%). Just under half of psychiatrists took 3-4 weeks’ vacation, compared with 44% of all physicians, and 33% took less than 3 weeks’ vacation.

More than three-quarters of psychiatrists reported that they had never felt suicidal, but 17% said that they had contemplated suicide and 1% reported that they had attempted suicide. About 45% said that they were currently seeking professional help, planning to seek help, or had used help in the past to deal with burnout or depression; 48% said that they were not planning to seek help and had not done so in the past.

In an interview, Carol A. Bernstein, MD, said it is challenging to find the meaning in these survey results.

“The challenge with surveys that measure burnout is that the drivers may be somewhat different in different specialties. I am less interested in looking at ‘who has it worse’ than I am at trying to address those systemic factors that are important for all physicians, regardless of specialty,” said Dr. Bernstein of Montefiore Medical Center/Albert Einstein College of Medicine, New York.

“The survey noted some of these factors: the increased burden of regulation and bureaucratic tasks, an EHR that was designed for billing and scheduling – not for taking care of patients – and challenges of professionalism in the workplace. These are issues that we must address for the benefit of all health care providers and patients.”

Dr. Bernstein, a past president of the American Psychiatric Association, is vice chair for faculty development and well-being at Montefiore/Albert Einstein. She is a professor in the departments of psychiatry and behavioral sciences, and obstetrics/gynecology & women’s health.

The Medscape survey was conducted from June 25 to Sept. 19, 2019, and involved 15,181 physicians.

[email protected]

Psychiatrists do better compared with those in most specialties in finding happiness at work, according to Medscape’s 2020 Lifestyle, Happiness, and Burnout Report.

About 32% of psychiatrists reported being happy at work, according to the Medscape survey, though they lagged well behind dermatologists, who were the most satisfied with their work lives. In terms of happiness outside the office, psychiatrists were in the middle of the pack with 51% reporting that they were happy.

Somewhat fewer psychiatrists reported being burned out, compared with physicians overall, at 37% versus 41%. The biggest contributing factors to psychiatrist burnout were an overabundance of bureaucratic tasks (63%), increased time devoted to EHRs (34%), and a lack of respect from colleagues in the workplace (32%).

Psychiatrists most commonly dealt with burnout by isolating themselves from others (57%), sleeping (43%), and talking with family/friends (42%). Just under half of psychiatrists took 3-4 weeks’ vacation, compared with 44% of all physicians, and 33% took less than 3 weeks’ vacation.

More than three-quarters of psychiatrists reported that they had never felt suicidal, but 17% said that they had contemplated suicide and 1% reported that they had attempted suicide. About 45% said that they were currently seeking professional help, planning to seek help, or had used help in the past to deal with burnout or depression; 48% said that they were not planning to seek help and had not done so in the past.

In an interview, Carol A. Bernstein, MD, said it is challenging to find the meaning in these survey results.

“The challenge with surveys that measure burnout is that the drivers may be somewhat different in different specialties. I am less interested in looking at ‘who has it worse’ than I am at trying to address those systemic factors that are important for all physicians, regardless of specialty,” said Dr. Bernstein of Montefiore Medical Center/Albert Einstein College of Medicine, New York.

“The survey noted some of these factors: the increased burden of regulation and bureaucratic tasks, an EHR that was designed for billing and scheduling – not for taking care of patients – and challenges of professionalism in the workplace. These are issues that we must address for the benefit of all health care providers and patients.”

Dr. Bernstein, a past president of the American Psychiatric Association, is vice chair for faculty development and well-being at Montefiore/Albert Einstein. She is a professor in the departments of psychiatry and behavioral sciences, and obstetrics/gynecology & women’s health.

The Medscape survey was conducted from June 25 to Sept. 19, 2019, and involved 15,181 physicians.

[email protected]

The Centers for Disease Control and Prevention announced two new patients now have the 2019 Novel Coronavirus (2019-nCoV), bringing the case total in the United States to 15.

The 14th case was discovered in California among a group of people under federal quarantine after returning from the Hubei Province in China. That patient was on a U.S. State Department–chartered flight that arrived in the United States on Feb. 7.

The 15th case was discovered in Texas among a group of people who also are under federal quarantine. That patient arrived on a State Department–chartered flight that arrived on Feb. 7. It is the first person in Texas that has tested positive for 2019-nCoV.

CDC said in a statement announcing the Texas case that there “will likely be additional cases in the coming days and weeks, including among other people recently returned from Wuhan.” Officials noted that more than 600 people who have returned as part of State Department–chartered flights are currently under that 14-day quarantine.

The agency is preparing for more widespread cases of 2019-nCoV.

Nancy Messonnier, MD, director of the CDC National Center for Immunization and Respiratory Diseases, said that containment has been the early focus for the agency.

“The goal of the measures we have taken to date are to slow the introduction and impact of this disease in the United States, but at some point, we are likely to see community spread in the U.S.,” Dr. Messonnier said during a Feb. 12 teleconference with reporters. She added that the federal response will change over time as the virus spreads.

Dr. Messonnier noted that public health officials are planning for the increased demands that a wider outbreak of 2019-nCov would place on the health care delivery system, including ensuring an adequate supply of medical equipment.

[email protected]

The Centers for Disease Control and Prevention announced two new patients now have the 2019 Novel Coronavirus (2019-nCoV), bringing the case total in the United States to 15.

The 14th case was discovered in California among a group of people under federal quarantine after returning from the Hubei Province in China. That patient was on a U.S. State Department–chartered flight that arrived in the United States on Feb. 7.

The 15th case was discovered in Texas among a group of people who also are under federal quarantine. That patient arrived on a State Department–chartered flight that arrived on Feb. 7. It is the first person in Texas that has tested positive for 2019-nCoV.

CDC said in a statement announcing the Texas case that there “will likely be additional cases in the coming days and weeks, including among other people recently returned from Wuhan.” Officials noted that more than 600 people who have returned as part of State Department–chartered flights are currently under that 14-day quarantine.

The agency is preparing for more widespread cases of 2019-nCoV.

Nancy Messonnier, MD, director of the CDC National Center for Immunization and Respiratory Diseases, said that containment has been the early focus for the agency.

“The goal of the measures we have taken to date are to slow the introduction and impact of this disease in the United States, but at some point, we are likely to see community spread in the U.S.,” Dr. Messonnier said during a Feb. 12 teleconference with reporters. She added that the federal response will change over time as the virus spreads.

Dr. Messonnier noted that public health officials are planning for the increased demands that a wider outbreak of 2019-nCov would place on the health care delivery system, including ensuring an adequate supply of medical equipment.

[email protected]

The Centers for Disease Control and Prevention announced two new patients now have the 2019 Novel Coronavirus (2019-nCoV), bringing the case total in the United States to 15.

The 14th case was discovered in California among a group of people under federal quarantine after returning from the Hubei Province in China. That patient was on a U.S. State Department–chartered flight that arrived in the United States on Feb. 7.

The 15th case was discovered in Texas among a group of people who also are under federal quarantine. That patient arrived on a State Department–chartered flight that arrived on Feb. 7. It is the first person in Texas that has tested positive for 2019-nCoV.

CDC said in a statement announcing the Texas case that there “will likely be additional cases in the coming days and weeks, including among other people recently returned from Wuhan.” Officials noted that more than 600 people who have returned as part of State Department–chartered flights are currently under that 14-day quarantine.

The agency is preparing for more widespread cases of 2019-nCoV.

Nancy Messonnier, MD, director of the CDC National Center for Immunization and Respiratory Diseases, said that containment has been the early focus for the agency.

“The goal of the measures we have taken to date are to slow the introduction and impact of this disease in the United States, but at some point, we are likely to see community spread in the U.S.,” Dr. Messonnier said during a Feb. 12 teleconference with reporters. She added that the federal response will change over time as the virus spreads.

Dr. Messonnier noted that public health officials are planning for the increased demands that a wider outbreak of 2019-nCov would place on the health care delivery system, including ensuring an adequate supply of medical equipment.

[email protected]

No specific treatment is currently available for human coronaviruses to date, but numerous antiviral agents are being identified through a variety of approaches, according to Thanigaimalai Pillaiyar, PhD, and colleagues in a review published in Drug Discovery Today.

Using the six previously discovered human coronaviruses – human CoV 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1); severe acute respiratory syndrome (SARS) CoV; and Middle East respiratory syndrome (MERS) CoV – the investigators examined progress in the use and development of therapeutic drugs, focusing on the potential roles of virus inhibitors.

“Research has mainly been focused on SARS- and MERS-CoV infections, because they were responsible for severe illness when compared with other CoVs,” Dr. Pillaiyar, of the department of pharmaceutical and medicinal chemistry at the University of Bonn (Germany), and colleagues wrote.

2019-nCov has been linked genomically as most closely related to SARS, and the Coronavirus Study Group of the International Committee on Virus Taxonomy, which has the responsibility for naming viruses, has designated the new virus SARS-CoV-2.
 

Examining extant drugs

The first approach to identifying possible antiviral agents reevaluates known, broadly acting antiviral drugs that have been used for other viral infections or other indications. The initial research into coronavirus therapeutics, in particular, has examined current antiviral therapeutics for their effectiveness against both SARS-CoV and MERS-CoV, but with mixed results.

For example, in a search of potential antiviral agents against CoVs, researchers identified four drugs – chloroquine, chlorpromazine, loperamide, and lopinavir – by screening drug libraries approved by the Food and Drug Administration. They were all able to inhibit the replication of MERS-CoV, SARS-CoV, and HCoV-229E in the low-micromolar range, which suggested that they could be used for broad-spectrum antiviral activity, according to Dr. Pillaiyar and colleagues.

Other research groups have also reported the discovery of antiviral drugs using this drug-repurposing approach, which included a number of broad-spectrum inhibitors of HCoVs (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) that showed strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations and suppressed the replication of all CoVs in a dose-dependent manner. Findings from in vivo studies showed lycorine protected mice against lethal HCoV-OC43 infection.

Along with the aforementioned drugs, a number of others have also shown potential usefulness, but, as yet, none has been validated for use in humans.
 

Developing new antivirals

The second approach for anti-CoV drug discovery involves the development of new therapeutics based on the genomic and biophysical understanding of the individual CoV in order to interfere with the virus itself or to disrupt its direct metabolic requirements. This can take several approaches.

MERS-CoV and SARS-CoV PL protease inhibitors

Of particular interest are antiviral therapies that attack papain-like protease, which is an important target because it is a multifunctional protein involved in proteolytic deubiquitination and viral evasion of the innate immune response. One such potential therapeutic that takes advantage of this target is disulfiram, an FDA-approved drug for use in alcohol-aversion therapy. Disulfiram has been reported as an allosteric inhibitor of MERS-CoV papain-like protease. Numerous other drug categories are being examined, with promising results in targeting the papain-like protease enzymes of both SARS and MERS.

Replicase inhibitors

Helicase (nsP13) protein is a crucial component required for virus replication in host cells and could serve as a feasible target for anti-MERS and anti-SARS chemical therapies, the review authors wrote, citing as an example, the recent development of a small 1,2,4-triazole derivative that inhibited the viral NTPase/helicase of SARS- and MERS-CoVs and demonstrated high antiviral activity and low cytotoxicity.

Membrane-bound viral RNA synthesis inhibitors

Antiviral agents that target membrane-bound coronaviral RNA synthesis represent a novel and attractive approach, according to Dr. Pillaiyar and colleagues. And recently, an inhibitor was developed that targets membrane-bound coronaviral RNA synthesis and “showed potent antiviral activity of MERS-CoV infection with remarkable efficacy.”

Host-based, anti-CoV treatment options

An alternate therapeutic tactic is to bolster host defenses or to modify host susceptibilities to prevent virus infection or replication. The innate interferon response of the host is crucial for the control of viral replication after infection, and the addition of exogenous recombinant interferon or use of drugs to stimulate the normal host interferon response are both potential therapeutic avenues. For example, nitazoxanide is a potent type I interferon inducer that has been used in humans for parasitic infections, and a synthetic nitrothiazolyl-salicylamide derivative was found to exhibit broad-spectrum antiviral activities against RNA and DNA viruses, including some coronaviruses.

Numerous other host pathways are being investigated as potential areas to enhance defense against infection and replication, for example, using inhibitors to block nucleic acid synthesis has been shown to provide broad-spectrum activity against SARS-CoV and MERS-CoV.

One particular example is remdesivir, a novel nucleotide analog antiviral drug, that was developed as a therapy for Ebola virus disease and Marburg virus infections. It was later shown to provide “reasonable antiviral activity against more distantly related viruses, such as respiratory syncytial virus, Junin virus, Lassa fever virus, and MERS-CoV,” the authors wrote.

Also of interest regarding remdesivir’s potential broad-spectrum use is that it has shown potent in vitro “antiviral activity against Malaysian and Bangladesh genotypes of Nipah virus (an RNA virus, although not a coronavirus, that infects both humans and animals) and reduced replication of Malaysian Nipah virus in primary human lung microvascular endothelial cells by more than four orders of magnitude,” Dr. Pillaiyar and colleagues added. Of particular note, all remdesivir-treated, Nipah virus–infected animals “survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment.”

In a press briefing earlier this month, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, reported that a randomized, controlled, phase 3 trial of the antiviral drug remdesivir is currently underway in China to establish whether the drug would be an effective and safe treatment for adults patients with mild or moderate 2019 Novel Coronavirus (2019-nCoV) disease.

“Our increasing understanding of novel emerging coronaviruses will be accompanied by increasing opportunities for the reasonable design of therapeutics. Importantly, understanding this basic information about CoV protease targets will not only aid the public health against SARS-CoV and MERS-CoV but also help in advance to target new coronaviruses that might emerge in the future,” the authors concluded.

Dr. Pillaiyar and colleagues reported that they had no financial conflicts of interest.

[email protected]

SOURCE: Pillaiyar T et al. Drug Discov Today. 2020 Jan 30. doi: 10.1016/j.drudis.2020.01.015.

No specific treatment is currently available for human coronaviruses to date, but numerous antiviral agents are being identified through a variety of approaches, according to Thanigaimalai Pillaiyar, PhD, and colleagues in a review published in Drug Discovery Today.

Using the six previously discovered human coronaviruses – human CoV 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1); severe acute respiratory syndrome (SARS) CoV; and Middle East respiratory syndrome (MERS) CoV – the investigators examined progress in the use and development of therapeutic drugs, focusing on the potential roles of virus inhibitors.

“Research has mainly been focused on SARS- and MERS-CoV infections, because they were responsible for severe illness when compared with other CoVs,” Dr. Pillaiyar, of the department of pharmaceutical and medicinal chemistry at the University of Bonn (Germany), and colleagues wrote.

2019-nCov has been linked genomically as most closely related to SARS, and the Coronavirus Study Group of the International Committee on Virus Taxonomy, which has the responsibility for naming viruses, has designated the new virus SARS-CoV-2.
 

Examining extant drugs

The first approach to identifying possible antiviral agents reevaluates known, broadly acting antiviral drugs that have been used for other viral infections or other indications. The initial research into coronavirus therapeutics, in particular, has examined current antiviral therapeutics for their effectiveness against both SARS-CoV and MERS-CoV, but with mixed results.

For example, in a search of potential antiviral agents against CoVs, researchers identified four drugs – chloroquine, chlorpromazine, loperamide, and lopinavir – by screening drug libraries approved by the Food and Drug Administration. They were all able to inhibit the replication of MERS-CoV, SARS-CoV, and HCoV-229E in the low-micromolar range, which suggested that they could be used for broad-spectrum antiviral activity, according to Dr. Pillaiyar and colleagues.

Other research groups have also reported the discovery of antiviral drugs using this drug-repurposing approach, which included a number of broad-spectrum inhibitors of HCoVs (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) that showed strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations and suppressed the replication of all CoVs in a dose-dependent manner. Findings from in vivo studies showed lycorine protected mice against lethal HCoV-OC43 infection.

Along with the aforementioned drugs, a number of others have also shown potential usefulness, but, as yet, none has been validated for use in humans.
 

Developing new antivirals

The second approach for anti-CoV drug discovery involves the development of new therapeutics based on the genomic and biophysical understanding of the individual CoV in order to interfere with the virus itself or to disrupt its direct metabolic requirements. This can take several approaches.

MERS-CoV and SARS-CoV PL protease inhibitors

Of particular interest are antiviral therapies that attack papain-like protease, which is an important target because it is a multifunctional protein involved in proteolytic deubiquitination and viral evasion of the innate immune response. One such potential therapeutic that takes advantage of this target is disulfiram, an FDA-approved drug for use in alcohol-aversion therapy. Disulfiram has been reported as an allosteric inhibitor of MERS-CoV papain-like protease. Numerous other drug categories are being examined, with promising results in targeting the papain-like protease enzymes of both SARS and MERS.

Replicase inhibitors

Helicase (nsP13) protein is a crucial component required for virus replication in host cells and could serve as a feasible target for anti-MERS and anti-SARS chemical therapies, the review authors wrote, citing as an example, the recent development of a small 1,2,4-triazole derivative that inhibited the viral NTPase/helicase of SARS- and MERS-CoVs and demonstrated high antiviral activity and low cytotoxicity.

Membrane-bound viral RNA synthesis inhibitors

Antiviral agents that target membrane-bound coronaviral RNA synthesis represent a novel and attractive approach, according to Dr. Pillaiyar and colleagues. And recently, an inhibitor was developed that targets membrane-bound coronaviral RNA synthesis and “showed potent antiviral activity of MERS-CoV infection with remarkable efficacy.”

Host-based, anti-CoV treatment options

An alternate therapeutic tactic is to bolster host defenses or to modify host susceptibilities to prevent virus infection or replication. The innate interferon response of the host is crucial for the control of viral replication after infection, and the addition of exogenous recombinant interferon or use of drugs to stimulate the normal host interferon response are both potential therapeutic avenues. For example, nitazoxanide is a potent type I interferon inducer that has been used in humans for parasitic infections, and a synthetic nitrothiazolyl-salicylamide derivative was found to exhibit broad-spectrum antiviral activities against RNA and DNA viruses, including some coronaviruses.

Numerous other host pathways are being investigated as potential areas to enhance defense against infection and replication, for example, using inhibitors to block nucleic acid synthesis has been shown to provide broad-spectrum activity against SARS-CoV and MERS-CoV.

One particular example is remdesivir, a novel nucleotide analog antiviral drug, that was developed as a therapy for Ebola virus disease and Marburg virus infections. It was later shown to provide “reasonable antiviral activity against more distantly related viruses, such as respiratory syncytial virus, Junin virus, Lassa fever virus, and MERS-CoV,” the authors wrote.

Also of interest regarding remdesivir’s potential broad-spectrum use is that it has shown potent in vitro “antiviral activity against Malaysian and Bangladesh genotypes of Nipah virus (an RNA virus, although not a coronavirus, that infects both humans and animals) and reduced replication of Malaysian Nipah virus in primary human lung microvascular endothelial cells by more than four orders of magnitude,” Dr. Pillaiyar and colleagues added. Of particular note, all remdesivir-treated, Nipah virus–infected animals “survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment.”

In a press briefing earlier this month, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, reported that a randomized, controlled, phase 3 trial of the antiviral drug remdesivir is currently underway in China to establish whether the drug would be an effective and safe treatment for adults patients with mild or moderate 2019 Novel Coronavirus (2019-nCoV) disease.

“Our increasing understanding of novel emerging coronaviruses will be accompanied by increasing opportunities for the reasonable design of therapeutics. Importantly, understanding this basic information about CoV protease targets will not only aid the public health against SARS-CoV and MERS-CoV but also help in advance to target new coronaviruses that might emerge in the future,” the authors concluded.

Dr. Pillaiyar and colleagues reported that they had no financial conflicts of interest.

[email protected]

SOURCE: Pillaiyar T et al. Drug Discov Today. 2020 Jan 30. doi: 10.1016/j.drudis.2020.01.015.

No specific treatment is currently available for human coronaviruses to date, but numerous antiviral agents are being identified through a variety of approaches, according to Thanigaimalai Pillaiyar, PhD, and colleagues in a review published in Drug Discovery Today.

Using the six previously discovered human coronaviruses – human CoV 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1); severe acute respiratory syndrome (SARS) CoV; and Middle East respiratory syndrome (MERS) CoV – the investigators examined progress in the use and development of therapeutic drugs, focusing on the potential roles of virus inhibitors.

“Research has mainly been focused on SARS- and MERS-CoV infections, because they were responsible for severe illness when compared with other CoVs,” Dr. Pillaiyar, of the department of pharmaceutical and medicinal chemistry at the University of Bonn (Germany), and colleagues wrote.

2019-nCov has been linked genomically as most closely related to SARS, and the Coronavirus Study Group of the International Committee on Virus Taxonomy, which has the responsibility for naming viruses, has designated the new virus SARS-CoV-2.
 

Examining extant drugs

The first approach to identifying possible antiviral agents reevaluates known, broadly acting antiviral drugs that have been used for other viral infections or other indications. The initial research into coronavirus therapeutics, in particular, has examined current antiviral therapeutics for their effectiveness against both SARS-CoV and MERS-CoV, but with mixed results.

For example, in a search of potential antiviral agents against CoVs, researchers identified four drugs – chloroquine, chlorpromazine, loperamide, and lopinavir – by screening drug libraries approved by the Food and Drug Administration. They were all able to inhibit the replication of MERS-CoV, SARS-CoV, and HCoV-229E in the low-micromolar range, which suggested that they could be used for broad-spectrum antiviral activity, according to Dr. Pillaiyar and colleagues.

Other research groups have also reported the discovery of antiviral drugs using this drug-repurposing approach, which included a number of broad-spectrum inhibitors of HCoVs (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) that showed strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations and suppressed the replication of all CoVs in a dose-dependent manner. Findings from in vivo studies showed lycorine protected mice against lethal HCoV-OC43 infection.

Along with the aforementioned drugs, a number of others have also shown potential usefulness, but, as yet, none has been validated for use in humans.
 

Developing new antivirals

The second approach for anti-CoV drug discovery involves the development of new therapeutics based on the genomic and biophysical understanding of the individual CoV in order to interfere with the virus itself or to disrupt its direct metabolic requirements. This can take several approaches.

MERS-CoV and SARS-CoV PL protease inhibitors

Of particular interest are antiviral therapies that attack papain-like protease, which is an important target because it is a multifunctional protein involved in proteolytic deubiquitination and viral evasion of the innate immune response. One such potential therapeutic that takes advantage of this target is disulfiram, an FDA-approved drug for use in alcohol-aversion therapy. Disulfiram has been reported as an allosteric inhibitor of MERS-CoV papain-like protease. Numerous other drug categories are being examined, with promising results in targeting the papain-like protease enzymes of both SARS and MERS.

Replicase inhibitors

Helicase (nsP13) protein is a crucial component required for virus replication in host cells and could serve as a feasible target for anti-MERS and anti-SARS chemical therapies, the review authors wrote, citing as an example, the recent development of a small 1,2,4-triazole derivative that inhibited the viral NTPase/helicase of SARS- and MERS-CoVs and demonstrated high antiviral activity and low cytotoxicity.

Membrane-bound viral RNA synthesis inhibitors

Antiviral agents that target membrane-bound coronaviral RNA synthesis represent a novel and attractive approach, according to Dr. Pillaiyar and colleagues. And recently, an inhibitor was developed that targets membrane-bound coronaviral RNA synthesis and “showed potent antiviral activity of MERS-CoV infection with remarkable efficacy.”

Host-based, anti-CoV treatment options

An alternate therapeutic tactic is to bolster host defenses or to modify host susceptibilities to prevent virus infection or replication. The innate interferon response of the host is crucial for the control of viral replication after infection, and the addition of exogenous recombinant interferon or use of drugs to stimulate the normal host interferon response are both potential therapeutic avenues. For example, nitazoxanide is a potent type I interferon inducer that has been used in humans for parasitic infections, and a synthetic nitrothiazolyl-salicylamide derivative was found to exhibit broad-spectrum antiviral activities against RNA and DNA viruses, including some coronaviruses.

Numerous other host pathways are being investigated as potential areas to enhance defense against infection and replication, for example, using inhibitors to block nucleic acid synthesis has been shown to provide broad-spectrum activity against SARS-CoV and MERS-CoV.

One particular example is remdesivir, a novel nucleotide analog antiviral drug, that was developed as a therapy for Ebola virus disease and Marburg virus infections. It was later shown to provide “reasonable antiviral activity against more distantly related viruses, such as respiratory syncytial virus, Junin virus, Lassa fever virus, and MERS-CoV,” the authors wrote.

Also of interest regarding remdesivir’s potential broad-spectrum use is that it has shown potent in vitro “antiviral activity against Malaysian and Bangladesh genotypes of Nipah virus (an RNA virus, although not a coronavirus, that infects both humans and animals) and reduced replication of Malaysian Nipah virus in primary human lung microvascular endothelial cells by more than four orders of magnitude,” Dr. Pillaiyar and colleagues added. Of particular note, all remdesivir-treated, Nipah virus–infected animals “survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment.”

In a press briefing earlier this month, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, reported that a randomized, controlled, phase 3 trial of the antiviral drug remdesivir is currently underway in China to establish whether the drug would be an effective and safe treatment for adults patients with mild or moderate 2019 Novel Coronavirus (2019-nCoV) disease.

“Our increasing understanding of novel emerging coronaviruses will be accompanied by increasing opportunities for the reasonable design of therapeutics. Importantly, understanding this basic information about CoV protease targets will not only aid the public health against SARS-CoV and MERS-CoV but also help in advance to target new coronaviruses that might emerge in the future,” the authors concluded.

Dr. Pillaiyar and colleagues reported that they had no financial conflicts of interest.

[email protected]

SOURCE: Pillaiyar T et al. Drug Discov Today. 2020 Jan 30. doi: 10.1016/j.drudis.2020.01.015.

The Trump administration on Feb. 10 argued for cutting spending for a federal agency at the forefront of the efforts to combat the coronavirus, while also seeking to slow spending in certain parts of the Medicare and Medicaid programs.

President Donald Trump presented his fiscal 2021 request to Congress for refilling the coffers of federal agencies. In any administration, an annual budget serves only as a political blueprint, as the White House document itself makes no changes in federal spending.

In Mr. Trump’s case, several of his requests for agencies within the Department of Health & Human Services run counter to recent budget trends. Republicans and Democrats in Congress have worked together in recent years to increase budgets for major federal health agencies.

But Mr. Trump asked Congress to cut annual budget authority for the National Institute of Allergy and Infectious Diseases by $430 million to $5.446 billion for fiscal 2021. In contrast, Congress has raised the annual budget for NIAID, a key agency in combating the coronavirus, from $5.545 billion in fiscal 2019 to $5.876 billion in fiscal 2020, which began in October, according to an HHS summary of Mr. Trump’s request.

For the Centers for Disease Control and Prevention, which is central to the battle against the coronavirus, Mr. Trump proposed a drop in discretionary funding to $5.627 billion. In contrast, Congress raised the CDC budget from $6.544 billion in fiscal 2019 to $6.917 in fiscal 2020.

Mr. Trump also wants to cut $559 million from the budget of the National Cancer Institute, dropping it to $5.881 billion in fiscal 2021. In contrast, Congress raised NCI’s budget from $6.121 billion in fiscal 2019 to $6.440 billion in fiscal 2020.

Mr. Trump requested a $2.6 billion reduction in the National Institutes of Health’s total discretionary budget, seeking to drop it to $37.70 billion. In contrast, Congress raised NIH’s budget from $37.887 in fiscal 2019 to $40.304 billion in fiscal 2020.

Mr. Trump’s budget proposal also includes an estimate of $152 billion in savings over a decade for Medicaid through the implementation of what the administration calls “community engagement” requirements.

The Trump administration has been at odds with Democrats for years about whether work requirements should be attached to Medicaid. “Well-designed community engagement incentives have great potential to improve health and well-being while empowering beneficiaries to rise out of poverty,” HHS said in a budget document.

Yet researchers last year reported that Arkansas’ attempt to attach work requirements to Medicaid caused almost 17,000 adults to lose this health care coverage within the first 6 months, and there was no significant difference in employment.

The researchers say this loss of coverage was partly a result of bureaucratic obstacles and confusion about the new rules. In June 2018, Arkansas became the first state to implement work requirements for Medicaid, Benjamin D. Sommers, MD, PhD, of the Harvard T.H. Chan School of Public Health, Boston, and colleagues wrote in the New England Journal of Medicine (2019 Sep 12;381[11]:1073-82). 

Budget ‘would thwart’ progress

A few medical groups on Monday quickly criticized Mr. Trump’s proposals.

“In a time where our nation continues to face significant public health challenges — including 2019 novel coronavirus, climate change, gun violence, and costly chronic diseases such as heart disease and cancer – the administration should be investing more resources in better health, not cutting federal health budgets,” said Georges C. Benjamin, MD, executive director of the American Public Health Association, in a statement.

David J. Skorton, MD, chief executive and president of the Association of American Medical Colleges (AAMC) also urged increased investment in fighting disease.

“We must continue the bipartisan budget trajectory set forth by Congress over the last several years, not reverse course,” Dr. Skorton said in a statement.

Mr. Trump’s proposed cuts in medical research “would thwart scientific progress on strategies to prevent, diagnose, treat, and cure medical conditions that affect countless patients nationwide,” he said.

In total, the new 2021 appropriations for HHS would fall by $9.46 billion to $85.667 billion under Mr. Trump’s proposal. Appropriations, also called discretionary budget authority, represents the operating budgets for federal agencies. These are decided through annual spending bills.

Congress has separate sets of laws for handling payments the federal government makes through Medicare and Medicaid. These are known as mandatory spending.

‘Untenable cuts’

AAMC’s Dr. Skorton also objected to what he termed Mr. Trump’s bid “to reduce and consolidate Medicare, Medicaid, and children’s hospital graduate medical education into a single grant program.”

This would force teaching hospitals to absorb $52 billion in “untenable cuts,” he said.

“The proposal ignores the intent of the Medicare GME program, which is to ensure an adequate physician workforce to care for Medicare beneficiaries and support the critical patient care missions of America’s teaching hospitals,” Dr. Skorton said.

The budget also seeks cuts to Medicaid, which come in addition to the administration’s “recent proposals to scale back Medicaid coverage,” Dr. Skorton said.

“More than 26% of all Medicaid hospitalizations occur at AAMC-member teaching hospitals, even though these institutions represent only 5% of all hospitals,” Dr. Skorton said. “Each of the administration’s proposals on their own would be devastating for patients – and combined, they would be disastrous.”

Rick Pollack, the chief executive and president of the American Hospital Association, described Mr. Trump’s fiscal 2021 proposal as another bid to undermine medical care in the United States.

“Every year, we adapt to a constantly changing environment, but every year, the administration aims to gut our nation’s health care infrastructure,” Mr. Pollack said in a statement.

In it, he noted that about one in five people in America depend on Medicaid, with children accounting for a large proportion of those covered by the state-federal program.

“The budget’s proposal on Medicaid financing and service delivery would cut hundreds of billions of dollars from the Medicaid program annually,” Mr. Pollack said.

He also objected to “hundreds of billions of proposed reductions to Medicare” endorsed by Mr. Trump.

Medical malpractice overhaul

The Trump administration also offered many suggestions for changing federal laws to reduce health care spending. Among these was a proposed overhaul of the approach to medical malpractice cases.

The president’s budget proposal estimates $40 billion in savings over a decade from steps to limit medical liability, according to a report from the Office of Management and Budget (OMB).

“The current medical liability system does not work for patients or providers, nor does it promote high-quality, evidence-based care,” OMB said. “Providers practice with a threat of potentially frivolous lawsuits, and injured patients often do not receive just compensation for their injuries.”

Mr. Trump’s fiscal 2021 budget calls for a cap on noneconomic damage awards of $250,000, which would increase with inflation over time, and a 3-year statute of limitations. Under this plan, courts could also modify attorney’s fee arrangements. HHS could provide guidance to states on how to create expert panels and administrative health care tribunals to review medical liability.

These steps would lead to lower health care spending, with clinicians dropping “defensive medicine practices,” OMB said. That would benefit the Medicare and Medicaid programs as well as lowering costs of health insurance in general.

Mr. Trump’s fiscal 2021 budget also includes a series of proposals for Medicare that it estimates would, in aggregate, save $755.5 billion over a decade.

Site-neutral policy

A large chunk of the estimated Medicare savings in Mr. Trump’s fiscal 2021 health budget would come from lowering payments to hospitals for services provided in their outpatient and physician offices.

In the fiscal 2021 proposal, HHS noted that “Medicare generally pays on-campus hospital outpatient departments substantially more than physician offices for the same services.”

Mr. Trump’s budget proposal seeks a more expansive shift to what’s called a “site-neutral” payment for services delivered in hospital outpatient programs or physician offices. This would bring these payments more in line with those made to independent physician practices.

“This proposal would eliminate the often significant disparity between what Medicare pays in these different settings for the same services,” HHS said in the budget summary.

HHS estimated this change in policy would generate $117.2 billion in savings over a decade. Combined with saving from medical malpractice reforms, the Trump administration estimates these two moves combined could save about $164 billion over a decade.

The site-neutral policy has been a legal battleground, with hospital and physician groups winning a round last year. 

Another Medicare proposal included in Mr. Trump’s fiscal 2021 budget homes in on this issue for cases where a hospital owns a physician office. Medicare now pays most off-campus hospital outpatient departments higher rates than the program’s physician fee schedule dictates for the same services.

Switching to a site-neutral policy for these hospital-owned physician offices would result in $47.2 billion in savings over a decade, HHS said in the budget document.
 

This article first appeared on Medscape.com.

The Trump administration on Feb. 10 argued for cutting spending for a federal agency at the forefront of the efforts to combat the coronavirus, while also seeking to slow spending in certain parts of the Medicare and Medicaid programs.

President Donald Trump presented his fiscal 2021 request to Congress for refilling the coffers of federal agencies. In any administration, an annual budget serves only as a political blueprint, as the White House document itself makes no changes in federal spending.

In Mr. Trump’s case, several of his requests for agencies within the Department of Health & Human Services run counter to recent budget trends. Republicans and Democrats in Congress have worked together in recent years to increase budgets for major federal health agencies.

But Mr. Trump asked Congress to cut annual budget authority for the National Institute of Allergy and Infectious Diseases by $430 million to $5.446 billion for fiscal 2021. In contrast, Congress has raised the annual budget for NIAID, a key agency in combating the coronavirus, from $5.545 billion in fiscal 2019 to $5.876 billion in fiscal 2020, which began in October, according to an HHS summary of Mr. Trump’s request.

For the Centers for Disease Control and Prevention, which is central to the battle against the coronavirus, Mr. Trump proposed a drop in discretionary funding to $5.627 billion. In contrast, Congress raised the CDC budget from $6.544 billion in fiscal 2019 to $6.917 in fiscal 2020.

Mr. Trump also wants to cut $559 million from the budget of the National Cancer Institute, dropping it to $5.881 billion in fiscal 2021. In contrast, Congress raised NCI’s budget from $6.121 billion in fiscal 2019 to $6.440 billion in fiscal 2020.

Mr. Trump requested a $2.6 billion reduction in the National Institutes of Health’s total discretionary budget, seeking to drop it to $37.70 billion. In contrast, Congress raised NIH’s budget from $37.887 in fiscal 2019 to $40.304 billion in fiscal 2020.

Mr. Trump’s budget proposal also includes an estimate of $152 billion in savings over a decade for Medicaid through the implementation of what the administration calls “community engagement” requirements.

The Trump administration has been at odds with Democrats for years about whether work requirements should be attached to Medicaid. “Well-designed community engagement incentives have great potential to improve health and well-being while empowering beneficiaries to rise out of poverty,” HHS said in a budget document.

Yet researchers last year reported that Arkansas’ attempt to attach work requirements to Medicaid caused almost 17,000 adults to lose this health care coverage within the first 6 months, and there was no significant difference in employment.

The researchers say this loss of coverage was partly a result of bureaucratic obstacles and confusion about the new rules. In June 2018, Arkansas became the first state to implement work requirements for Medicaid, Benjamin D. Sommers, MD, PhD, of the Harvard T.H. Chan School of Public Health, Boston, and colleagues wrote in the New England Journal of Medicine (2019 Sep 12;381[11]:1073-82). 

Budget ‘would thwart’ progress

A few medical groups on Monday quickly criticized Mr. Trump’s proposals.

“In a time where our nation continues to face significant public health challenges — including 2019 novel coronavirus, climate change, gun violence, and costly chronic diseases such as heart disease and cancer – the administration should be investing more resources in better health, not cutting federal health budgets,” said Georges C. Benjamin, MD, executive director of the American Public Health Association, in a statement.

David J. Skorton, MD, chief executive and president of the Association of American Medical Colleges (AAMC) also urged increased investment in fighting disease.

“We must continue the bipartisan budget trajectory set forth by Congress over the last several years, not reverse course,” Dr. Skorton said in a statement.

Mr. Trump’s proposed cuts in medical research “would thwart scientific progress on strategies to prevent, diagnose, treat, and cure medical conditions that affect countless patients nationwide,” he said.

In total, the new 2021 appropriations for HHS would fall by $9.46 billion to $85.667 billion under Mr. Trump’s proposal. Appropriations, also called discretionary budget authority, represents the operating budgets for federal agencies. These are decided through annual spending bills.

Congress has separate sets of laws for handling payments the federal government makes through Medicare and Medicaid. These are known as mandatory spending.

‘Untenable cuts’

AAMC’s Dr. Skorton also objected to what he termed Mr. Trump’s bid “to reduce and consolidate Medicare, Medicaid, and children’s hospital graduate medical education into a single grant program.”

This would force teaching hospitals to absorb $52 billion in “untenable cuts,” he said.

“The proposal ignores the intent of the Medicare GME program, which is to ensure an adequate physician workforce to care for Medicare beneficiaries and support the critical patient care missions of America’s teaching hospitals,” Dr. Skorton said.

The budget also seeks cuts to Medicaid, which come in addition to the administration’s “recent proposals to scale back Medicaid coverage,” Dr. Skorton said.

“More than 26% of all Medicaid hospitalizations occur at AAMC-member teaching hospitals, even though these institutions represent only 5% of all hospitals,” Dr. Skorton said. “Each of the administration’s proposals on their own would be devastating for patients – and combined, they would be disastrous.”

Rick Pollack, the chief executive and president of the American Hospital Association, described Mr. Trump’s fiscal 2021 proposal as another bid to undermine medical care in the United States.

“Every year, we adapt to a constantly changing environment, but every year, the administration aims to gut our nation’s health care infrastructure,” Mr. Pollack said in a statement.

In it, he noted that about one in five people in America depend on Medicaid, with children accounting for a large proportion of those covered by the state-federal program.

“The budget’s proposal on Medicaid financing and service delivery would cut hundreds of billions of dollars from the Medicaid program annually,” Mr. Pollack said.

He also objected to “hundreds of billions of proposed reductions to Medicare” endorsed by Mr. Trump.

Medical malpractice overhaul

The Trump administration also offered many suggestions for changing federal laws to reduce health care spending. Among these was a proposed overhaul of the approach to medical malpractice cases.

The president’s budget proposal estimates $40 billion in savings over a decade from steps to limit medical liability, according to a report from the Office of Management and Budget (OMB).

“The current medical liability system does not work for patients or providers, nor does it promote high-quality, evidence-based care,” OMB said. “Providers practice with a threat of potentially frivolous lawsuits, and injured patients often do not receive just compensation for their injuries.”

Mr. Trump’s fiscal 2021 budget calls for a cap on noneconomic damage awards of $250,000, which would increase with inflation over time, and a 3-year statute of limitations. Under this plan, courts could also modify attorney’s fee arrangements. HHS could provide guidance to states on how to create expert panels and administrative health care tribunals to review medical liability.

These steps would lead to lower health care spending, with clinicians dropping “defensive medicine practices,” OMB said. That would benefit the Medicare and Medicaid programs as well as lowering costs of health insurance in general.

Mr. Trump’s fiscal 2021 budget also includes a series of proposals for Medicare that it estimates would, in aggregate, save $755.5 billion over a decade.

Site-neutral policy

A large chunk of the estimated Medicare savings in Mr. Trump’s fiscal 2021 health budget would come from lowering payments to hospitals for services provided in their outpatient and physician offices.

In the fiscal 2021 proposal, HHS noted that “Medicare generally pays on-campus hospital outpatient departments substantially more than physician offices for the same services.”

Mr. Trump’s budget proposal seeks a more expansive shift to what’s called a “site-neutral” payment for services delivered in hospital outpatient programs or physician offices. This would bring these payments more in line with those made to independent physician practices.

“This proposal would eliminate the often significant disparity between what Medicare pays in these different settings for the same services,” HHS said in the budget summary.

HHS estimated this change in policy would generate $117.2 billion in savings over a decade. Combined with saving from medical malpractice reforms, the Trump administration estimates these two moves combined could save about $164 billion over a decade.

The site-neutral policy has been a legal battleground, with hospital and physician groups winning a round last year. 

Another Medicare proposal included in Mr. Trump’s fiscal 2021 budget homes in on this issue for cases where a hospital owns a physician office. Medicare now pays most off-campus hospital outpatient departments higher rates than the program’s physician fee schedule dictates for the same services.

Switching to a site-neutral policy for these hospital-owned physician offices would result in $47.2 billion in savings over a decade, HHS said in the budget document.
 

This article first appeared on Medscape.com.

The Trump administration on Feb. 10 argued for cutting spending for a federal agency at the forefront of the efforts to combat the coronavirus, while also seeking to slow spending in certain parts of the Medicare and Medicaid programs.

President Donald Trump presented his fiscal 2021 request to Congress for refilling the coffers of federal agencies. In any administration, an annual budget serves only as a political blueprint, as the White House document itself makes no changes in federal spending.

In Mr. Trump’s case, several of his requests for agencies within the Department of Health & Human Services run counter to recent budget trends. Republicans and Democrats in Congress have worked together in recent years to increase budgets for major federal health agencies.

But Mr. Trump asked Congress to cut annual budget authority for the National Institute of Allergy and Infectious Diseases by $430 million to $5.446 billion for fiscal 2021. In contrast, Congress has raised the annual budget for NIAID, a key agency in combating the coronavirus, from $5.545 billion in fiscal 2019 to $5.876 billion in fiscal 2020, which began in October, according to an HHS summary of Mr. Trump’s request.

For the Centers for Disease Control and Prevention, which is central to the battle against the coronavirus, Mr. Trump proposed a drop in discretionary funding to $5.627 billion. In contrast, Congress raised the CDC budget from $6.544 billion in fiscal 2019 to $6.917 in fiscal 2020.

Mr. Trump also wants to cut $559 million from the budget of the National Cancer Institute, dropping it to $5.881 billion in fiscal 2021. In contrast, Congress raised NCI’s budget from $6.121 billion in fiscal 2019 to $6.440 billion in fiscal 2020.

Mr. Trump requested a $2.6 billion reduction in the National Institutes of Health’s total discretionary budget, seeking to drop it to $37.70 billion. In contrast, Congress raised NIH’s budget from $37.887 in fiscal 2019 to $40.304 billion in fiscal 2020.

Mr. Trump’s budget proposal also includes an estimate of $152 billion in savings over a decade for Medicaid through the implementation of what the administration calls “community engagement” requirements.

The Trump administration has been at odds with Democrats for years about whether work requirements should be attached to Medicaid. “Well-designed community engagement incentives have great potential to improve health and well-being while empowering beneficiaries to rise out of poverty,” HHS said in a budget document.

Yet researchers last year reported that Arkansas’ attempt to attach work requirements to Medicaid caused almost 17,000 adults to lose this health care coverage within the first 6 months, and there was no significant difference in employment.

The researchers say this loss of coverage was partly a result of bureaucratic obstacles and confusion about the new rules. In June 2018, Arkansas became the first state to implement work requirements for Medicaid, Benjamin D. Sommers, MD, PhD, of the Harvard T.H. Chan School of Public Health, Boston, and colleagues wrote in the New England Journal of Medicine (2019 Sep 12;381[11]:1073-82). 

Budget ‘would thwart’ progress

A few medical groups on Monday quickly criticized Mr. Trump’s proposals.

“In a time where our nation continues to face significant public health challenges — including 2019 novel coronavirus, climate change, gun violence, and costly chronic diseases such as heart disease and cancer – the administration should be investing more resources in better health, not cutting federal health budgets,” said Georges C. Benjamin, MD, executive director of the American Public Health Association, in a statement.

David J. Skorton, MD, chief executive and president of the Association of American Medical Colleges (AAMC) also urged increased investment in fighting disease.

“We must continue the bipartisan budget trajectory set forth by Congress over the last several years, not reverse course,” Dr. Skorton said in a statement.

Mr. Trump’s proposed cuts in medical research “would thwart scientific progress on strategies to prevent, diagnose, treat, and cure medical conditions that affect countless patients nationwide,” he said.

In total, the new 2021 appropriations for HHS would fall by $9.46 billion to $85.667 billion under Mr. Trump’s proposal. Appropriations, also called discretionary budget authority, represents the operating budgets for federal agencies. These are decided through annual spending bills.

Congress has separate sets of laws for handling payments the federal government makes through Medicare and Medicaid. These are known as mandatory spending.

‘Untenable cuts’

AAMC’s Dr. Skorton also objected to what he termed Mr. Trump’s bid “to reduce and consolidate Medicare, Medicaid, and children’s hospital graduate medical education into a single grant program.”

This would force teaching hospitals to absorb $52 billion in “untenable cuts,” he said.

“The proposal ignores the intent of the Medicare GME program, which is to ensure an adequate physician workforce to care for Medicare beneficiaries and support the critical patient care missions of America’s teaching hospitals,” Dr. Skorton said.

The budget also seeks cuts to Medicaid, which come in addition to the administration’s “recent proposals to scale back Medicaid coverage,” Dr. Skorton said.

“More than 26% of all Medicaid hospitalizations occur at AAMC-member teaching hospitals, even though these institutions represent only 5% of all hospitals,” Dr. Skorton said. “Each of the administration’s proposals on their own would be devastating for patients – and combined, they would be disastrous.”

Rick Pollack, the chief executive and president of the American Hospital Association, described Mr. Trump’s fiscal 2021 proposal as another bid to undermine medical care in the United States.

“Every year, we adapt to a constantly changing environment, but every year, the administration aims to gut our nation’s health care infrastructure,” Mr. Pollack said in a statement.

In it, he noted that about one in five people in America depend on Medicaid, with children accounting for a large proportion of those covered by the state-federal program.

“The budget’s proposal on Medicaid financing and service delivery would cut hundreds of billions of dollars from the Medicaid program annually,” Mr. Pollack said.

He also objected to “hundreds of billions of proposed reductions to Medicare” endorsed by Mr. Trump.

Medical malpractice overhaul

The Trump administration also offered many suggestions for changing federal laws to reduce health care spending. Among these was a proposed overhaul of the approach to medical malpractice cases.

The president’s budget proposal estimates $40 billion in savings over a decade from steps to limit medical liability, according to a report from the Office of Management and Budget (OMB).

“The current medical liability system does not work for patients or providers, nor does it promote high-quality, evidence-based care,” OMB said. “Providers practice with a threat of potentially frivolous lawsuits, and injured patients often do not receive just compensation for their injuries.”

Mr. Trump’s fiscal 2021 budget calls for a cap on noneconomic damage awards of $250,000, which would increase with inflation over time, and a 3-year statute of limitations. Under this plan, courts could also modify attorney’s fee arrangements. HHS could provide guidance to states on how to create expert panels and administrative health care tribunals to review medical liability.

These steps would lead to lower health care spending, with clinicians dropping “defensive medicine practices,” OMB said. That would benefit the Medicare and Medicaid programs as well as lowering costs of health insurance in general.

Mr. Trump’s fiscal 2021 budget also includes a series of proposals for Medicare that it estimates would, in aggregate, save $755.5 billion over a decade.

Site-neutral policy

A large chunk of the estimated Medicare savings in Mr. Trump’s fiscal 2021 health budget would come from lowering payments to hospitals for services provided in their outpatient and physician offices.

In the fiscal 2021 proposal, HHS noted that “Medicare generally pays on-campus hospital outpatient departments substantially more than physician offices for the same services.”

Mr. Trump’s budget proposal seeks a more expansive shift to what’s called a “site-neutral” payment for services delivered in hospital outpatient programs or physician offices. This would bring these payments more in line with those made to independent physician practices.

“This proposal would eliminate the often significant disparity between what Medicare pays in these different settings for the same services,” HHS said in the budget summary.

HHS estimated this change in policy would generate $117.2 billion in savings over a decade. Combined with saving from medical malpractice reforms, the Trump administration estimates these two moves combined could save about $164 billion over a decade.

The site-neutral policy has been a legal battleground, with hospital and physician groups winning a round last year. 

Another Medicare proposal included in Mr. Trump’s fiscal 2021 budget homes in on this issue for cases where a hospital owns a physician office. Medicare now pays most off-campus hospital outpatient departments higher rates than the program’s physician fee schedule dictates for the same services.

Switching to a site-neutral policy for these hospital-owned physician offices would result in $47.2 billion in savings over a decade, HHS said in the budget document.
 

This article first appeared on Medscape.com.

Clinical trials supporting Food and Drug Adminstration approval of contemporary cancer therapies frequently failed to capture major adverse cardiovascular events (MACE) and, when they did, reported rates 2.6-fold lower than noncancer trials, new research shows.

Overall, 51.3% of trials did not report MACE, with that number reaching 57.6% in trials enrolling patients with baseline cardiovascular disease (CVD).

Nearly 40% of trials did not report any CVD events in follow-up, the authors reported online Feb. 10, 2020, in the Journal of the American College of Cardiology (2020;75:620-8).

“Even in drug classes where there were established or emerging associations with cardiotoxic events, often there were no reported heart events or cardiovascular events across years of follow-up in trials that examined hundreds or even thousands of patients. That was actually pretty surprising,” senior author Daniel Addison, MD, codirector of the cardio-oncology program at the Ohio State University Medical Center, Columbus, said in an interview.

The study was prompted by a series of events that crescendoed when his team was called to the ICU to determine whether a novel targeted agent played a role in the heart decline of a patient with acute myeloid leukemia. “I had a resident ask me a very important question: ‘How do we really know for sure that the trial actually reflects the true risk of heart events?’ to which I told him, ‘it’s difficult to know,’ ” he said.

“I think many of us rely heavily on what we see in the trials, particularly when they make it to the top journals, and quite frankly, we generally take it at face value,” Dr. Addison observed.
 

Lower Rate of Reported Events

The investigators reviewed CV events reported in 97,365 patients (median age, 61 years; 46% female) enrolled in 189 phase 2 and 3 trials supporting FDA approval of 123 anticancer drugs from 1998 to 2018. Biologic, targeted, or immune-based therapies accounted for 72.5% of drug approvals.

Over 148,138 person-years of follow-up (median trial duration, 30 months), there were 1,148 incidents of MACE (375 heart failure, 253 MIs, 180 strokes, 65 atrial fibrillation, 29 coronary revascularizations, and 246 CVD deaths). MACE rates were higher in the intervention group than in the control group (792 vs. 356; P less than .01). Among the 64 trials that excluded patients with baseline CVD, there were 269 incidents of MACE.

To put this finding in context, the researchers examined the reported incidence of MACE among some 6,000 similarly aged participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The overall weighted-average incidence rate was 1,408 per 100,000 person-years among MESA participants, compared with 542 events per 100,000 person-years among oncology trial participants (716 per 100,000 in the intervention arm). This represents a reported-to-expected ratio of 0.38 – a 2.6-fold lower rate of reported events (P less than .001) – and a risk difference of 866.

Further, MACE reporting was lower by a factor of 1.7 among all cancer trial participants irrespective of baseline CVD status (reported-to-expected ratio, 0.56; risk difference, 613; P less than .001).

There was no significant difference in MACE reporting between independent or industry-sponsored trials, the authors report.
 

No malicious intent

“There are likely some that might lean toward not wanting to attribute blame to a new drug when the drug is in a study, but I really think that the leading factor is lack of awareness,” Dr. Addison said. “I’ve talked with several cancer collaborators around the country who run large clinical trials, and I think often, when an event may be brought to someone’s attention, there is a tendency to just write it off as kind of a generic expected event due to age, or just something that’s not really pertinent to the study. So they don’t really focus on it as much.”

“Closer collaboration between cardiologists and cancer physicians is needed to better determine true cardiac risks among patients treated with these drugs.”

Breast cancer oncologist Marc E. Lippman, MD, of Georgetown University Medical Center and Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., isn’t convinced a lack of awareness is the culprit.

“I don’t agree with that at all,” he said in an interview. “I think there are very, very clear rules and guidelines these days for adverse-event reporting. I think that’s not a very likely explanation – that it’s not on the radar.”

Part of the problem may be that some of the toxicities, particularly cardiovascular, may not emerge for years, he said. Participant screening for the trials also likely removed patients with high cardiovascular risk. “It’s very understandable to me – I’m not saying it’s good particularly – but I think it’s very understandable that, if you’re trying to develop a drug, the last thing you’d want to have is a lot of toxicity that you might have avoided by just being restrictive in who you let into the study,” Dr. Lippman said.

The underreported CVD events may also reflect the rapidly changing profile of cardiovascular toxicities associated with novel anticancer therapies.

“Providers, both cancer and noncancer, generally put cardiotoxicity in the box of anthracyclines and radiation, but particularly over the last decade, we’ve begun to understand it’s well beyond any one class of drugs,” Dr. Addison said.

“I agree completely,” Dr. Lippman said. For example, “the checkpoint inhibitors are so unbelievably different in terms of their toxicities that many people simply didn’t even know what they were getting into at first.”
 

One size does not fit all

Javid Moslehi, MD, director of the cardio-oncology program at Vanderbilt University, Nashville, Tenn., said echocardiography – recommended to detect changes in left ventricular function in patients exposed to anthracyclines or targeted agents like trastuzumab (Herceptin) – isn’t enough to address today’s cancer therapy–related CVD events.

Courtesy Joe Howell

“Initial drugs like anthracyclines or Herceptin in cardio-oncology were associated with systolic cardiac dysfunction, whereas the majority of issues we see in the cardio-oncology clinics today are vascular, metabolic, arrhythmogenic, and inflammatory,” he said in an interview. “Echocardiography misses the big and increasingly complex picture.”

His group, for example, has been studying myocarditis associated with immunotherapies, but none of the clinical trials require screening or surveillance for myocarditis with a cardiac biomarker like troponin.

The group also recently identified 303 deaths in patients exposed to ibrutinib, a drug that revolutionized the treatment of several B-cell malignancies but is associated with higher rates of atrial fibrillation, which is also associated with increased bleeding risk. “So there’s a little bit of a double whammy there, given that we often treat atrial fibrillation with anticoagulation and where we can cause complications in patients,” Dr. Moslehi noted.

Although there needs to be closer collaboration between cardiologists and oncologists on individual trials, cardiologists also have to realize that oncology care has become very personalized, he suggested.

“What’s probably relevant for the breast cancer patient may not be relevant for the prostate cancer patient and their respective treatments,” Dr. Moslehi said. “So if we were to say, ‘every person should get an echo,’ that may be less relevant to the prostate cancer patient where treatments can cause vascular and metabolic perturbations or to the patient treated with immunotherapy who may have myocarditis, where many of the echos can be normal. There’s no one-size-fits-all for these things.”

Wearable technologies like smartwatches could play a role in improving the reporting of CVD events with novel therapies but a lot more research needs to be done to validate these tools, Dr. Addison said. “But as we continue on into the 21st century, this is going to expand and may potentially help us,” he added.

In the interim, better standardization is needed of the cardiovascular events reported in oncology trials, particularly the Common Terminology Criteria for Adverse Events (CTCAE), said Dr. Moslehi, who also serves as chair of the American Heart Association’s subcommittee on cardio-oncology.

“Cardiovascular definitions are not exactly uniform and are not consistent with what we in cardiology consider to be important or relevant,” he said. “So I think there needs to be better standardization of these definitions, specifically within the CTCAE, which is what the oncologists use to identify adverse events.”

In a linked editorial (J Am Coll Cardiol. 2020;75:629-31), Dr. Lippman and cardiologist Nanette Bishopric, MD, of the Medstar Heart and Vascular Institute in Washington, D.C., suggested it may also be time to organize a consortium that can carry out “rigorous multicenter clinical investigations to evaluate the cardiotoxicity of emerging cancer treatments,” similar to the Thrombosis in Myocardial Infarction Study Group.

“The success of this consortium in pioneering and targeting multiple generations of drugs for the treatment of MI, involving tens of thousands of patients and thousands of collaborations across multiple national borders, is a model for how to move forward in providing the new hope of cancer cure without the trade-off of years lost to heart disease,” the editorialists concluded.

The study was supported in part by National Institutes of Health grants, including a K12-CA133250 grant to Dr. Addison. Dr. Bishopric reported being on the scientific board of C&C Biopharma. Dr. Lippman reports being on the board of directors of and holding stock in Seattle Genetics. Dr. Moslehi reported having served on advisory boards for Pfizer, Novartis, Bristol-Myers Squibb, Deciphera, Audentes Pharmaceuticals, Nektar, Takeda, Ipsen, Myokardia, AstraZeneca, GlaxoSmithKline, Intrexon, and Regeneron.

This article first appeared on Medscape.com.

Clinical trials supporting Food and Drug Adminstration approval of contemporary cancer therapies frequently failed to capture major adverse cardiovascular events (MACE) and, when they did, reported rates 2.6-fold lower than noncancer trials, new research shows.

Overall, 51.3% of trials did not report MACE, with that number reaching 57.6% in trials enrolling patients with baseline cardiovascular disease (CVD).

Nearly 40% of trials did not report any CVD events in follow-up, the authors reported online Feb. 10, 2020, in the Journal of the American College of Cardiology (2020;75:620-8).

“Even in drug classes where there were established or emerging associations with cardiotoxic events, often there were no reported heart events or cardiovascular events across years of follow-up in trials that examined hundreds or even thousands of patients. That was actually pretty surprising,” senior author Daniel Addison, MD, codirector of the cardio-oncology program at the Ohio State University Medical Center, Columbus, said in an interview.

The study was prompted by a series of events that crescendoed when his team was called to the ICU to determine whether a novel targeted agent played a role in the heart decline of a patient with acute myeloid leukemia. “I had a resident ask me a very important question: ‘How do we really know for sure that the trial actually reflects the true risk of heart events?’ to which I told him, ‘it’s difficult to know,’ ” he said.

“I think many of us rely heavily on what we see in the trials, particularly when they make it to the top journals, and quite frankly, we generally take it at face value,” Dr. Addison observed.
 

Lower Rate of Reported Events

The investigators reviewed CV events reported in 97,365 patients (median age, 61 years; 46% female) enrolled in 189 phase 2 and 3 trials supporting FDA approval of 123 anticancer drugs from 1998 to 2018. Biologic, targeted, or immune-based therapies accounted for 72.5% of drug approvals.

Over 148,138 person-years of follow-up (median trial duration, 30 months), there were 1,148 incidents of MACE (375 heart failure, 253 MIs, 180 strokes, 65 atrial fibrillation, 29 coronary revascularizations, and 246 CVD deaths). MACE rates were higher in the intervention group than in the control group (792 vs. 356; P less than .01). Among the 64 trials that excluded patients with baseline CVD, there were 269 incidents of MACE.

To put this finding in context, the researchers examined the reported incidence of MACE among some 6,000 similarly aged participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The overall weighted-average incidence rate was 1,408 per 100,000 person-years among MESA participants, compared with 542 events per 100,000 person-years among oncology trial participants (716 per 100,000 in the intervention arm). This represents a reported-to-expected ratio of 0.38 – a 2.6-fold lower rate of reported events (P less than .001) – and a risk difference of 866.

Further, MACE reporting was lower by a factor of 1.7 among all cancer trial participants irrespective of baseline CVD status (reported-to-expected ratio, 0.56; risk difference, 613; P less than .001).

There was no significant difference in MACE reporting between independent or industry-sponsored trials, the authors report.
 

No malicious intent

“There are likely some that might lean toward not wanting to attribute blame to a new drug when the drug is in a study, but I really think that the leading factor is lack of awareness,” Dr. Addison said. “I’ve talked with several cancer collaborators around the country who run large clinical trials, and I think often, when an event may be brought to someone’s attention, there is a tendency to just write it off as kind of a generic expected event due to age, or just something that’s not really pertinent to the study. So they don’t really focus on it as much.”

“Closer collaboration between cardiologists and cancer physicians is needed to better determine true cardiac risks among patients treated with these drugs.”

Breast cancer oncologist Marc E. Lippman, MD, of Georgetown University Medical Center and Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., isn’t convinced a lack of awareness is the culprit.

“I don’t agree with that at all,” he said in an interview. “I think there are very, very clear rules and guidelines these days for adverse-event reporting. I think that’s not a very likely explanation – that it’s not on the radar.”

Part of the problem may be that some of the toxicities, particularly cardiovascular, may not emerge for years, he said. Participant screening for the trials also likely removed patients with high cardiovascular risk. “It’s very understandable to me – I’m not saying it’s good particularly – but I think it’s very understandable that, if you’re trying to develop a drug, the last thing you’d want to have is a lot of toxicity that you might have avoided by just being restrictive in who you let into the study,” Dr. Lippman said.

The underreported CVD events may also reflect the rapidly changing profile of cardiovascular toxicities associated with novel anticancer therapies.

“Providers, both cancer and noncancer, generally put cardiotoxicity in the box of anthracyclines and radiation, but particularly over the last decade, we’ve begun to understand it’s well beyond any one class of drugs,” Dr. Addison said.

“I agree completely,” Dr. Lippman said. For example, “the checkpoint inhibitors are so unbelievably different in terms of their toxicities that many people simply didn’t even know what they were getting into at first.”
 

One size does not fit all

Javid Moslehi, MD, director of the cardio-oncology program at Vanderbilt University, Nashville, Tenn., said echocardiography – recommended to detect changes in left ventricular function in patients exposed to anthracyclines or targeted agents like trastuzumab (Herceptin) – isn’t enough to address today’s cancer therapy–related CVD events.

Courtesy Joe Howell

“Initial drugs like anthracyclines or Herceptin in cardio-oncology were associated with systolic cardiac dysfunction, whereas the majority of issues we see in the cardio-oncology clinics today are vascular, metabolic, arrhythmogenic, and inflammatory,” he said in an interview. “Echocardiography misses the big and increasingly complex picture.”

His group, for example, has been studying myocarditis associated with immunotherapies, but none of the clinical trials require screening or surveillance for myocarditis with a cardiac biomarker like troponin.

The group also recently identified 303 deaths in patients exposed to ibrutinib, a drug that revolutionized the treatment of several B-cell malignancies but is associated with higher rates of atrial fibrillation, which is also associated with increased bleeding risk. “So there’s a little bit of a double whammy there, given that we often treat atrial fibrillation with anticoagulation and where we can cause complications in patients,” Dr. Moslehi noted.

Although there needs to be closer collaboration between cardiologists and oncologists on individual trials, cardiologists also have to realize that oncology care has become very personalized, he suggested.

“What’s probably relevant for the breast cancer patient may not be relevant for the prostate cancer patient and their respective treatments,” Dr. Moslehi said. “So if we were to say, ‘every person should get an echo,’ that may be less relevant to the prostate cancer patient where treatments can cause vascular and metabolic perturbations or to the patient treated with immunotherapy who may have myocarditis, where many of the echos can be normal. There’s no one-size-fits-all for these things.”

Wearable technologies like smartwatches could play a role in improving the reporting of CVD events with novel therapies but a lot more research needs to be done to validate these tools, Dr. Addison said. “But as we continue on into the 21st century, this is going to expand and may potentially help us,” he added.

In the interim, better standardization is needed of the cardiovascular events reported in oncology trials, particularly the Common Terminology Criteria for Adverse Events (CTCAE), said Dr. Moslehi, who also serves as chair of the American Heart Association’s subcommittee on cardio-oncology.

“Cardiovascular definitions are not exactly uniform and are not consistent with what we in cardiology consider to be important or relevant,” he said. “So I think there needs to be better standardization of these definitions, specifically within the CTCAE, which is what the oncologists use to identify adverse events.”

In a linked editorial (J Am Coll Cardiol. 2020;75:629-31), Dr. Lippman and cardiologist Nanette Bishopric, MD, of the Medstar Heart and Vascular Institute in Washington, D.C., suggested it may also be time to organize a consortium that can carry out “rigorous multicenter clinical investigations to evaluate the cardiotoxicity of emerging cancer treatments,” similar to the Thrombosis in Myocardial Infarction Study Group.

“The success of this consortium in pioneering and targeting multiple generations of drugs for the treatment of MI, involving tens of thousands of patients and thousands of collaborations across multiple national borders, is a model for how to move forward in providing the new hope of cancer cure without the trade-off of years lost to heart disease,” the editorialists concluded.

The study was supported in part by National Institutes of Health grants, including a K12-CA133250 grant to Dr. Addison. Dr. Bishopric reported being on the scientific board of C&C Biopharma. Dr. Lippman reports being on the board of directors of and holding stock in Seattle Genetics. Dr. Moslehi reported having served on advisory boards for Pfizer, Novartis, Bristol-Myers Squibb, Deciphera, Audentes Pharmaceuticals, Nektar, Takeda, Ipsen, Myokardia, AstraZeneca, GlaxoSmithKline, Intrexon, and Regeneron.

This article first appeared on Medscape.com.

Clinical trials supporting Food and Drug Adminstration approval of contemporary cancer therapies frequently failed to capture major adverse cardiovascular events (MACE) and, when they did, reported rates 2.6-fold lower than noncancer trials, new research shows.

Overall, 51.3% of trials did not report MACE, with that number reaching 57.6% in trials enrolling patients with baseline cardiovascular disease (CVD).

Nearly 40% of trials did not report any CVD events in follow-up, the authors reported online Feb. 10, 2020, in the Journal of the American College of Cardiology (2020;75:620-8).

“Even in drug classes where there were established or emerging associations with cardiotoxic events, often there were no reported heart events or cardiovascular events across years of follow-up in trials that examined hundreds or even thousands of patients. That was actually pretty surprising,” senior author Daniel Addison, MD, codirector of the cardio-oncology program at the Ohio State University Medical Center, Columbus, said in an interview.

The study was prompted by a series of events that crescendoed when his team was called to the ICU to determine whether a novel targeted agent played a role in the heart decline of a patient with acute myeloid leukemia. “I had a resident ask me a very important question: ‘How do we really know for sure that the trial actually reflects the true risk of heart events?’ to which I told him, ‘it’s difficult to know,’ ” he said.

“I think many of us rely heavily on what we see in the trials, particularly when they make it to the top journals, and quite frankly, we generally take it at face value,” Dr. Addison observed.
 

Lower Rate of Reported Events

The investigators reviewed CV events reported in 97,365 patients (median age, 61 years; 46% female) enrolled in 189 phase 2 and 3 trials supporting FDA approval of 123 anticancer drugs from 1998 to 2018. Biologic, targeted, or immune-based therapies accounted for 72.5% of drug approvals.

Over 148,138 person-years of follow-up (median trial duration, 30 months), there were 1,148 incidents of MACE (375 heart failure, 253 MIs, 180 strokes, 65 atrial fibrillation, 29 coronary revascularizations, and 246 CVD deaths). MACE rates were higher in the intervention group than in the control group (792 vs. 356; P less than .01). Among the 64 trials that excluded patients with baseline CVD, there were 269 incidents of MACE.

To put this finding in context, the researchers examined the reported incidence of MACE among some 6,000 similarly aged participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The overall weighted-average incidence rate was 1,408 per 100,000 person-years among MESA participants, compared with 542 events per 100,000 person-years among oncology trial participants (716 per 100,000 in the intervention arm). This represents a reported-to-expected ratio of 0.38 – a 2.6-fold lower rate of reported events (P less than .001) – and a risk difference of 866.

Further, MACE reporting was lower by a factor of 1.7 among all cancer trial participants irrespective of baseline CVD status (reported-to-expected ratio, 0.56; risk difference, 613; P less than .001).

There was no significant difference in MACE reporting between independent or industry-sponsored trials, the authors report.
 

No malicious intent

“There are likely some that might lean toward not wanting to attribute blame to a new drug when the drug is in a study, but I really think that the leading factor is lack of awareness,” Dr. Addison said. “I’ve talked with several cancer collaborators around the country who run large clinical trials, and I think often, when an event may be brought to someone’s attention, there is a tendency to just write it off as kind of a generic expected event due to age, or just something that’s not really pertinent to the study. So they don’t really focus on it as much.”

“Closer collaboration between cardiologists and cancer physicians is needed to better determine true cardiac risks among patients treated with these drugs.”

Breast cancer oncologist Marc E. Lippman, MD, of Georgetown University Medical Center and Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., isn’t convinced a lack of awareness is the culprit.

“I don’t agree with that at all,” he said in an interview. “I think there are very, very clear rules and guidelines these days for adverse-event reporting. I think that’s not a very likely explanation – that it’s not on the radar.”

Part of the problem may be that some of the toxicities, particularly cardiovascular, may not emerge for years, he said. Participant screening for the trials also likely removed patients with high cardiovascular risk. “It’s very understandable to me – I’m not saying it’s good particularly – but I think it’s very understandable that, if you’re trying to develop a drug, the last thing you’d want to have is a lot of toxicity that you might have avoided by just being restrictive in who you let into the study,” Dr. Lippman said.

The underreported CVD events may also reflect the rapidly changing profile of cardiovascular toxicities associated with novel anticancer therapies.

“Providers, both cancer and noncancer, generally put cardiotoxicity in the box of anthracyclines and radiation, but particularly over the last decade, we’ve begun to understand it’s well beyond any one class of drugs,” Dr. Addison said.

“I agree completely,” Dr. Lippman said. For example, “the checkpoint inhibitors are so unbelievably different in terms of their toxicities that many people simply didn’t even know what they were getting into at first.”
 

One size does not fit all

Javid Moslehi, MD, director of the cardio-oncology program at Vanderbilt University, Nashville, Tenn., said echocardiography – recommended to detect changes in left ventricular function in patients exposed to anthracyclines or targeted agents like trastuzumab (Herceptin) – isn’t enough to address today’s cancer therapy–related CVD events.

Courtesy Joe Howell

“Initial drugs like anthracyclines or Herceptin in cardio-oncology were associated with systolic cardiac dysfunction, whereas the majority of issues we see in the cardio-oncology clinics today are vascular, metabolic, arrhythmogenic, and inflammatory,” he said in an interview. “Echocardiography misses the big and increasingly complex picture.”

His group, for example, has been studying myocarditis associated with immunotherapies, but none of the clinical trials require screening or surveillance for myocarditis with a cardiac biomarker like troponin.

The group also recently identified 303 deaths in patients exposed to ibrutinib, a drug that revolutionized the treatment of several B-cell malignancies but is associated with higher rates of atrial fibrillation, which is also associated with increased bleeding risk. “So there’s a little bit of a double whammy there, given that we often treat atrial fibrillation with anticoagulation and where we can cause complications in patients,” Dr. Moslehi noted.

Although there needs to be closer collaboration between cardiologists and oncologists on individual trials, cardiologists also have to realize that oncology care has become very personalized, he suggested.

“What’s probably relevant for the breast cancer patient may not be relevant for the prostate cancer patient and their respective treatments,” Dr. Moslehi said. “So if we were to say, ‘every person should get an echo,’ that may be less relevant to the prostate cancer patient where treatments can cause vascular and metabolic perturbations or to the patient treated with immunotherapy who may have myocarditis, where many of the echos can be normal. There’s no one-size-fits-all for these things.”

Wearable technologies like smartwatches could play a role in improving the reporting of CVD events with novel therapies but a lot more research needs to be done to validate these tools, Dr. Addison said. “But as we continue on into the 21st century, this is going to expand and may potentially help us,” he added.

In the interim, better standardization is needed of the cardiovascular events reported in oncology trials, particularly the Common Terminology Criteria for Adverse Events (CTCAE), said Dr. Moslehi, who also serves as chair of the American Heart Association’s subcommittee on cardio-oncology.

“Cardiovascular definitions are not exactly uniform and are not consistent with what we in cardiology consider to be important or relevant,” he said. “So I think there needs to be better standardization of these definitions, specifically within the CTCAE, which is what the oncologists use to identify adverse events.”

In a linked editorial (J Am Coll Cardiol. 2020;75:629-31), Dr. Lippman and cardiologist Nanette Bishopric, MD, of the Medstar Heart and Vascular Institute in Washington, D.C., suggested it may also be time to organize a consortium that can carry out “rigorous multicenter clinical investigations to evaluate the cardiotoxicity of emerging cancer treatments,” similar to the Thrombosis in Myocardial Infarction Study Group.

“The success of this consortium in pioneering and targeting multiple generations of drugs for the treatment of MI, involving tens of thousands of patients and thousands of collaborations across multiple national borders, is a model for how to move forward in providing the new hope of cancer cure without the trade-off of years lost to heart disease,” the editorialists concluded.

The study was supported in part by National Institutes of Health grants, including a K12-CA133250 grant to Dr. Addison. Dr. Bishopric reported being on the scientific board of C&C Biopharma. Dr. Lippman reports being on the board of directors of and holding stock in Seattle Genetics. Dr. Moslehi reported having served on advisory boards for Pfizer, Novartis, Bristol-Myers Squibb, Deciphera, Audentes Pharmaceuticals, Nektar, Takeda, Ipsen, Myokardia, AstraZeneca, GlaxoSmithKline, Intrexon, and Regeneron.

This article first appeared on Medscape.com.

Candida auris (C. auris) infection was first detected in New York, in July 2016. As of June 2019, 801 patients have been identified in New York as having C auris—and of those, 3 had pan-resistant infection.

CDC researchers say C auris is “a globally emerging yeast.” Cases with resistance to all 3 classes of commonly prescribed antifungal drugs have been reported in multiple countries.

In New York, of the first 277 available clinical isolates, 276 were resistant to fluconazole and 170 were resistant to amphotericin B. None were resistant to echinocandins. Subsequent testing found 99.7% of 331 isolates from infected patients with susceptibilities were resistant to fluconazole, 63% were resistant to amphotericin B, and 4% were resistant to echinocandins. Three of the subsequent isolates were pan-resistant.

The first 2 of those 3 patients were > 50 years old and residents of long-term care facilities. Each had multiple medical conditions, including ventilator dependence and colonization with multidrug-resistant bacteria. Neither patient was known to have received antifungal medications before the diagnosis of C. auris infection, but both were treated with prolonged courses of echinocandins after the diagnosis. Cultures taken after echinocandin therapy showed resistance to fluconazole, amphotericin B, and echinocandins. Both patients died, but the role of C. auris in their deaths is unclear.

The researchers found no epidemiologic links between the 2 patients. They were residents at different health care facilities, neither had any known domestic or foreign travel. No pan-resistant isolates were identified among contacts or on environmental surfaces from their rooms or common equipment at the 3 facilities where they had been patients. Although C. auris was isolated from other patients, none was pan-resistant.

A retrospective review of all New York C. auris isolates turned up a third pan-resistant patient. The patient also was aged > 50 years old , had multiple comorbidities, and a prolonged hospital and long-term care stay. However, the patient received care at a third unique facility. This third patient, who died from underlying medical conditions, was also not known to have traveled recently, and had no known contact with the other 2 patients.

Isolates from all 3 patients were initially sensitive to echinocandins. Resistance was detected after treatment, indicating it emerged during treatment with the drugs. The researchers found no evidence of transmission.

Approximately 3 years after the beginning of the New York outbreak, the pan-resistant isolates still appear to be rare, the researchers say, but “their emergence is concerning.” They urge close monitoring for patients on antifungal treatment for C. auris, along with follow-up cultures and repeat susceptibility testing, especially in patients previously treated with echinocandins.

Candida auris (C. auris) infection was first detected in New York, in July 2016. As of June 2019, 801 patients have been identified in New York as having C auris—and of those, 3 had pan-resistant infection.

CDC researchers say C auris is “a globally emerging yeast.” Cases with resistance to all 3 classes of commonly prescribed antifungal drugs have been reported in multiple countries.

In New York, of the first 277 available clinical isolates, 276 were resistant to fluconazole and 170 were resistant to amphotericin B. None were resistant to echinocandins. Subsequent testing found 99.7% of 331 isolates from infected patients with susceptibilities were resistant to fluconazole, 63% were resistant to amphotericin B, and 4% were resistant to echinocandins. Three of the subsequent isolates were pan-resistant.

The first 2 of those 3 patients were > 50 years old and residents of long-term care facilities. Each had multiple medical conditions, including ventilator dependence and colonization with multidrug-resistant bacteria. Neither patient was known to have received antifungal medications before the diagnosis of C. auris infection, but both were treated with prolonged courses of echinocandins after the diagnosis. Cultures taken after echinocandin therapy showed resistance to fluconazole, amphotericin B, and echinocandins. Both patients died, but the role of C. auris in their deaths is unclear.

The researchers found no epidemiologic links between the 2 patients. They were residents at different health care facilities, neither had any known domestic or foreign travel. No pan-resistant isolates were identified among contacts or on environmental surfaces from their rooms or common equipment at the 3 facilities where they had been patients. Although C. auris was isolated from other patients, none was pan-resistant.

A retrospective review of all New York C. auris isolates turned up a third pan-resistant patient. The patient also was aged > 50 years old , had multiple comorbidities, and a prolonged hospital and long-term care stay. However, the patient received care at a third unique facility. This third patient, who died from underlying medical conditions, was also not known to have traveled recently, and had no known contact with the other 2 patients.

Isolates from all 3 patients were initially sensitive to echinocandins. Resistance was detected after treatment, indicating it emerged during treatment with the drugs. The researchers found no evidence of transmission.

Approximately 3 years after the beginning of the New York outbreak, the pan-resistant isolates still appear to be rare, the researchers say, but “their emergence is concerning.” They urge close monitoring for patients on antifungal treatment for C. auris, along with follow-up cultures and repeat susceptibility testing, especially in patients previously treated with echinocandins.

Candida auris (C. auris) infection was first detected in New York, in July 2016. As of June 2019, 801 patients have been identified in New York as having C auris—and of those, 3 had pan-resistant infection.

CDC researchers say C auris is “a globally emerging yeast.” Cases with resistance to all 3 classes of commonly prescribed antifungal drugs have been reported in multiple countries.

In New York, of the first 277 available clinical isolates, 276 were resistant to fluconazole and 170 were resistant to amphotericin B. None were resistant to echinocandins. Subsequent testing found 99.7% of 331 isolates from infected patients with susceptibilities were resistant to fluconazole, 63% were resistant to amphotericin B, and 4% were resistant to echinocandins. Three of the subsequent isolates were pan-resistant.

The first 2 of those 3 patients were > 50 years old and residents of long-term care facilities. Each had multiple medical conditions, including ventilator dependence and colonization with multidrug-resistant bacteria. Neither patient was known to have received antifungal medications before the diagnosis of C. auris infection, but both were treated with prolonged courses of echinocandins after the diagnosis. Cultures taken after echinocandin therapy showed resistance to fluconazole, amphotericin B, and echinocandins. Both patients died, but the role of C. auris in their deaths is unclear.

The researchers found no epidemiologic links between the 2 patients. They were residents at different health care facilities, neither had any known domestic or foreign travel. No pan-resistant isolates were identified among contacts or on environmental surfaces from their rooms or common equipment at the 3 facilities where they had been patients. Although C. auris was isolated from other patients, none was pan-resistant.

A retrospective review of all New York C. auris isolates turned up a third pan-resistant patient. The patient also was aged > 50 years old , had multiple comorbidities, and a prolonged hospital and long-term care stay. However, the patient received care at a third unique facility. This third patient, who died from underlying medical conditions, was also not known to have traveled recently, and had no known contact with the other 2 patients.

Isolates from all 3 patients were initially sensitive to echinocandins. Resistance was detected after treatment, indicating it emerged during treatment with the drugs. The researchers found no evidence of transmission.

Approximately 3 years after the beginning of the New York outbreak, the pan-resistant isolates still appear to be rare, the researchers say, but “their emergence is concerning.” They urge close monitoring for patients on antifungal treatment for C. auris, along with follow-up cultures and repeat susceptibility testing, especially in patients previously treated with echinocandins.

Carbon monoxide (CO)—colorless, odorless, tasteless and highly toxic—is one of the most common causes of unintentional poisoning deaths in the US. Researchers who described their analysis of CO-related incidents in the military for the Medical Surveillance Monthly Report say military activities, materials, and settings pose “unique and potentially lethal sources of significant CO exposure.”

They reported on episodes of CO poisoning among members of the US Armed Forces between 2009 and 2019 and expanded on reports that dated back to 2001. Their analysis included reserve members and nonservice member beneficiaries.

Over the 10 years, there were 1,288 confirmed/probable cases of CO poisoning among active component service members, 366 among reserve component service members, and 4,754 among nonservice member beneficiaries. The highest number of active-duty members with CO confirmed/probable poisoning were reported at Fort Carson, Colorado (60) and NMC San Diego, California (52).

Of the confirmed/probable cases among active-duty members, 613 were classified as having unintentional intent, 538 undetermined intent, and 136 self-harm intent. One was due to assault. Most of the cases were related to work in repair/engineering occupations. Although the majority of sources were “other or unspecified,” motor vehicle exhaust accounted for 17% of the confirmed cases and all of the probable cases. Similarly, in the reserve component and among nonservice member beneficiaries, vehicle exhaust was the second-most common source.

The researchers found that CO poisoning-related injuries/diagnoses in the military often involved a single exposure that affected multiple personnel. For example, 21 soldiers showed symptoms during a multi-day exercise at the Yukon Training Center.

Excessive CO exposure is “entirely preventable,” the researchers say. Primary medical care providers—including unit medics and emergency medical technicians—should be knowledgeable about and sensitive to the “diverse and nonspecific” early clinical manifestations of CO intoxication, such as dizziness, headache, malaise, fatigue, disorientation, nausea, and vomiting. High CO exposure can cause more pronounced and severe symptoms, including syncope, seizures, acute stroke-like syndromes, and coma.

 It’s important to remember, the researchers add, that increased oxygen demand from muscular activity exacerbates the symptoms of CO exposure, but individuals at rest may experience no other symptoms before losing consciousness.

An editorial comment notes that the full impact of morbidity and mortality from CO poisoning is difficult to estimate. For one thing, because the symptoms can be so nonspecific, clinicians may not consider CO poisoning when patients present for care.

This study differs from previous ones in that it uses code data from both the Ninth and Tenth Revisions of the International Classification of Diseases. Such data, the editorial comment says, can be used at national and Military Health System–wide levels with relatively few resources, providing useful information on trends and risk factors that can be used in designing interventions

Carbon monoxide (CO)—colorless, odorless, tasteless and highly toxic—is one of the most common causes of unintentional poisoning deaths in the US. Researchers who described their analysis of CO-related incidents in the military for the Medical Surveillance Monthly Report say military activities, materials, and settings pose “unique and potentially lethal sources of significant CO exposure.”

They reported on episodes of CO poisoning among members of the US Armed Forces between 2009 and 2019 and expanded on reports that dated back to 2001. Their analysis included reserve members and nonservice member beneficiaries.

Over the 10 years, there were 1,288 confirmed/probable cases of CO poisoning among active component service members, 366 among reserve component service members, and 4,754 among nonservice member beneficiaries. The highest number of active-duty members with CO confirmed/probable poisoning were reported at Fort Carson, Colorado (60) and NMC San Diego, California (52).

Of the confirmed/probable cases among active-duty members, 613 were classified as having unintentional intent, 538 undetermined intent, and 136 self-harm intent. One was due to assault. Most of the cases were related to work in repair/engineering occupations. Although the majority of sources were “other or unspecified,” motor vehicle exhaust accounted for 17% of the confirmed cases and all of the probable cases. Similarly, in the reserve component and among nonservice member beneficiaries, vehicle exhaust was the second-most common source.

The researchers found that CO poisoning-related injuries/diagnoses in the military often involved a single exposure that affected multiple personnel. For example, 21 soldiers showed symptoms during a multi-day exercise at the Yukon Training Center.

Excessive CO exposure is “entirely preventable,” the researchers say. Primary medical care providers—including unit medics and emergency medical technicians—should be knowledgeable about and sensitive to the “diverse and nonspecific” early clinical manifestations of CO intoxication, such as dizziness, headache, malaise, fatigue, disorientation, nausea, and vomiting. High CO exposure can cause more pronounced and severe symptoms, including syncope, seizures, acute stroke-like syndromes, and coma.

 It’s important to remember, the researchers add, that increased oxygen demand from muscular activity exacerbates the symptoms of CO exposure, but individuals at rest may experience no other symptoms before losing consciousness.

An editorial comment notes that the full impact of morbidity and mortality from CO poisoning is difficult to estimate. For one thing, because the symptoms can be so nonspecific, clinicians may not consider CO poisoning when patients present for care.

This study differs from previous ones in that it uses code data from both the Ninth and Tenth Revisions of the International Classification of Diseases. Such data, the editorial comment says, can be used at national and Military Health System–wide levels with relatively few resources, providing useful information on trends and risk factors that can be used in designing interventions

Carbon monoxide (CO)—colorless, odorless, tasteless and highly toxic—is one of the most common causes of unintentional poisoning deaths in the US. Researchers who described their analysis of CO-related incidents in the military for the Medical Surveillance Monthly Report say military activities, materials, and settings pose “unique and potentially lethal sources of significant CO exposure.”

They reported on episodes of CO poisoning among members of the US Armed Forces between 2009 and 2019 and expanded on reports that dated back to 2001. Their analysis included reserve members and nonservice member beneficiaries.

Over the 10 years, there were 1,288 confirmed/probable cases of CO poisoning among active component service members, 366 among reserve component service members, and 4,754 among nonservice member beneficiaries. The highest number of active-duty members with CO confirmed/probable poisoning were reported at Fort Carson, Colorado (60) and NMC San Diego, California (52).

Of the confirmed/probable cases among active-duty members, 613 were classified as having unintentional intent, 538 undetermined intent, and 136 self-harm intent. One was due to assault. Most of the cases were related to work in repair/engineering occupations. Although the majority of sources were “other or unspecified,” motor vehicle exhaust accounted for 17% of the confirmed cases and all of the probable cases. Similarly, in the reserve component and among nonservice member beneficiaries, vehicle exhaust was the second-most common source.

The researchers found that CO poisoning-related injuries/diagnoses in the military often involved a single exposure that affected multiple personnel. For example, 21 soldiers showed symptoms during a multi-day exercise at the Yukon Training Center.

Excessive CO exposure is “entirely preventable,” the researchers say. Primary medical care providers—including unit medics and emergency medical technicians—should be knowledgeable about and sensitive to the “diverse and nonspecific” early clinical manifestations of CO intoxication, such as dizziness, headache, malaise, fatigue, disorientation, nausea, and vomiting. High CO exposure can cause more pronounced and severe symptoms, including syncope, seizures, acute stroke-like syndromes, and coma.

 It’s important to remember, the researchers add, that increased oxygen demand from muscular activity exacerbates the symptoms of CO exposure, but individuals at rest may experience no other symptoms before losing consciousness.

An editorial comment notes that the full impact of morbidity and mortality from CO poisoning is difficult to estimate. For one thing, because the symptoms can be so nonspecific, clinicians may not consider CO poisoning when patients present for care.

This study differs from previous ones in that it uses code data from both the Ninth and Tenth Revisions of the International Classification of Diseases. Such data, the editorial comment says, can be used at national and Military Health System–wide levels with relatively few resources, providing useful information on trends and risk factors that can be used in designing interventions

ANSWER

The correct answer is psoriasis vulgaris (choice “a”).

DISCUSSION

At least 30% of patients with psoriasis have a family history of the disease—a meaningful clue in developing a differential. Besides asking about the history, always look for corroborating signs in areas where the disease is commonly seen (eg, the fingernails). In this case, further corroboration was provided by the history of illness at the time of the rash’s onset; what was initially strep-driven guttate psoriasis morphed into full-blown psoriasis vulgaris.

The heavy scales, with their salmon-pink base, tipped the scales in favor of psoriasis as the diagnosis. The pinpoint bleeding (known as the Auspitz sign), although not pathognomic for psoriasis, is certainly suggestive of it.

In adults, these findings would probably have been sufficient to settle on psoriasis. But before labeling a young child with a serious, lifelong diagnosis, it was necessary to be sure. For one thing, advanced psoriasis is very unusual in children as young as this patient, and for another, treatment would likely be problematic. Fortunately for clarity’s sake, the biopsy was consistent with psoriasis and inconsistent with the other items in the differential.

TREATMENT

The patient was prescribed a topical steroid cream to apply every other day, alternating with vitamin D–derived ointment. In addition, he was advised to increase his exposure to natural sunlight. Phototherapy with narrow-band ultraviolet light B would be a superior option, but his family lives too far from the clinic to make 3 roundtrips per week for such treatment.

If these measures fail, a biologic agent may be appropriate. Unfortunately, the patient’s insurance carrier requires the failure of several other modalities before it will approve use of such therapy.

ANSWER

The correct answer is psoriasis vulgaris (choice “a”).

DISCUSSION

At least 30% of patients with psoriasis have a family history of the disease—a meaningful clue in developing a differential. Besides asking about the history, always look for corroborating signs in areas where the disease is commonly seen (eg, the fingernails). In this case, further corroboration was provided by the history of illness at the time of the rash’s onset; what was initially strep-driven guttate psoriasis morphed into full-blown psoriasis vulgaris.

The heavy scales, with their salmon-pink base, tipped the scales in favor of psoriasis as the diagnosis. The pinpoint bleeding (known as the Auspitz sign), although not pathognomic for psoriasis, is certainly suggestive of it.

In adults, these findings would probably have been sufficient to settle on psoriasis. But before labeling a young child with a serious, lifelong diagnosis, it was necessary to be sure. For one thing, advanced psoriasis is very unusual in children as young as this patient, and for another, treatment would likely be problematic. Fortunately for clarity’s sake, the biopsy was consistent with psoriasis and inconsistent with the other items in the differential.

TREATMENT

The patient was prescribed a topical steroid cream to apply every other day, alternating with vitamin D–derived ointment. In addition, he was advised to increase his exposure to natural sunlight. Phototherapy with narrow-band ultraviolet light B would be a superior option, but his family lives too far from the clinic to make 3 roundtrips per week for such treatment.

If these measures fail, a biologic agent may be appropriate. Unfortunately, the patient’s insurance carrier requires the failure of several other modalities before it will approve use of such therapy.

ANSWER

The correct answer is psoriasis vulgaris (choice “a”).

DISCUSSION

At least 30% of patients with psoriasis have a family history of the disease—a meaningful clue in developing a differential. Besides asking about the history, always look for corroborating signs in areas where the disease is commonly seen (eg, the fingernails). In this case, further corroboration was provided by the history of illness at the time of the rash’s onset; what was initially strep-driven guttate psoriasis morphed into full-blown psoriasis vulgaris.

The heavy scales, with their salmon-pink base, tipped the scales in favor of psoriasis as the diagnosis. The pinpoint bleeding (known as the Auspitz sign), although not pathognomic for psoriasis, is certainly suggestive of it.

In adults, these findings would probably have been sufficient to settle on psoriasis. But before labeling a young child with a serious, lifelong diagnosis, it was necessary to be sure. For one thing, advanced psoriasis is very unusual in children as young as this patient, and for another, treatment would likely be problematic. Fortunately for clarity’s sake, the biopsy was consistent with psoriasis and inconsistent with the other items in the differential.

TREATMENT

The patient was prescribed a topical steroid cream to apply every other day, alternating with vitamin D–derived ointment. In addition, he was advised to increase his exposure to natural sunlight. Phototherapy with narrow-band ultraviolet light B would be a superior option, but his family lives too far from the clinic to make 3 roundtrips per week for such treatment.

If these measures fail, a biologic agent may be appropriate. Unfortunately, the patient’s insurance carrier requires the failure of several other modalities before it will approve use of such therapy.

Older long-term survivors of non-Hodgkin lymphoma (NHL) may have worse cognitive outcomes compared with the noncancer aging population, according to a cross-sectional study.

The findings suggest additional research is needed to better understand cognitive decline in older survivors of NHL.

“The aim of the present study was to examine the difference in cognitive status between a group of long-term older survivors of NHL compared with a group of noncancer controls of the same age,” wrote Domenico La Carpia, MD, of Fondazione ANT Italia Onlus, Florence, Italy, and colleagues.

The researchers conducted a multicenter cross-sectional cohort study involving 63 long-term survivors of NHL and 61 age-matched controls. Their report was published in the Journal of Geriatric Oncology.

Eligible survivors and controls were aged 65 years and older. Among both groups, the mean age of study participants was 74 years, and most survivors were women (58.7%).

While cognitive decline was assessed via standardized neuropsychological testing, the team also evaluated polypharmacy, functional status, and level of multimorbidity in the cohort.

Other clinical data, including the time from complete remission, type of treatment received, and histopathological type of tumor, were collected from patient charts and included in the analysis.

After analysis, the researchers found that NHL survivors had a higher mean number of chronic conditions (3.4 vs. 2.3; P = .003), were receiving more medications (3.4 vs. 2.3; P = .03), and had worse functional status compared with controls.

In addition, survivors had impaired executive functioning compared with control subjects (Trail Making Test B-A, 47.9 vs. 32.1; P = .04), but scores on the Mini Mental State Examination (MMSE) did not differ between the groups.

“A small, statistically significant difference was also observed in verbal memory scores between the two groups,” they reported.

The researchers acknowledged that a key limitation was the cross-sectional nature of the study; hence, causality cannot be inferred from the data.

“Comprehensive geriatric assessment for older cancer survivors is advisable to identify those individuals who are at highest risk of developing disability and to implement tailored early interventions,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: La Carpia D et al. J Geriatr Oncol. 2020 Jan 31. doi: 10.1016/j.jgo.2020.01.007.

Older long-term survivors of non-Hodgkin lymphoma (NHL) may have worse cognitive outcomes compared with the noncancer aging population, according to a cross-sectional study.

The findings suggest additional research is needed to better understand cognitive decline in older survivors of NHL.

“The aim of the present study was to examine the difference in cognitive status between a group of long-term older survivors of NHL compared with a group of noncancer controls of the same age,” wrote Domenico La Carpia, MD, of Fondazione ANT Italia Onlus, Florence, Italy, and colleagues.

The researchers conducted a multicenter cross-sectional cohort study involving 63 long-term survivors of NHL and 61 age-matched controls. Their report was published in the Journal of Geriatric Oncology.

Eligible survivors and controls were aged 65 years and older. Among both groups, the mean age of study participants was 74 years, and most survivors were women (58.7%).

While cognitive decline was assessed via standardized neuropsychological testing, the team also evaluated polypharmacy, functional status, and level of multimorbidity in the cohort.

Other clinical data, including the time from complete remission, type of treatment received, and histopathological type of tumor, were collected from patient charts and included in the analysis.

After analysis, the researchers found that NHL survivors had a higher mean number of chronic conditions (3.4 vs. 2.3; P = .003), were receiving more medications (3.4 vs. 2.3; P = .03), and had worse functional status compared with controls.

In addition, survivors had impaired executive functioning compared with control subjects (Trail Making Test B-A, 47.9 vs. 32.1; P = .04), but scores on the Mini Mental State Examination (MMSE) did not differ between the groups.

“A small, statistically significant difference was also observed in verbal memory scores between the two groups,” they reported.

The researchers acknowledged that a key limitation was the cross-sectional nature of the study; hence, causality cannot be inferred from the data.

“Comprehensive geriatric assessment for older cancer survivors is advisable to identify those individuals who are at highest risk of developing disability and to implement tailored early interventions,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: La Carpia D et al. J Geriatr Oncol. 2020 Jan 31. doi: 10.1016/j.jgo.2020.01.007.

Older long-term survivors of non-Hodgkin lymphoma (NHL) may have worse cognitive outcomes compared with the noncancer aging population, according to a cross-sectional study.

The findings suggest additional research is needed to better understand cognitive decline in older survivors of NHL.

“The aim of the present study was to examine the difference in cognitive status between a group of long-term older survivors of NHL compared with a group of noncancer controls of the same age,” wrote Domenico La Carpia, MD, of Fondazione ANT Italia Onlus, Florence, Italy, and colleagues.

The researchers conducted a multicenter cross-sectional cohort study involving 63 long-term survivors of NHL and 61 age-matched controls. Their report was published in the Journal of Geriatric Oncology.

Eligible survivors and controls were aged 65 years and older. Among both groups, the mean age of study participants was 74 years, and most survivors were women (58.7%).

While cognitive decline was assessed via standardized neuropsychological testing, the team also evaluated polypharmacy, functional status, and level of multimorbidity in the cohort.

Other clinical data, including the time from complete remission, type of treatment received, and histopathological type of tumor, were collected from patient charts and included in the analysis.

After analysis, the researchers found that NHL survivors had a higher mean number of chronic conditions (3.4 vs. 2.3; P = .003), were receiving more medications (3.4 vs. 2.3; P = .03), and had worse functional status compared with controls.

In addition, survivors had impaired executive functioning compared with control subjects (Trail Making Test B-A, 47.9 vs. 32.1; P = .04), but scores on the Mini Mental State Examination (MMSE) did not differ between the groups.

“A small, statistically significant difference was also observed in verbal memory scores between the two groups,” they reported.

The researchers acknowledged that a key limitation was the cross-sectional nature of the study; hence, causality cannot be inferred from the data.

“Comprehensive geriatric assessment for older cancer survivors is advisable to identify those individuals who are at highest risk of developing disability and to implement tailored early interventions,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: La Carpia D et al. J Geriatr Oncol. 2020 Jan 31. doi: 10.1016/j.jgo.2020.01.007.