The Association for the Advancement of Blood and Biotherapies has released clinical practice guidelines for using COVID-19 convalescent plasma (CCP) in hospital and outpatient settings.

In summarizing the practice statement, the authors write, “CCP is most effective when transfused with high neutralizing titers early after symptom onset.”

The five guidelines, were published in Annals of Internal Medicine. The guidelines and strength of recommendations are:

• Nonhospitalized patients at high risk for disease progression should have CCP transfusion in addition to usual standard of care. (weak)
• CCP transfusion should not be done for unselected hospitalized patients with moderate or severe disease. This does not apply to immunosuppressed patients or those who lack antibodies against SARS-CoV-2. (strong)
• CCP transfusion is suggested in addition to the usual standard of care for hospitalized patients with COVID-19 who do not have SARS-CoV-2 antibodies at admission. (weak)
• Prophylactic CCP transfusion is not recommended for uninfected people with close contact exposure to someone with COVID-19. (weak)
• The AABB suggests CCP transfusion along with standard of care for hospitalized patients with COVID-19 and preexisting immunosuppression. (weak)

Multiple guidelines for use of CCP are similar

In an accompanying editorial, Jason V. Baker, MD, MS, and H. Clifford Lane, MD, who are part of the National Institutes of Health Treatment Guidelines Panel, say guidelines from that organization around CCP generally align with those of the AABB and the Infectious Diseases Society of America.

They all note CCP’s potential for helping immunocompromised patients and they recommend against CCP in unselected, hospitalized patients.

The main difference is that the AABB also “suggests” using CCP in combination with other standard treatments for outpatients at high risk for disease progression, regardless of their immune status, write Dr. Baker, who is with Hennepin Healthcare and the department of medicine at the University of Minnesota in Minneapolis, and Dr. Lane, who is with the National Institutes of Health.

The precise circumstance for recommending CCP remains unclear, Dr. Baker and Dr. Lane write. That’s because most available evidence has come in the absence of vaccines and antiviral agents, including nirmatrelvir–ritonavir (Paxlovid), they explain.

“At this point in the pandemic, it seems that the patient most likely to benefit from passive antibody therapy is the immunocompromised host with COVID-19 who cannot mount their own antibody response to vaccine or prior infection,” they write.

“In that setting, and in the absence of other antiviral treatments or progression despite receipt of standard treatments, high-titer CCP from a recently recovered donor is a reasonable approach,” they conclude.

Eileen Barrett, MD, MPH, an assistant professor in the division of hospital medicine at the University of New Mexico in Albuquerque, said in an interview that “clinical guidelines like this really help practicing physicians as we navigate the explosion of research findings since the start of the pandemic.”

One strong recommendation

Dr. Barrett pointed out that four of the five recommendations are rated “weak.”

“The weak recommendations for convalescent plasma in most situations is very humbling,” she said, “particularly as we recall the earliest days of the pandemic when many hospitalized patients received this treatment when little was known about what could help.”

She highlighted the paper’s only strong recommendation, which was against convalescent plasma use for the vast majority of hospitalized patients with COVID.

“That clinical bottom line is what most clinicians will look for,” she said.

“Similarly,” she said, “the accompanying editorial is so helpful in reminding the reader that, despite some possible benefit to convalescent plasma in a smaller subgroup of patients, variant-appropriate monoclonal antibodies and antivirals are better options.”

The disclosures for lead author of the guidelines, Lise J. Estcourt, MB BChir, DPhil, with the National Health Service Blood and Transplant Department and Radcliffe department of medicine at the University of Oxford (England) and her colleagues are available at https://rmed.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-1079. The editorialists and Dr. Barrett declare no relevant financial relationships.

The Association for the Advancement of Blood and Biotherapies has released clinical practice guidelines for using COVID-19 convalescent plasma (CCP) in hospital and outpatient settings.

In summarizing the practice statement, the authors write, “CCP is most effective when transfused with high neutralizing titers early after symptom onset.”

The five guidelines, were published in Annals of Internal Medicine. The guidelines and strength of recommendations are:

• Nonhospitalized patients at high risk for disease progression should have CCP transfusion in addition to usual standard of care. (weak)
• CCP transfusion should not be done for unselected hospitalized patients with moderate or severe disease. This does not apply to immunosuppressed patients or those who lack antibodies against SARS-CoV-2. (strong)
• CCP transfusion is suggested in addition to the usual standard of care for hospitalized patients with COVID-19 who do not have SARS-CoV-2 antibodies at admission. (weak)
• Prophylactic CCP transfusion is not recommended for uninfected people with close contact exposure to someone with COVID-19. (weak)
• The AABB suggests CCP transfusion along with standard of care for hospitalized patients with COVID-19 and preexisting immunosuppression. (weak)

Multiple guidelines for use of CCP are similar

In an accompanying editorial, Jason V. Baker, MD, MS, and H. Clifford Lane, MD, who are part of the National Institutes of Health Treatment Guidelines Panel, say guidelines from that organization around CCP generally align with those of the AABB and the Infectious Diseases Society of America.

They all note CCP’s potential for helping immunocompromised patients and they recommend against CCP in unselected, hospitalized patients.

The main difference is that the AABB also “suggests” using CCP in combination with other standard treatments for outpatients at high risk for disease progression, regardless of their immune status, write Dr. Baker, who is with Hennepin Healthcare and the department of medicine at the University of Minnesota in Minneapolis, and Dr. Lane, who is with the National Institutes of Health.

The precise circumstance for recommending CCP remains unclear, Dr. Baker and Dr. Lane write. That’s because most available evidence has come in the absence of vaccines and antiviral agents, including nirmatrelvir–ritonavir (Paxlovid), they explain.

“At this point in the pandemic, it seems that the patient most likely to benefit from passive antibody therapy is the immunocompromised host with COVID-19 who cannot mount their own antibody response to vaccine or prior infection,” they write.

“In that setting, and in the absence of other antiviral treatments or progression despite receipt of standard treatments, high-titer CCP from a recently recovered donor is a reasonable approach,” they conclude.

Eileen Barrett, MD, MPH, an assistant professor in the division of hospital medicine at the University of New Mexico in Albuquerque, said in an interview that “clinical guidelines like this really help practicing physicians as we navigate the explosion of research findings since the start of the pandemic.”

One strong recommendation

Dr. Barrett pointed out that four of the five recommendations are rated “weak.”

“The weak recommendations for convalescent plasma in most situations is very humbling,” she said, “particularly as we recall the earliest days of the pandemic when many hospitalized patients received this treatment when little was known about what could help.”

She highlighted the paper’s only strong recommendation, which was against convalescent plasma use for the vast majority of hospitalized patients with COVID.

“That clinical bottom line is what most clinicians will look for,” she said.

“Similarly,” she said, “the accompanying editorial is so helpful in reminding the reader that, despite some possible benefit to convalescent plasma in a smaller subgroup of patients, variant-appropriate monoclonal antibodies and antivirals are better options.”

The disclosures for lead author of the guidelines, Lise J. Estcourt, MB BChir, DPhil, with the National Health Service Blood and Transplant Department and Radcliffe department of medicine at the University of Oxford (England) and her colleagues are available at https://rmed.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-1079. The editorialists and Dr. Barrett declare no relevant financial relationships.

The Association for the Advancement of Blood and Biotherapies has released clinical practice guidelines for using COVID-19 convalescent plasma (CCP) in hospital and outpatient settings.

In summarizing the practice statement, the authors write, “CCP is most effective when transfused with high neutralizing titers early after symptom onset.”

The five guidelines, were published in Annals of Internal Medicine. The guidelines and strength of recommendations are:

• Nonhospitalized patients at high risk for disease progression should have CCP transfusion in addition to usual standard of care. (weak)
• CCP transfusion should not be done for unselected hospitalized patients with moderate or severe disease. This does not apply to immunosuppressed patients or those who lack antibodies against SARS-CoV-2. (strong)
• CCP transfusion is suggested in addition to the usual standard of care for hospitalized patients with COVID-19 who do not have SARS-CoV-2 antibodies at admission. (weak)
• Prophylactic CCP transfusion is not recommended for uninfected people with close contact exposure to someone with COVID-19. (weak)
• The AABB suggests CCP transfusion along with standard of care for hospitalized patients with COVID-19 and preexisting immunosuppression. (weak)

Multiple guidelines for use of CCP are similar

In an accompanying editorial, Jason V. Baker, MD, MS, and H. Clifford Lane, MD, who are part of the National Institutes of Health Treatment Guidelines Panel, say guidelines from that organization around CCP generally align with those of the AABB and the Infectious Diseases Society of America.

They all note CCP’s potential for helping immunocompromised patients and they recommend against CCP in unselected, hospitalized patients.

The main difference is that the AABB also “suggests” using CCP in combination with other standard treatments for outpatients at high risk for disease progression, regardless of their immune status, write Dr. Baker, who is with Hennepin Healthcare and the department of medicine at the University of Minnesota in Minneapolis, and Dr. Lane, who is with the National Institutes of Health.

The precise circumstance for recommending CCP remains unclear, Dr. Baker and Dr. Lane write. That’s because most available evidence has come in the absence of vaccines and antiviral agents, including nirmatrelvir–ritonavir (Paxlovid), they explain.

“At this point in the pandemic, it seems that the patient most likely to benefit from passive antibody therapy is the immunocompromised host with COVID-19 who cannot mount their own antibody response to vaccine or prior infection,” they write.

“In that setting, and in the absence of other antiviral treatments or progression despite receipt of standard treatments, high-titer CCP from a recently recovered donor is a reasonable approach,” they conclude.

Eileen Barrett, MD, MPH, an assistant professor in the division of hospital medicine at the University of New Mexico in Albuquerque, said in an interview that “clinical guidelines like this really help practicing physicians as we navigate the explosion of research findings since the start of the pandemic.”

One strong recommendation

Dr. Barrett pointed out that four of the five recommendations are rated “weak.”

“The weak recommendations for convalescent plasma in most situations is very humbling,” she said, “particularly as we recall the earliest days of the pandemic when many hospitalized patients received this treatment when little was known about what could help.”

She highlighted the paper’s only strong recommendation, which was against convalescent plasma use for the vast majority of hospitalized patients with COVID.

“That clinical bottom line is what most clinicians will look for,” she said.

“Similarly,” she said, “the accompanying editorial is so helpful in reminding the reader that, despite some possible benefit to convalescent plasma in a smaller subgroup of patients, variant-appropriate monoclonal antibodies and antivirals are better options.”

The disclosures for lead author of the guidelines, Lise J. Estcourt, MB BChir, DPhil, with the National Health Service Blood and Transplant Department and Radcliffe department of medicine at the University of Oxford (England) and her colleagues are available at https://rmed.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-1079. The editorialists and Dr. Barrett declare no relevant financial relationships.

Here’s another vote for less screen time. Using a smartphone application to track blood pressure won’t lead to any greater reduction in BP than self-monitoring the old-fashioned way, a new study finds.

“By itself, standard self-measured blood pressure (SMBP) has minimal effect on BP control,” wrote lead author Mark J. Pletcher, MD, of the University of California, San Francisco, and colleagues in JAMA Internal Medicine. “To improve BP control, SMBP must be accompanied by patient feedback, counseling, or other cointerventions, and the BP-lowering effects of SMBP appear to be proportional to the intensity of the cointervention.”

While this is known, higher-intensity cointerventions demand both money and time, prompting development of new devices that link with smartphone apps, they continued.

In the prospective randomized trial, patients with hypertension were randomly assigned to self-measure their blood pressure using a standard device that paired with a connected smartphone application or to self-measure their blood pressure with a standard device alone. Both groups achieved about an 11 mm Hg reduction in systolic BP over 6 months, reported similar levels of satisfaction with the monitoring process, and shared their readings with their physicians with similar frequency.

Methods

Dr. Pletcher and colleagues enrolled 2,101 adults who self-reported a systolic BP greater than 145 mm Hg and expressed a commitment to reduce their BP by at least 10 points in their trial. The participants, who were generally middle-aged or older, were randomized in a 1:1 ratio to monitor their BP using standard SMBP or “enhanced” SMBP. The standard group used the OMRON BP monitor alone, while the enhanced group used the same BP monitor coupled with the OMRON Connect smartphone app.

After 6 months of follow-up for each patient, mean BP reduction from baseline in the standard group was 10.6 mm Hg, compared with 10.7 mm Hg in the enhanced group, a nonsignificant difference (P = .81). While slightly more patients in the enhanced group achieved a BP lower than 140/90 mm Hg (32% vs. 29%; odds ratio, 1.17; 95% confidence interval, 1.01-1.34), this trend did not extend below the 130/80 mm Hg threshold.

Other secondary outcomes were also similar between groups. For example, 70% of participants in the enhanced group said they would recommend their SMBP process to a friend, compared with 69% of participants who followed the standard monitoring approach. The smartphone app had little impact on sharing readings with physicians, either, based on a 44% share rate in the enhanced group versus 48% in the standard group (P = .22).

“Enhanced SMBP does not provide any additional reduction in BP,” the investigators concluded.

New devices that link with smartphone apps, like the one used in this trial, “transmit BP measurements via wireless connection to the patient’s smartphone, where they are processed in a smartphone application to support tracking, visualization, interpretation, reminders to measure BP and/or take medications; recommendations for lifestyle interventions, medication adherence, or to discuss their BP with their clinician; and communications (for example, emailing a summary to a family member or clinician),” the researchers explained. While these devices are “only slightly more expensive than standard SMBP devices,” their relative efficacy over standard SMBP is “unclear.”

Findings can likely be extrapolated to other apps

Although the trial evaluated just one smartphone app, Dr. Pletcher suggested that the findings can likely be extrapolated to other apps.

“Most basic BP-tracking apps have some version or subset of the same essential functionality,” he said, in an interview. “My guess is that apps that meet this description without some substantially different technology or feature would likely show the same basic results as we did.”

Making a similar remark, Matthew Jung, MD, of Keck Medicine of USC, Los Angeles, stated that the findings can be “reasonably extrapolated” to other BP-tracking apps with similar functionality “if we put aside the study’s issues with power.”

When it comes to smartphone apps, active engagement is needed to achieve greater impacts on blood pressure, Dr. Pletcher said, but “there is so much competition for people’s attention on their phone that it is hard to maintain active engagement with any health-related app for long.”

Still, Dr. Pletcher hasn’t given up on biometric apps, noting that “with the right technology and connectivity and user experience (for both patient and clinician), they still could be game-changing for managing chronic conditions like hypertension.”

To this end, he and his colleagues are exploring technologies to passively monitor health-related measurements like BP, potentially sidestepping the pitfall of active engagement.

Dr. Jung said the study is noteworthy for several reasons, including its large size, similar level of comfort with technology reported by both groups, and representation of Black and Hispanic participants, who accounted for almost one-third of the population.
 

Study limitations

Dr. Jung pointed out several study limitations, including the lack of standardized measurement of BP, which left more than one-third of patients unevaluated via chart review, as well as gaps in usage data, such as that one-third of the participants never confirmed receipt of a device, and less than half of the enhanced group reported using the smartphone application.

These limitations “may have detracted from its ability to identify the true efficacy of an enhanced app-based BP tracking device,” he said. “In contrast, each of these issues also helped us get a better picture for how well these devices may work in the real world.”

Dr. Jung also commented on the duration of the study, noting that only 10 weeks passed, on average, from baseline to follow-up BP measurement, which “may not have been sufficient for a possible difference between enhanced and standard BP monitoring to become noticeable.”

“This may be especially important when taking into consideration the time required to mail the devices out to patients, for patients to become familiar with usage of the devices, and for them to start using the devices in a meaningful way,” he added.

The study was supported the Patient-Centered Outcomes Research Institute, the American Medical Association, and the American Heart Association. The investigators disclosed additional relationships with Pfizer, Bristol Myers Squibb, and Novartis. Dr. Jung, who was not involved in the study, disclosed no relevant conflicts of interest.

Here’s another vote for less screen time. Using a smartphone application to track blood pressure won’t lead to any greater reduction in BP than self-monitoring the old-fashioned way, a new study finds.

“By itself, standard self-measured blood pressure (SMBP) has minimal effect on BP control,” wrote lead author Mark J. Pletcher, MD, of the University of California, San Francisco, and colleagues in JAMA Internal Medicine. “To improve BP control, SMBP must be accompanied by patient feedback, counseling, or other cointerventions, and the BP-lowering effects of SMBP appear to be proportional to the intensity of the cointervention.”

While this is known, higher-intensity cointerventions demand both money and time, prompting development of new devices that link with smartphone apps, they continued.

In the prospective randomized trial, patients with hypertension were randomly assigned to self-measure their blood pressure using a standard device that paired with a connected smartphone application or to self-measure their blood pressure with a standard device alone. Both groups achieved about an 11 mm Hg reduction in systolic BP over 6 months, reported similar levels of satisfaction with the monitoring process, and shared their readings with their physicians with similar frequency.

Methods

Dr. Pletcher and colleagues enrolled 2,101 adults who self-reported a systolic BP greater than 145 mm Hg and expressed a commitment to reduce their BP by at least 10 points in their trial. The participants, who were generally middle-aged or older, were randomized in a 1:1 ratio to monitor their BP using standard SMBP or “enhanced” SMBP. The standard group used the OMRON BP monitor alone, while the enhanced group used the same BP monitor coupled with the OMRON Connect smartphone app.

After 6 months of follow-up for each patient, mean BP reduction from baseline in the standard group was 10.6 mm Hg, compared with 10.7 mm Hg in the enhanced group, a nonsignificant difference (P = .81). While slightly more patients in the enhanced group achieved a BP lower than 140/90 mm Hg (32% vs. 29%; odds ratio, 1.17; 95% confidence interval, 1.01-1.34), this trend did not extend below the 130/80 mm Hg threshold.

Other secondary outcomes were also similar between groups. For example, 70% of participants in the enhanced group said they would recommend their SMBP process to a friend, compared with 69% of participants who followed the standard monitoring approach. The smartphone app had little impact on sharing readings with physicians, either, based on a 44% share rate in the enhanced group versus 48% in the standard group (P = .22).

“Enhanced SMBP does not provide any additional reduction in BP,” the investigators concluded.

New devices that link with smartphone apps, like the one used in this trial, “transmit BP measurements via wireless connection to the patient’s smartphone, where they are processed in a smartphone application to support tracking, visualization, interpretation, reminders to measure BP and/or take medications; recommendations for lifestyle interventions, medication adherence, or to discuss their BP with their clinician; and communications (for example, emailing a summary to a family member or clinician),” the researchers explained. While these devices are “only slightly more expensive than standard SMBP devices,” their relative efficacy over standard SMBP is “unclear.”

Findings can likely be extrapolated to other apps

Although the trial evaluated just one smartphone app, Dr. Pletcher suggested that the findings can likely be extrapolated to other apps.

“Most basic BP-tracking apps have some version or subset of the same essential functionality,” he said, in an interview. “My guess is that apps that meet this description without some substantially different technology or feature would likely show the same basic results as we did.”

Making a similar remark, Matthew Jung, MD, of Keck Medicine of USC, Los Angeles, stated that the findings can be “reasonably extrapolated” to other BP-tracking apps with similar functionality “if we put aside the study’s issues with power.”

When it comes to smartphone apps, active engagement is needed to achieve greater impacts on blood pressure, Dr. Pletcher said, but “there is so much competition for people’s attention on their phone that it is hard to maintain active engagement with any health-related app for long.”

Still, Dr. Pletcher hasn’t given up on biometric apps, noting that “with the right technology and connectivity and user experience (for both patient and clinician), they still could be game-changing for managing chronic conditions like hypertension.”

To this end, he and his colleagues are exploring technologies to passively monitor health-related measurements like BP, potentially sidestepping the pitfall of active engagement.

Dr. Jung said the study is noteworthy for several reasons, including its large size, similar level of comfort with technology reported by both groups, and representation of Black and Hispanic participants, who accounted for almost one-third of the population.
 

Study limitations

Dr. Jung pointed out several study limitations, including the lack of standardized measurement of BP, which left more than one-third of patients unevaluated via chart review, as well as gaps in usage data, such as that one-third of the participants never confirmed receipt of a device, and less than half of the enhanced group reported using the smartphone application.

These limitations “may have detracted from its ability to identify the true efficacy of an enhanced app-based BP tracking device,” he said. “In contrast, each of these issues also helped us get a better picture for how well these devices may work in the real world.”

Dr. Jung also commented on the duration of the study, noting that only 10 weeks passed, on average, from baseline to follow-up BP measurement, which “may not have been sufficient for a possible difference between enhanced and standard BP monitoring to become noticeable.”

“This may be especially important when taking into consideration the time required to mail the devices out to patients, for patients to become familiar with usage of the devices, and for them to start using the devices in a meaningful way,” he added.

The study was supported the Patient-Centered Outcomes Research Institute, the American Medical Association, and the American Heart Association. The investigators disclosed additional relationships with Pfizer, Bristol Myers Squibb, and Novartis. Dr. Jung, who was not involved in the study, disclosed no relevant conflicts of interest.

Here’s another vote for less screen time. Using a smartphone application to track blood pressure won’t lead to any greater reduction in BP than self-monitoring the old-fashioned way, a new study finds.

“By itself, standard self-measured blood pressure (SMBP) has minimal effect on BP control,” wrote lead author Mark J. Pletcher, MD, of the University of California, San Francisco, and colleagues in JAMA Internal Medicine. “To improve BP control, SMBP must be accompanied by patient feedback, counseling, or other cointerventions, and the BP-lowering effects of SMBP appear to be proportional to the intensity of the cointervention.”

While this is known, higher-intensity cointerventions demand both money and time, prompting development of new devices that link with smartphone apps, they continued.

In the prospective randomized trial, patients with hypertension were randomly assigned to self-measure their blood pressure using a standard device that paired with a connected smartphone application or to self-measure their blood pressure with a standard device alone. Both groups achieved about an 11 mm Hg reduction in systolic BP over 6 months, reported similar levels of satisfaction with the monitoring process, and shared their readings with their physicians with similar frequency.

Methods

Dr. Pletcher and colleagues enrolled 2,101 adults who self-reported a systolic BP greater than 145 mm Hg and expressed a commitment to reduce their BP by at least 10 points in their trial. The participants, who were generally middle-aged or older, were randomized in a 1:1 ratio to monitor their BP using standard SMBP or “enhanced” SMBP. The standard group used the OMRON BP monitor alone, while the enhanced group used the same BP monitor coupled with the OMRON Connect smartphone app.

After 6 months of follow-up for each patient, mean BP reduction from baseline in the standard group was 10.6 mm Hg, compared with 10.7 mm Hg in the enhanced group, a nonsignificant difference (P = .81). While slightly more patients in the enhanced group achieved a BP lower than 140/90 mm Hg (32% vs. 29%; odds ratio, 1.17; 95% confidence interval, 1.01-1.34), this trend did not extend below the 130/80 mm Hg threshold.

Other secondary outcomes were also similar between groups. For example, 70% of participants in the enhanced group said they would recommend their SMBP process to a friend, compared with 69% of participants who followed the standard monitoring approach. The smartphone app had little impact on sharing readings with physicians, either, based on a 44% share rate in the enhanced group versus 48% in the standard group (P = .22).

“Enhanced SMBP does not provide any additional reduction in BP,” the investigators concluded.

New devices that link with smartphone apps, like the one used in this trial, “transmit BP measurements via wireless connection to the patient’s smartphone, where they are processed in a smartphone application to support tracking, visualization, interpretation, reminders to measure BP and/or take medications; recommendations for lifestyle interventions, medication adherence, or to discuss their BP with their clinician; and communications (for example, emailing a summary to a family member or clinician),” the researchers explained. While these devices are “only slightly more expensive than standard SMBP devices,” their relative efficacy over standard SMBP is “unclear.”

Findings can likely be extrapolated to other apps

Although the trial evaluated just one smartphone app, Dr. Pletcher suggested that the findings can likely be extrapolated to other apps.

“Most basic BP-tracking apps have some version or subset of the same essential functionality,” he said, in an interview. “My guess is that apps that meet this description without some substantially different technology or feature would likely show the same basic results as we did.”

Making a similar remark, Matthew Jung, MD, of Keck Medicine of USC, Los Angeles, stated that the findings can be “reasonably extrapolated” to other BP-tracking apps with similar functionality “if we put aside the study’s issues with power.”

When it comes to smartphone apps, active engagement is needed to achieve greater impacts on blood pressure, Dr. Pletcher said, but “there is so much competition for people’s attention on their phone that it is hard to maintain active engagement with any health-related app for long.”

Still, Dr. Pletcher hasn’t given up on biometric apps, noting that “with the right technology and connectivity and user experience (for both patient and clinician), they still could be game-changing for managing chronic conditions like hypertension.”

To this end, he and his colleagues are exploring technologies to passively monitor health-related measurements like BP, potentially sidestepping the pitfall of active engagement.

Dr. Jung said the study is noteworthy for several reasons, including its large size, similar level of comfort with technology reported by both groups, and representation of Black and Hispanic participants, who accounted for almost one-third of the population.
 

Study limitations

Dr. Jung pointed out several study limitations, including the lack of standardized measurement of BP, which left more than one-third of patients unevaluated via chart review, as well as gaps in usage data, such as that one-third of the participants never confirmed receipt of a device, and less than half of the enhanced group reported using the smartphone application.

These limitations “may have detracted from its ability to identify the true efficacy of an enhanced app-based BP tracking device,” he said. “In contrast, each of these issues also helped us get a better picture for how well these devices may work in the real world.”

Dr. Jung also commented on the duration of the study, noting that only 10 weeks passed, on average, from baseline to follow-up BP measurement, which “may not have been sufficient for a possible difference between enhanced and standard BP monitoring to become noticeable.”

“This may be especially important when taking into consideration the time required to mail the devices out to patients, for patients to become familiar with usage of the devices, and for them to start using the devices in a meaningful way,” he added.

The study was supported the Patient-Centered Outcomes Research Institute, the American Medical Association, and the American Heart Association. The investigators disclosed additional relationships with Pfizer, Bristol Myers Squibb, and Novartis. Dr. Jung, who was not involved in the study, disclosed no relevant conflicts of interest.

Sleep behaviors, both individually and combined, are associated with an increased risk of developing metabolic dysfunction–associated fatty liver disease (MAFLD), according to a Chinese analysis that suggests the effect may be independent of obesity.

Yan Liu, PhD, from the School of Public Health at Sun Yat-sen University in Guangzhou, China, and colleagues studied data on over 5,000 individuals who self-reported sleep behaviors and underwent liver ultrasound.

Late bedtimes, snoring, and prolonged daytime napping were significantly associated with MAFLD, increasing the risk by 37%, 59%, and 17%, respectively, whereas people with both poor nighttime sleep and prolonged daytime napping had the “highest risk for developing fatty liver disease,” said Dr. Liu in a press release.

In contrast, having any of six healthy sleep behaviors decreased the risk by 16% each, and even a “moderate improvement in sleep quality was related to a 29% reduction in the risk for fatty liver disease,” he added.

The research, published online in the Journal of Clinical Endocrinology & Metabolism, also indicated that obesity accounted for only one fifth of the effect of sleep quality on MAFLD risk.

Rise in unhealthy lifestyles leads to increase in MALFD

The authors write that MAFLD is the “leading chronic liver disease worldwide,” affecting around a quarter of the adult population, and may lead to end-stage liver diseases and extrahepatic complications, thus “posing a major health and economic burden.”

Moreover, the disease prevalence is “soaring at an unanticipated rate,” increasing from 18% to 29% in China over the past decade, because of a “rapid rise in unhealthy lifestyles,” the authors note.

Sleep disturbance is increasingly prevalent, “and an emerging contributor to multiple metabolic disorders,” with insomnia and habitual snoring, for example, positively correlated with hypertension, impaired glucose metabolism, and dyslipidemia, report the authors.

However, whether sleep quality, which includes “several metabolic-related sleep behaviors,” constitutes an independent risk for MAFLD “over and above” the effect of obesity remains unclear.

To investigate further, the researchers examined data from the baseline survey of the community-based, prospective South China Cohort study, which was conducted in four regions of Southern China and involved 5,430 individuals aged 30-79 years.

Between March 2018 and October 2019, the participants self-reported sleep behaviors on the Pittsburgh Sleep Quality Index questionnaire and underwent ultrasound examination of the liver.

MAFLD was diagnosed in those with hepatic steatosis and one of the following:

• Overweight/obesity, defined by this study as a body mass index greater than or equal to 23 kg/m².
• Presence of diabetes.
• Evidence of metabolic dysregulation.

After excluding patients with insufficient data, and those with a history of liver cirrhosis, hepatectomy, or liver cancer, among others, the team included 5,011 individuals with an average age of 64 years and a mean body mass index of 24.31 kg/m². Forty percent were male.

Obesity was present in 13% of participants, whereas 15% had diabetes, 58% hypertension, and 35% metabolic syndrome.

MAFLD was diagnosed in 28% of the study population. They were older, more likely to be female with a higher education, and had a higher prevalence of preexisting metabolic disorders and worse metabolic profiles, than those without the disease.

Turning to the associations between sleep and the risk of MAFLD, the researchers say that “in contrast to previous reports, neither shorter nor longer sleep duration was found to be associated with the risk for MAFLD.”

However, after adjusting for demographics, lifestyles, medication, and preexisting metabolic comorbidities including hypertension, diabetes, and obesity, they found that the risk of MAFLD was significantly associated with late bedtime (defined as after 10 p.m.), at an odds ratio of 1.37 (P < .05).

MAFLD was also linked to snoring, at an odds ratio of 1.59, and to daytime napping for longer than 30 minutes, at an odds ratio of 1.17 (P < .05 for both).

When the team compared low-risk and high-risk sleep factors, they found that participants who had an early bedtime, slept 7-8 hours per night, never or rarely had insomnia or snoring, had infrequent daytime sleepiness, and daytime napping of half-hour or less had an odds ratio for MAFLD vs. other participants of 0.64 (P < .05).

Combining those factors into a healthy sleep score, the team found that each additional increase of healthy sleep score was associated with a fully adjusted odds ratio for MAFLD of 0.84 (P < .05).

In contrast, individuals with poor nocturnal sleep patterns and prolonged daytime napping had a higher risk for developing MAFLD, compared with those with a healthy nocturnal sleep pattern and daytime napping of half-hour or less, at an odds ratio of 2.38 (P < .05).

Further analysis indicated that individuals with a sedentary lifestyle and central obesity had a higher risk of MAFLD, but that the presence of obesity accounted for only 20.8% of the total effect of sleep quality on the risk of MAFLD.

“Taken together, our results suggests that obesity only partially mediates the effect of overall sleep quality on MAFLD,” the authors write.

“Given that large proportions of subjects suffering from poor sleep quality are underdiagnosed and undertreated, our study calls for more research into this field and strategies to improve sleep quality,” Dr. Liu said.

The study was supported by the “National Key R&D Program” of China, the Fundamental Research Funds for the Central Universities (Sun Yat-sen University), Natural Science Foundation of Guangdong Province, the Key Project of Medicine Discipline of Guangzhou, and Basic Research Project of Key Laboratory of Guangzhou.

The authors report no relevant financial relationships.

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

Sleep behaviors, both individually and combined, are associated with an increased risk of developing metabolic dysfunction–associated fatty liver disease (MAFLD), according to a Chinese analysis that suggests the effect may be independent of obesity.

Yan Liu, PhD, from the School of Public Health at Sun Yat-sen University in Guangzhou, China, and colleagues studied data on over 5,000 individuals who self-reported sleep behaviors and underwent liver ultrasound.

Late bedtimes, snoring, and prolonged daytime napping were significantly associated with MAFLD, increasing the risk by 37%, 59%, and 17%, respectively, whereas people with both poor nighttime sleep and prolonged daytime napping had the “highest risk for developing fatty liver disease,” said Dr. Liu in a press release.

In contrast, having any of six healthy sleep behaviors decreased the risk by 16% each, and even a “moderate improvement in sleep quality was related to a 29% reduction in the risk for fatty liver disease,” he added.

The research, published online in the Journal of Clinical Endocrinology & Metabolism, also indicated that obesity accounted for only one fifth of the effect of sleep quality on MAFLD risk.

Rise in unhealthy lifestyles leads to increase in MALFD

The authors write that MAFLD is the “leading chronic liver disease worldwide,” affecting around a quarter of the adult population, and may lead to end-stage liver diseases and extrahepatic complications, thus “posing a major health and economic burden.”

Moreover, the disease prevalence is “soaring at an unanticipated rate,” increasing from 18% to 29% in China over the past decade, because of a “rapid rise in unhealthy lifestyles,” the authors note.

Sleep disturbance is increasingly prevalent, “and an emerging contributor to multiple metabolic disorders,” with insomnia and habitual snoring, for example, positively correlated with hypertension, impaired glucose metabolism, and dyslipidemia, report the authors.

However, whether sleep quality, which includes “several metabolic-related sleep behaviors,” constitutes an independent risk for MAFLD “over and above” the effect of obesity remains unclear.

To investigate further, the researchers examined data from the baseline survey of the community-based, prospective South China Cohort study, which was conducted in four regions of Southern China and involved 5,430 individuals aged 30-79 years.

Between March 2018 and October 2019, the participants self-reported sleep behaviors on the Pittsburgh Sleep Quality Index questionnaire and underwent ultrasound examination of the liver.

MAFLD was diagnosed in those with hepatic steatosis and one of the following:

• Overweight/obesity, defined by this study as a body mass index greater than or equal to 23 kg/m².
• Presence of diabetes.
• Evidence of metabolic dysregulation.

After excluding patients with insufficient data, and those with a history of liver cirrhosis, hepatectomy, or liver cancer, among others, the team included 5,011 individuals with an average age of 64 years and a mean body mass index of 24.31 kg/m². Forty percent were male.

Obesity was present in 13% of participants, whereas 15% had diabetes, 58% hypertension, and 35% metabolic syndrome.

MAFLD was diagnosed in 28% of the study population. They were older, more likely to be female with a higher education, and had a higher prevalence of preexisting metabolic disorders and worse metabolic profiles, than those without the disease.

Turning to the associations between sleep and the risk of MAFLD, the researchers say that “in contrast to previous reports, neither shorter nor longer sleep duration was found to be associated with the risk for MAFLD.”

However, after adjusting for demographics, lifestyles, medication, and preexisting metabolic comorbidities including hypertension, diabetes, and obesity, they found that the risk of MAFLD was significantly associated with late bedtime (defined as after 10 p.m.), at an odds ratio of 1.37 (P < .05).

MAFLD was also linked to snoring, at an odds ratio of 1.59, and to daytime napping for longer than 30 minutes, at an odds ratio of 1.17 (P < .05 for both).

When the team compared low-risk and high-risk sleep factors, they found that participants who had an early bedtime, slept 7-8 hours per night, never or rarely had insomnia or snoring, had infrequent daytime sleepiness, and daytime napping of half-hour or less had an odds ratio for MAFLD vs. other participants of 0.64 (P < .05).

Combining those factors into a healthy sleep score, the team found that each additional increase of healthy sleep score was associated with a fully adjusted odds ratio for MAFLD of 0.84 (P < .05).

In contrast, individuals with poor nocturnal sleep patterns and prolonged daytime napping had a higher risk for developing MAFLD, compared with those with a healthy nocturnal sleep pattern and daytime napping of half-hour or less, at an odds ratio of 2.38 (P < .05).

Further analysis indicated that individuals with a sedentary lifestyle and central obesity had a higher risk of MAFLD, but that the presence of obesity accounted for only 20.8% of the total effect of sleep quality on the risk of MAFLD.

“Taken together, our results suggests that obesity only partially mediates the effect of overall sleep quality on MAFLD,” the authors write.

“Given that large proportions of subjects suffering from poor sleep quality are underdiagnosed and undertreated, our study calls for more research into this field and strategies to improve sleep quality,” Dr. Liu said.

The study was supported by the “National Key R&D Program” of China, the Fundamental Research Funds for the Central Universities (Sun Yat-sen University), Natural Science Foundation of Guangdong Province, the Key Project of Medicine Discipline of Guangzhou, and Basic Research Project of Key Laboratory of Guangzhou.

The authors report no relevant financial relationships.

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

Sleep behaviors, both individually and combined, are associated with an increased risk of developing metabolic dysfunction–associated fatty liver disease (MAFLD), according to a Chinese analysis that suggests the effect may be independent of obesity.

Yan Liu, PhD, from the School of Public Health at Sun Yat-sen University in Guangzhou, China, and colleagues studied data on over 5,000 individuals who self-reported sleep behaviors and underwent liver ultrasound.

Late bedtimes, snoring, and prolonged daytime napping were significantly associated with MAFLD, increasing the risk by 37%, 59%, and 17%, respectively, whereas people with both poor nighttime sleep and prolonged daytime napping had the “highest risk for developing fatty liver disease,” said Dr. Liu in a press release.

In contrast, having any of six healthy sleep behaviors decreased the risk by 16% each, and even a “moderate improvement in sleep quality was related to a 29% reduction in the risk for fatty liver disease,” he added.

The research, published online in the Journal of Clinical Endocrinology & Metabolism, also indicated that obesity accounted for only one fifth of the effect of sleep quality on MAFLD risk.

Rise in unhealthy lifestyles leads to increase in MALFD

The authors write that MAFLD is the “leading chronic liver disease worldwide,” affecting around a quarter of the adult population, and may lead to end-stage liver diseases and extrahepatic complications, thus “posing a major health and economic burden.”

Moreover, the disease prevalence is “soaring at an unanticipated rate,” increasing from 18% to 29% in China over the past decade, because of a “rapid rise in unhealthy lifestyles,” the authors note.

Sleep disturbance is increasingly prevalent, “and an emerging contributor to multiple metabolic disorders,” with insomnia and habitual snoring, for example, positively correlated with hypertension, impaired glucose metabolism, and dyslipidemia, report the authors.

However, whether sleep quality, which includes “several metabolic-related sleep behaviors,” constitutes an independent risk for MAFLD “over and above” the effect of obesity remains unclear.

To investigate further, the researchers examined data from the baseline survey of the community-based, prospective South China Cohort study, which was conducted in four regions of Southern China and involved 5,430 individuals aged 30-79 years.

Between March 2018 and October 2019, the participants self-reported sleep behaviors on the Pittsburgh Sleep Quality Index questionnaire and underwent ultrasound examination of the liver.

MAFLD was diagnosed in those with hepatic steatosis and one of the following:

• Overweight/obesity, defined by this study as a body mass index greater than or equal to 23 kg/m².
• Presence of diabetes.
• Evidence of metabolic dysregulation.

After excluding patients with insufficient data, and those with a history of liver cirrhosis, hepatectomy, or liver cancer, among others, the team included 5,011 individuals with an average age of 64 years and a mean body mass index of 24.31 kg/m². Forty percent were male.

Obesity was present in 13% of participants, whereas 15% had diabetes, 58% hypertension, and 35% metabolic syndrome.

MAFLD was diagnosed in 28% of the study population. They were older, more likely to be female with a higher education, and had a higher prevalence of preexisting metabolic disorders and worse metabolic profiles, than those without the disease.

Turning to the associations between sleep and the risk of MAFLD, the researchers say that “in contrast to previous reports, neither shorter nor longer sleep duration was found to be associated with the risk for MAFLD.”

However, after adjusting for demographics, lifestyles, medication, and preexisting metabolic comorbidities including hypertension, diabetes, and obesity, they found that the risk of MAFLD was significantly associated with late bedtime (defined as after 10 p.m.), at an odds ratio of 1.37 (P < .05).

MAFLD was also linked to snoring, at an odds ratio of 1.59, and to daytime napping for longer than 30 minutes, at an odds ratio of 1.17 (P < .05 for both).

When the team compared low-risk and high-risk sleep factors, they found that participants who had an early bedtime, slept 7-8 hours per night, never or rarely had insomnia or snoring, had infrequent daytime sleepiness, and daytime napping of half-hour or less had an odds ratio for MAFLD vs. other participants of 0.64 (P < .05).

Combining those factors into a healthy sleep score, the team found that each additional increase of healthy sleep score was associated with a fully adjusted odds ratio for MAFLD of 0.84 (P < .05).

In contrast, individuals with poor nocturnal sleep patterns and prolonged daytime napping had a higher risk for developing MAFLD, compared with those with a healthy nocturnal sleep pattern and daytime napping of half-hour or less, at an odds ratio of 2.38 (P < .05).

Further analysis indicated that individuals with a sedentary lifestyle and central obesity had a higher risk of MAFLD, but that the presence of obesity accounted for only 20.8% of the total effect of sleep quality on the risk of MAFLD.

“Taken together, our results suggests that obesity only partially mediates the effect of overall sleep quality on MAFLD,” the authors write.

“Given that large proportions of subjects suffering from poor sleep quality are underdiagnosed and undertreated, our study calls for more research into this field and strategies to improve sleep quality,” Dr. Liu said.

The study was supported by the “National Key R&D Program” of China, the Fundamental Research Funds for the Central Universities (Sun Yat-sen University), Natural Science Foundation of Guangdong Province, the Key Project of Medicine Discipline of Guangzhou, and Basic Research Project of Key Laboratory of Guangzhou.

The authors report no relevant financial relationships.

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

Hepatic protein PP2A-C-alpha may serve as a protective factor against parenteral nutrition–associated hepatic steatosis by improving liver function, according to a recent study published in Cellular and Molecular Gastroenterology and Hepatology.

Parenteral nutrition–associated hepatic steatosis likely involves the down-regulation of hepatic PP2A-C-alpha and consequent increased phosphorylation of Akt2; this in turn alters hepatic lipid metabolism, promotes triglyceride accumulation, and leads to liver injury, wrote the researchers, led by Gulisudumu Maitiabula and Feng Tian of the Research Institute of General Surgery at Jinling Hospital, Nanjing, China, and the Medical School of Nanjing University.

“Our study provides a strong rationale that PP2A-C-alpha may be involved in the pathogenesis of [parenteral nutrition–associated hepatic steatosis],” they wrote. “Further research is merited to establish whether interventions to enhance PP2A function might suppress the development of hepatic steatosis in patients receiving long-term [parenteral nutrition].”

Parenteral nutrition can be a lifesaving therapy for patients with intestinal failure caused by insufficient bowel length or function, the authors noted However, long-term use can lead to potentially fatal complications such as liver disease, but an understanding of the pathological mechanisms behind parenteral nutrition–associated hepatic steatosis limited.

The research team performed comparative proteomic/phosphoproteomic analyses of liver samples from 10 patients with parenteral nutrition–associated hepatic steatosis, as well as 8 cholelithiasis patients as controls, who were admitted to Jinling Hospital between June 2018 and June 2019. The researchers also assessed the effect of PP2A-C-alpha on liver injury from total parenteral nutrition in mice.

The research team found that PP2A-C-alpha was down-regulated in patients and mice with parenteral nutrition–associated hepatic steatosis. In addition, in patients with parenteral nutrition–associated hepatic steatosis, they found enhanced activation of serine/threonine kinase Akt2 and decreased activation of AMPK.

Mice that were given total parenteral nutrition infusion for 14 days developed hepatic steatosis, down-regulation of PP2A-C-alpha, activation of Akt2, and inhibition of AMPK. Hepatocyte-specific deletion of PP2A-C-alpha in mice given parenteral nutrition exacerbated the Akt2 activation, AMPK inhibition, and hepatic steatosis through an effect on fatty acid degradation.

On the other hand, forced expression of PP2A-C-alpha led to reductions in hepatocyte fat deposition and the pathological score for liver steatosis. Overexpression also significantly improved hepatic steatosis, suppressed Akt2, and activated AMPK. In addition, pharmacological activation of Akt2 in mice overexpressing PP2A-C-alpha led to the aggravation of hepatic steatosis.

“Collectively, these observations suggest that [parenteral nutrition] for [more than] 14 days leads to a down-regulation in PP2A-C-alpha expression that activates Akt2-dependent signaling, which would likely lead to hepatic steatosis,” the study authors wrote.

Intervention trials of PP2A-C-alpha in humans have not been performed because PP2A-C-alpha activators or effector analogs were unavailable for clinical use, they wrote. Additional clinical studies are needed to investigate the effects of PP2A-C-alpha intervention on the development of hepatic steatosis in patients receiving long-term parenteral nutrition.

The study was supported by the National Natural Science Foundation of China, the Science Foundation of Outstanding Youth in Jiangsu Province, the National Science and Technology Research Funding for Public Welfare Medical Projects, “The 13th Five-Year Plan” Foundation of Jiangsu Province for Medical Key Talents, and the Natural Science Foundation of Jiangsu Province. The study authors disclosed no conflicts of interest.

Hepatic protein PP2A-C-alpha may serve as a protective factor against parenteral nutrition–associated hepatic steatosis by improving liver function, according to a recent study published in Cellular and Molecular Gastroenterology and Hepatology.

Parenteral nutrition–associated hepatic steatosis likely involves the down-regulation of hepatic PP2A-C-alpha and consequent increased phosphorylation of Akt2; this in turn alters hepatic lipid metabolism, promotes triglyceride accumulation, and leads to liver injury, wrote the researchers, led by Gulisudumu Maitiabula and Feng Tian of the Research Institute of General Surgery at Jinling Hospital, Nanjing, China, and the Medical School of Nanjing University.

“Our study provides a strong rationale that PP2A-C-alpha may be involved in the pathogenesis of [parenteral nutrition–associated hepatic steatosis],” they wrote. “Further research is merited to establish whether interventions to enhance PP2A function might suppress the development of hepatic steatosis in patients receiving long-term [parenteral nutrition].”

Parenteral nutrition can be a lifesaving therapy for patients with intestinal failure caused by insufficient bowel length or function, the authors noted However, long-term use can lead to potentially fatal complications such as liver disease, but an understanding of the pathological mechanisms behind parenteral nutrition–associated hepatic steatosis limited.

The research team performed comparative proteomic/phosphoproteomic analyses of liver samples from 10 patients with parenteral nutrition–associated hepatic steatosis, as well as 8 cholelithiasis patients as controls, who were admitted to Jinling Hospital between June 2018 and June 2019. The researchers also assessed the effect of PP2A-C-alpha on liver injury from total parenteral nutrition in mice.

The research team found that PP2A-C-alpha was down-regulated in patients and mice with parenteral nutrition–associated hepatic steatosis. In addition, in patients with parenteral nutrition–associated hepatic steatosis, they found enhanced activation of serine/threonine kinase Akt2 and decreased activation of AMPK.

Mice that were given total parenteral nutrition infusion for 14 days developed hepatic steatosis, down-regulation of PP2A-C-alpha, activation of Akt2, and inhibition of AMPK. Hepatocyte-specific deletion of PP2A-C-alpha in mice given parenteral nutrition exacerbated the Akt2 activation, AMPK inhibition, and hepatic steatosis through an effect on fatty acid degradation.

On the other hand, forced expression of PP2A-C-alpha led to reductions in hepatocyte fat deposition and the pathological score for liver steatosis. Overexpression also significantly improved hepatic steatosis, suppressed Akt2, and activated AMPK. In addition, pharmacological activation of Akt2 in mice overexpressing PP2A-C-alpha led to the aggravation of hepatic steatosis.

“Collectively, these observations suggest that [parenteral nutrition] for [more than] 14 days leads to a down-regulation in PP2A-C-alpha expression that activates Akt2-dependent signaling, which would likely lead to hepatic steatosis,” the study authors wrote.

Intervention trials of PP2A-C-alpha in humans have not been performed because PP2A-C-alpha activators or effector analogs were unavailable for clinical use, they wrote. Additional clinical studies are needed to investigate the effects of PP2A-C-alpha intervention on the development of hepatic steatosis in patients receiving long-term parenteral nutrition.

The study was supported by the National Natural Science Foundation of China, the Science Foundation of Outstanding Youth in Jiangsu Province, the National Science and Technology Research Funding for Public Welfare Medical Projects, “The 13th Five-Year Plan” Foundation of Jiangsu Province for Medical Key Talents, and the Natural Science Foundation of Jiangsu Province. The study authors disclosed no conflicts of interest.

Hepatic protein PP2A-C-alpha may serve as a protective factor against parenteral nutrition–associated hepatic steatosis by improving liver function, according to a recent study published in Cellular and Molecular Gastroenterology and Hepatology.

Parenteral nutrition–associated hepatic steatosis likely involves the down-regulation of hepatic PP2A-C-alpha and consequent increased phosphorylation of Akt2; this in turn alters hepatic lipid metabolism, promotes triglyceride accumulation, and leads to liver injury, wrote the researchers, led by Gulisudumu Maitiabula and Feng Tian of the Research Institute of General Surgery at Jinling Hospital, Nanjing, China, and the Medical School of Nanjing University.

“Our study provides a strong rationale that PP2A-C-alpha may be involved in the pathogenesis of [parenteral nutrition–associated hepatic steatosis],” they wrote. “Further research is merited to establish whether interventions to enhance PP2A function might suppress the development of hepatic steatosis in patients receiving long-term [parenteral nutrition].”

Parenteral nutrition can be a lifesaving therapy for patients with intestinal failure caused by insufficient bowel length or function, the authors noted However, long-term use can lead to potentially fatal complications such as liver disease, but an understanding of the pathological mechanisms behind parenteral nutrition–associated hepatic steatosis limited.

The research team performed comparative proteomic/phosphoproteomic analyses of liver samples from 10 patients with parenteral nutrition–associated hepatic steatosis, as well as 8 cholelithiasis patients as controls, who were admitted to Jinling Hospital between June 2018 and June 2019. The researchers also assessed the effect of PP2A-C-alpha on liver injury from total parenteral nutrition in mice.

The research team found that PP2A-C-alpha was down-regulated in patients and mice with parenteral nutrition–associated hepatic steatosis. In addition, in patients with parenteral nutrition–associated hepatic steatosis, they found enhanced activation of serine/threonine kinase Akt2 and decreased activation of AMPK.

Mice that were given total parenteral nutrition infusion for 14 days developed hepatic steatosis, down-regulation of PP2A-C-alpha, activation of Akt2, and inhibition of AMPK. Hepatocyte-specific deletion of PP2A-C-alpha in mice given parenteral nutrition exacerbated the Akt2 activation, AMPK inhibition, and hepatic steatosis through an effect on fatty acid degradation.

On the other hand, forced expression of PP2A-C-alpha led to reductions in hepatocyte fat deposition and the pathological score for liver steatosis. Overexpression also significantly improved hepatic steatosis, suppressed Akt2, and activated AMPK. In addition, pharmacological activation of Akt2 in mice overexpressing PP2A-C-alpha led to the aggravation of hepatic steatosis.

“Collectively, these observations suggest that [parenteral nutrition] for [more than] 14 days leads to a down-regulation in PP2A-C-alpha expression that activates Akt2-dependent signaling, which would likely lead to hepatic steatosis,” the study authors wrote.

Intervention trials of PP2A-C-alpha in humans have not been performed because PP2A-C-alpha activators or effector analogs were unavailable for clinical use, they wrote. Additional clinical studies are needed to investigate the effects of PP2A-C-alpha intervention on the development of hepatic steatosis in patients receiving long-term parenteral nutrition.

The study was supported by the National Natural Science Foundation of China, the Science Foundation of Outstanding Youth in Jiangsu Province, the National Science and Technology Research Funding for Public Welfare Medical Projects, “The 13th Five-Year Plan” Foundation of Jiangsu Province for Medical Key Talents, and the Natural Science Foundation of Jiangsu Province. The study authors disclosed no conflicts of interest.

In a case-control study, atherosclerotic risk factors were uncommon in childhood and did not appear to be associated with the pathogenesis of arterial ischemic stroke in children or in early young adulthood.

But by the fourth and fifth decades of life, these risk factors were strongly associated with a significant risk for stroke, heightening that risk almost tenfold.

“While strokes in childhood and very early adulthood are not likely caused by atherosclerotic risk factors, it does look like these risk factors increase throughout early and young adulthood and become significant risk factors for stroke in the 30s and 40s,” lead author Sharon N. Poisson, MD, MAS, associate professor of neurology at the University of Colorado at Denver, Aurora, said in an interview.

The findings were published online in JAMA Neurology.

In this study, the researchers focused on arterial ischemic stroke, not hemorrhagic stroke. “We know that high blood pressure, diabetes, smoking, obesity, all of these are risk factors for ischemic stroke, but what we didn’t know is at what age do those atherosclerotic risk factors actually start to cause stroke,” Dr. Poisson said.

To find out more, she and her team did a case control study of data in the Kaiser Permanente Northern California system, which had been accumulating relevant data over a period of 14 years, from Jan. 1, 2000, through Dec. 31, 2014.

The analysis included 141 children and 455 young adults with arterial ischemic stroke and 1,382 age-matched controls.

The children were divided into two age categories: ages 29 days to 9 years and ages 10-19 years.

In the younger group, there were 69 cases of arterial ischemic stroke. In the older age group, there were 72 cases.

Young adults were divided into three age categories: 20-29 years (n = 71 cases), 30-39 years (144 cases), and 40-49 years (240 cases).

Among pediatric controls, 168 children aged 29 days to 9 years (46.5%) and 196 children aged 10-19 years (53.8%) developed arterial ischemic stroke.

There were 121 cases of ischemic stroke among young adult controls aged 20-29 years, 298 cases among controls aged 30-39 years, and 599 cases in those aged 40-49 years.

Both childhood cases and controls had a low prevalence of documented diagnoses of atherosclerotic risk factors (ARFs). The odds ratio of having any ARFs on arterial ischemic stroke was 1.87 for ages 0-9 years, and 1.00 for ages 10-19.

However, cases rose with age.

The OR was 2.3 for age range 20-29 years, 3.57 for age range 30-39 years, and 4.91 for age range 40-49 years.

The analysis also showed that the OR associated with multiple ARFs was 5.29 for age range 0-9 years, 2.75 for age range 10-19 years, 7.33 for age range 20-29 years, 9.86 for age range 30-39 years, and 9.35 for age range 40-49 years.

Multiple risk factors were rare in children but became more prevalent with each decade of young adult life.

The presumed cause of arterial ischemic stroke was atherosclerosis. Evidence of atherosclerosis was present in 1.4% of those aged 10-19 years, 8.5% of those aged 20-29 years, 21.5% of those aged 30-39 years, and 42.5% of those aged 40-49 years.

“This study tells us that, while stroke in adolescence and very early adulthood may not be caused by atherosclerotic risk factors, starting to accumulate those risk factors early in life clearly increases the risk of stroke in the 30s and 40s. I hope we can get this message across, because the sooner we can treat the risk factors, the better the outcome,” Dr. Poisson said.
 

Prevention starts in childhood

Prevention of cardiovascular disease begins in childhood, which is a paradigm shift from the way cardiovascular disease was thought of a couple of decades ago, noted pediatric cardiologist Guilherme Baptista de Faia, MD, from the Ann & Robert H. Lurie Children’s Hospital in Chicago.

“Our guidelines for risk factor reduction in children aim to address how or when do we screen for these risk factors, how or when do we intervene, and do these interventions impact cardiovascular outcomes later in life? This article is part of the mounting research that aims to understand the relationship between childhood cardiovascular risk factors and early cardiovascular disease,” Dr. Baptista de Faia said.

“There has been an interesting progression in our understanding of the impact of CV risk factors early in life. Large cohorts such as Bogalusa Heart Study, Risk in Young Finns Study, Muscatine Study, the Childhood Determinants of Adult Health, CARDIA, and the International Childhood Cardiovascular Cohorts (i3C) have been instrumental in evaluating this question,” he said.

The knowledge that atherosclerotic risk factors in children can lead to acceleration of atherosclerosis in later life opens the door to preventive medicine, said Dr. Baptista de Faia, who was not part of the study.

“This is where preventive medicine comes in. If we can identify the children at increased risk, can we intervene to improve outcomes later in life?” he said. Familial hypercholesterolemia is “a great example of this. We can screen children early in life, there is an effective treatment, and we know from populations studies that early treatment significantly decreases the risk for cardiovascular disease later in life.”

Dr. Poisson reported that she received grants from the National Institutes of Health during the conduct of this study, which was supported by the NIH.

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

In a case-control study, atherosclerotic risk factors were uncommon in childhood and did not appear to be associated with the pathogenesis of arterial ischemic stroke in children or in early young adulthood.

But by the fourth and fifth decades of life, these risk factors were strongly associated with a significant risk for stroke, heightening that risk almost tenfold.

“While strokes in childhood and very early adulthood are not likely caused by atherosclerotic risk factors, it does look like these risk factors increase throughout early and young adulthood and become significant risk factors for stroke in the 30s and 40s,” lead author Sharon N. Poisson, MD, MAS, associate professor of neurology at the University of Colorado at Denver, Aurora, said in an interview.

The findings were published online in JAMA Neurology.

In this study, the researchers focused on arterial ischemic stroke, not hemorrhagic stroke. “We know that high blood pressure, diabetes, smoking, obesity, all of these are risk factors for ischemic stroke, but what we didn’t know is at what age do those atherosclerotic risk factors actually start to cause stroke,” Dr. Poisson said.

To find out more, she and her team did a case control study of data in the Kaiser Permanente Northern California system, which had been accumulating relevant data over a period of 14 years, from Jan. 1, 2000, through Dec. 31, 2014.

The analysis included 141 children and 455 young adults with arterial ischemic stroke and 1,382 age-matched controls.

The children were divided into two age categories: ages 29 days to 9 years and ages 10-19 years.

In the younger group, there were 69 cases of arterial ischemic stroke. In the older age group, there were 72 cases.

Young adults were divided into three age categories: 20-29 years (n = 71 cases), 30-39 years (144 cases), and 40-49 years (240 cases).

Among pediatric controls, 168 children aged 29 days to 9 years (46.5%) and 196 children aged 10-19 years (53.8%) developed arterial ischemic stroke.

There were 121 cases of ischemic stroke among young adult controls aged 20-29 years, 298 cases among controls aged 30-39 years, and 599 cases in those aged 40-49 years.

Both childhood cases and controls had a low prevalence of documented diagnoses of atherosclerotic risk factors (ARFs). The odds ratio of having any ARFs on arterial ischemic stroke was 1.87 for ages 0-9 years, and 1.00 for ages 10-19.

However, cases rose with age.

The OR was 2.3 for age range 20-29 years, 3.57 for age range 30-39 years, and 4.91 for age range 40-49 years.

The analysis also showed that the OR associated with multiple ARFs was 5.29 for age range 0-9 years, 2.75 for age range 10-19 years, 7.33 for age range 20-29 years, 9.86 for age range 30-39 years, and 9.35 for age range 40-49 years.

Multiple risk factors were rare in children but became more prevalent with each decade of young adult life.

The presumed cause of arterial ischemic stroke was atherosclerosis. Evidence of atherosclerosis was present in 1.4% of those aged 10-19 years, 8.5% of those aged 20-29 years, 21.5% of those aged 30-39 years, and 42.5% of those aged 40-49 years.

“This study tells us that, while stroke in adolescence and very early adulthood may not be caused by atherosclerotic risk factors, starting to accumulate those risk factors early in life clearly increases the risk of stroke in the 30s and 40s. I hope we can get this message across, because the sooner we can treat the risk factors, the better the outcome,” Dr. Poisson said.
 

Prevention starts in childhood

Prevention of cardiovascular disease begins in childhood, which is a paradigm shift from the way cardiovascular disease was thought of a couple of decades ago, noted pediatric cardiologist Guilherme Baptista de Faia, MD, from the Ann & Robert H. Lurie Children’s Hospital in Chicago.

“Our guidelines for risk factor reduction in children aim to address how or when do we screen for these risk factors, how or when do we intervene, and do these interventions impact cardiovascular outcomes later in life? This article is part of the mounting research that aims to understand the relationship between childhood cardiovascular risk factors and early cardiovascular disease,” Dr. Baptista de Faia said.

“There has been an interesting progression in our understanding of the impact of CV risk factors early in life. Large cohorts such as Bogalusa Heart Study, Risk in Young Finns Study, Muscatine Study, the Childhood Determinants of Adult Health, CARDIA, and the International Childhood Cardiovascular Cohorts (i3C) have been instrumental in evaluating this question,” he said.

The knowledge that atherosclerotic risk factors in children can lead to acceleration of atherosclerosis in later life opens the door to preventive medicine, said Dr. Baptista de Faia, who was not part of the study.

“This is where preventive medicine comes in. If we can identify the children at increased risk, can we intervene to improve outcomes later in life?” he said. Familial hypercholesterolemia is “a great example of this. We can screen children early in life, there is an effective treatment, and we know from populations studies that early treatment significantly decreases the risk for cardiovascular disease later in life.”

Dr. Poisson reported that she received grants from the National Institutes of Health during the conduct of this study, which was supported by the NIH.

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

In a case-control study, atherosclerotic risk factors were uncommon in childhood and did not appear to be associated with the pathogenesis of arterial ischemic stroke in children or in early young adulthood.

But by the fourth and fifth decades of life, these risk factors were strongly associated with a significant risk for stroke, heightening that risk almost tenfold.

“While strokes in childhood and very early adulthood are not likely caused by atherosclerotic risk factors, it does look like these risk factors increase throughout early and young adulthood and become significant risk factors for stroke in the 30s and 40s,” lead author Sharon N. Poisson, MD, MAS, associate professor of neurology at the University of Colorado at Denver, Aurora, said in an interview.

The findings were published online in JAMA Neurology.

In this study, the researchers focused on arterial ischemic stroke, not hemorrhagic stroke. “We know that high blood pressure, diabetes, smoking, obesity, all of these are risk factors for ischemic stroke, but what we didn’t know is at what age do those atherosclerotic risk factors actually start to cause stroke,” Dr. Poisson said.

To find out more, she and her team did a case control study of data in the Kaiser Permanente Northern California system, which had been accumulating relevant data over a period of 14 years, from Jan. 1, 2000, through Dec. 31, 2014.

The analysis included 141 children and 455 young adults with arterial ischemic stroke and 1,382 age-matched controls.

The children were divided into two age categories: ages 29 days to 9 years and ages 10-19 years.

In the younger group, there were 69 cases of arterial ischemic stroke. In the older age group, there were 72 cases.

Young adults were divided into three age categories: 20-29 years (n = 71 cases), 30-39 years (144 cases), and 40-49 years (240 cases).

Among pediatric controls, 168 children aged 29 days to 9 years (46.5%) and 196 children aged 10-19 years (53.8%) developed arterial ischemic stroke.

There were 121 cases of ischemic stroke among young adult controls aged 20-29 years, 298 cases among controls aged 30-39 years, and 599 cases in those aged 40-49 years.

Both childhood cases and controls had a low prevalence of documented diagnoses of atherosclerotic risk factors (ARFs). The odds ratio of having any ARFs on arterial ischemic stroke was 1.87 for ages 0-9 years, and 1.00 for ages 10-19.

However, cases rose with age.

The OR was 2.3 for age range 20-29 years, 3.57 for age range 30-39 years, and 4.91 for age range 40-49 years.

The analysis also showed that the OR associated with multiple ARFs was 5.29 for age range 0-9 years, 2.75 for age range 10-19 years, 7.33 for age range 20-29 years, 9.86 for age range 30-39 years, and 9.35 for age range 40-49 years.

Multiple risk factors were rare in children but became more prevalent with each decade of young adult life.

The presumed cause of arterial ischemic stroke was atherosclerosis. Evidence of atherosclerosis was present in 1.4% of those aged 10-19 years, 8.5% of those aged 20-29 years, 21.5% of those aged 30-39 years, and 42.5% of those aged 40-49 years.

“This study tells us that, while stroke in adolescence and very early adulthood may not be caused by atherosclerotic risk factors, starting to accumulate those risk factors early in life clearly increases the risk of stroke in the 30s and 40s. I hope we can get this message across, because the sooner we can treat the risk factors, the better the outcome,” Dr. Poisson said.
 

Prevention starts in childhood

Prevention of cardiovascular disease begins in childhood, which is a paradigm shift from the way cardiovascular disease was thought of a couple of decades ago, noted pediatric cardiologist Guilherme Baptista de Faia, MD, from the Ann & Robert H. Lurie Children’s Hospital in Chicago.

“Our guidelines for risk factor reduction in children aim to address how or when do we screen for these risk factors, how or when do we intervene, and do these interventions impact cardiovascular outcomes later in life? This article is part of the mounting research that aims to understand the relationship between childhood cardiovascular risk factors and early cardiovascular disease,” Dr. Baptista de Faia said.

“There has been an interesting progression in our understanding of the impact of CV risk factors early in life. Large cohorts such as Bogalusa Heart Study, Risk in Young Finns Study, Muscatine Study, the Childhood Determinants of Adult Health, CARDIA, and the International Childhood Cardiovascular Cohorts (i3C) have been instrumental in evaluating this question,” he said.

The knowledge that atherosclerotic risk factors in children can lead to acceleration of atherosclerosis in later life opens the door to preventive medicine, said Dr. Baptista de Faia, who was not part of the study.

“This is where preventive medicine comes in. If we can identify the children at increased risk, can we intervene to improve outcomes later in life?” he said. Familial hypercholesterolemia is “a great example of this. We can screen children early in life, there is an effective treatment, and we know from populations studies that early treatment significantly decreases the risk for cardiovascular disease later in life.”

Dr. Poisson reported that she received grants from the National Institutes of Health during the conduct of this study, which was supported by the NIH.

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

Primary care clinicians often struggle to care for their patients with chronic obstructive pulmonary disease (COPD), thanks to a lack of real-world evidence as to which treatments work best.

As a result, potentially preventable life-threatening exacerbations are common among people with the condition. Central to the problem, some experts believe, is that the average patient bears little resemblance to participants in clinical trials of the medications used to treat COPD.

Indeed, a recent study showed that many COPD patients who were receiving maintenance therapy that should have been controlling their disease experienced severe flare-ups – a finding that caught the researchers by surprise.

“We know the benefit of COPD treatments in the context of clinical trials. However, the kinds of patients in primary care may not completely mimic those in clinical trials,” one of the authors, MeiLan Han, MD, a professor of medicine in the division of pulmonary and critical care at the University of Michigan, Ann Arbor, told this news organization. Dr. Han, a volunteer medical spokesperson for the American Lung Association, added that patients “may not be as adherent to medications in real life as they are in clinical trials.”

Randomized controlled trials that support regulatory drug approvals typically enroll patients who do not have comorbid conditions, who are younger than the average patient with COPD, and who typically are male. Patients are seen in resource-abundant settings designed to maximize adherence to treatment, with supports such as free medication and frequent monitoring – settings far different from those in which most primary care physicians practice.

The authors of the new article said trials conducted with typical patients in primary care settings could help physicians to optimize treatment.

Real-world evidence can shed light on physicians’ intent and on barriers to following guidelines, as well as important patient factors, such as adherence and good inhaler technique, Barbara Yawn, MD, an adjunct professor in the department of family and community health at the University of Minnesota, Minneapolis, and a coauthor of the study, said in an interview.
 

A window onto patient burden

According to the Centers for Disease Control and Prevention, an estimated $15 million Americans have COPD. Annual costs to the health care system approach $50 billion a year. The death rate for COPD has increased since 1969 as death rates of other major killers in the United States, such as heart disease and cancer, declined, according to a 2015 analysis of death records.

The new study, published in the July/August issue of the Annals of Family Medicine, provides a snapshot of COPD’s toll on patients.

Researchers examined electronic health records of 17,192 patients treated at primary care clinics in five states using a dataset maintained by DARTNet Institute, a nonprofit organization that supports research and quality improvement. They also analyzed self-reported assessments from 1,354 patients in the dataset who are in a registry called Advancing the Patient Experience in COPD.

Over half (56%) of patients were female, White (64%), aged 55-84 years (81%), and current or exsmokers (80%). The vast majority had three or more comorbidities, including hypertension, diabetes, and depression.

Serious flare-ups were common; 38% of patients had experienced one or more exacerbations in the previous year. Of registry respondents, half said they had had at least one exacerbation, and 20% said they had been hospitalized for COPD during that period.

Among patients in the registry, 43% reported that COPD had a high or very high impact on their health, and 45% could not walk at a normal pace without losing their breath.

Almost 90% of patients were receiving a maintenance therapy regimen. The number of exacerbations was “somewhat surprising,” the authors say. They write that the findings may indicate that patients were not receiving appropriate treatment or were not complying with their medication regimens and that there may be a need for nonpharmacologic interventions, such as smoking cessation. They also write that physician education is needed to support earlier diagnosis and treatment so as to delay declines in lung function.

The researchers say their findings highlight “the need for more real-life effectiveness trials to better support decision-making at the primary care level.”

Dr. Yawn is a coinvestigator of one such study, called CAPTURE, which is assessing a screening tool for COPD in primary care practices.

At the University of Illinois, Chicago, Jerry Krishnan, MD, PhD, pulmonologist and professor of medicine and public health, is running the RELIANCE study, which is comparing the use of azithromycin and roflumilast in preventing hospitalization and death among patients with COPD who continue to have exacerbations.

Although RELIANCE involves pulmonologists, Dr. Krishnan told this news organization, it offers a model for building real-world evidence on questions relevant to primary care. “We don’t really know if medications used by patients in my clinic are as effective as reported in clinical trials that were used to obtain regulatory approvals by the U.S. Food and Drug Administration,” he said.

Wilson Pace, MD, a family physician and chief medical officer and chief technology officer of DARTNet, said funders of research are becoming aware of the need for real-world studies along with “gold standard” efficacy trials.

Dr. Pace, who helped conduct the new study, said a remaining obstacle to improving care is “a defeatist attitude of clinicians” who are skeptical about the ability of therapy to have an effect.

Real-world evidence could remedy clinician frustrations, he said. When clinicians are shown that they can improve patients’ quality of life and maybe even reduce the cost of care, “then they will hopefully pay attention,” he said.

Some experts who were not involved in the study said the findings offer an illuminating, although incomplete, picture. Nonpharmacologic interventions, the management of other health problems, and access to specialty care are not addressed, and the researchers didn’t have data on treatment adherence, inhaler technique, and patients’ peak inspiratory flow – factors that influence the effectiveness of medications. The study also lacked information on whether patients received pulmonary rehabilitation to help their heart and lungs work better.

Nicola Hanania, MD, a professor of medicine and director of the Airways Clinical Research Center at Baylor College of Medicine, Houston, said the study “adds a lot to what we have known” but pointed out that COPD is grossly underdiagnosed.

According to one analysis of National Health and Nutrition Examination Surveys, 72% of individuals with COPD don’t know they have the condition. Such patients were not included in the study, Dr. Hanania noted.

“We need pragmatic studies over multiple years to better understand” the condition, Dr. Yawn said. Real-world evidence “based in an academic setting or specialty practices is not sufficient,” she added. “We need to see results from patients and clinics that look like what we have.”

The registry was established and funded by Optimum Patient Care Global, a nonprofit organization, and Boehringer Ingelheim. Dr. Han has consulted for Boehringer Ingelheim, GlaxoSmithKline, and AstraZeneca and has received research support from Novartis and Sunovion. Dr. Yawn has served on advisory boards for GlaxoSmithKline, Astra-Zeneca, Novartis, and Boehringer Ingelheim and has received research funds from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, and Novartis. Dr. Krishnan has disclosed no relevant financial relationshps. Dr. Hanania has received honoraria for serving as consultant or advisory board member for GSK, Boehringer Ingelheim, Novartis, Sanofi, AstraZeneca, Teva, Genentech, and Amgen. His institution has received research grant support on his behalf from GSK, Sanofi, Boehringer Ingelheim, AstraZeneca, Genentech, Teva, and Novartis. Dr. Pace is on the advisory board for Mylan and has received stock from Novo Nordisk, Pfizer, Novartis, Johnson & Johnson, Stryker, Amgen, Gilead, and Sanofi.

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

Primary care clinicians often struggle to care for their patients with chronic obstructive pulmonary disease (COPD), thanks to a lack of real-world evidence as to which treatments work best.

As a result, potentially preventable life-threatening exacerbations are common among people with the condition. Central to the problem, some experts believe, is that the average patient bears little resemblance to participants in clinical trials of the medications used to treat COPD.

Indeed, a recent study showed that many COPD patients who were receiving maintenance therapy that should have been controlling their disease experienced severe flare-ups – a finding that caught the researchers by surprise.

“We know the benefit of COPD treatments in the context of clinical trials. However, the kinds of patients in primary care may not completely mimic those in clinical trials,” one of the authors, MeiLan Han, MD, a professor of medicine in the division of pulmonary and critical care at the University of Michigan, Ann Arbor, told this news organization. Dr. Han, a volunteer medical spokesperson for the American Lung Association, added that patients “may not be as adherent to medications in real life as they are in clinical trials.”

Randomized controlled trials that support regulatory drug approvals typically enroll patients who do not have comorbid conditions, who are younger than the average patient with COPD, and who typically are male. Patients are seen in resource-abundant settings designed to maximize adherence to treatment, with supports such as free medication and frequent monitoring – settings far different from those in which most primary care physicians practice.

The authors of the new article said trials conducted with typical patients in primary care settings could help physicians to optimize treatment.

Real-world evidence can shed light on physicians’ intent and on barriers to following guidelines, as well as important patient factors, such as adherence and good inhaler technique, Barbara Yawn, MD, an adjunct professor in the department of family and community health at the University of Minnesota, Minneapolis, and a coauthor of the study, said in an interview.
 

A window onto patient burden

According to the Centers for Disease Control and Prevention, an estimated $15 million Americans have COPD. Annual costs to the health care system approach $50 billion a year. The death rate for COPD has increased since 1969 as death rates of other major killers in the United States, such as heart disease and cancer, declined, according to a 2015 analysis of death records.

The new study, published in the July/August issue of the Annals of Family Medicine, provides a snapshot of COPD’s toll on patients.

Researchers examined electronic health records of 17,192 patients treated at primary care clinics in five states using a dataset maintained by DARTNet Institute, a nonprofit organization that supports research and quality improvement. They also analyzed self-reported assessments from 1,354 patients in the dataset who are in a registry called Advancing the Patient Experience in COPD.

Over half (56%) of patients were female, White (64%), aged 55-84 years (81%), and current or exsmokers (80%). The vast majority had three or more comorbidities, including hypertension, diabetes, and depression.

Serious flare-ups were common; 38% of patients had experienced one or more exacerbations in the previous year. Of registry respondents, half said they had had at least one exacerbation, and 20% said they had been hospitalized for COPD during that period.

Among patients in the registry, 43% reported that COPD had a high or very high impact on their health, and 45% could not walk at a normal pace without losing their breath.

Almost 90% of patients were receiving a maintenance therapy regimen. The number of exacerbations was “somewhat surprising,” the authors say. They write that the findings may indicate that patients were not receiving appropriate treatment or were not complying with their medication regimens and that there may be a need for nonpharmacologic interventions, such as smoking cessation. They also write that physician education is needed to support earlier diagnosis and treatment so as to delay declines in lung function.

The researchers say their findings highlight “the need for more real-life effectiveness trials to better support decision-making at the primary care level.”

Dr. Yawn is a coinvestigator of one such study, called CAPTURE, which is assessing a screening tool for COPD in primary care practices.

At the University of Illinois, Chicago, Jerry Krishnan, MD, PhD, pulmonologist and professor of medicine and public health, is running the RELIANCE study, which is comparing the use of azithromycin and roflumilast in preventing hospitalization and death among patients with COPD who continue to have exacerbations.

Although RELIANCE involves pulmonologists, Dr. Krishnan told this news organization, it offers a model for building real-world evidence on questions relevant to primary care. “We don’t really know if medications used by patients in my clinic are as effective as reported in clinical trials that were used to obtain regulatory approvals by the U.S. Food and Drug Administration,” he said.

Wilson Pace, MD, a family physician and chief medical officer and chief technology officer of DARTNet, said funders of research are becoming aware of the need for real-world studies along with “gold standard” efficacy trials.

Dr. Pace, who helped conduct the new study, said a remaining obstacle to improving care is “a defeatist attitude of clinicians” who are skeptical about the ability of therapy to have an effect.

Real-world evidence could remedy clinician frustrations, he said. When clinicians are shown that they can improve patients’ quality of life and maybe even reduce the cost of care, “then they will hopefully pay attention,” he said.

Some experts who were not involved in the study said the findings offer an illuminating, although incomplete, picture. Nonpharmacologic interventions, the management of other health problems, and access to specialty care are not addressed, and the researchers didn’t have data on treatment adherence, inhaler technique, and patients’ peak inspiratory flow – factors that influence the effectiveness of medications. The study also lacked information on whether patients received pulmonary rehabilitation to help their heart and lungs work better.

Nicola Hanania, MD, a professor of medicine and director of the Airways Clinical Research Center at Baylor College of Medicine, Houston, said the study “adds a lot to what we have known” but pointed out that COPD is grossly underdiagnosed.

According to one analysis of National Health and Nutrition Examination Surveys, 72% of individuals with COPD don’t know they have the condition. Such patients were not included in the study, Dr. Hanania noted.

“We need pragmatic studies over multiple years to better understand” the condition, Dr. Yawn said. Real-world evidence “based in an academic setting or specialty practices is not sufficient,” she added. “We need to see results from patients and clinics that look like what we have.”

The registry was established and funded by Optimum Patient Care Global, a nonprofit organization, and Boehringer Ingelheim. Dr. Han has consulted for Boehringer Ingelheim, GlaxoSmithKline, and AstraZeneca and has received research support from Novartis and Sunovion. Dr. Yawn has served on advisory boards for GlaxoSmithKline, Astra-Zeneca, Novartis, and Boehringer Ingelheim and has received research funds from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, and Novartis. Dr. Krishnan has disclosed no relevant financial relationshps. Dr. Hanania has received honoraria for serving as consultant or advisory board member for GSK, Boehringer Ingelheim, Novartis, Sanofi, AstraZeneca, Teva, Genentech, and Amgen. His institution has received research grant support on his behalf from GSK, Sanofi, Boehringer Ingelheim, AstraZeneca, Genentech, Teva, and Novartis. Dr. Pace is on the advisory board for Mylan and has received stock from Novo Nordisk, Pfizer, Novartis, Johnson & Johnson, Stryker, Amgen, Gilead, and Sanofi.

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

Primary care clinicians often struggle to care for their patients with chronic obstructive pulmonary disease (COPD), thanks to a lack of real-world evidence as to which treatments work best.

As a result, potentially preventable life-threatening exacerbations are common among people with the condition. Central to the problem, some experts believe, is that the average patient bears little resemblance to participants in clinical trials of the medications used to treat COPD.

Indeed, a recent study showed that many COPD patients who were receiving maintenance therapy that should have been controlling their disease experienced severe flare-ups – a finding that caught the researchers by surprise.

“We know the benefit of COPD treatments in the context of clinical trials. However, the kinds of patients in primary care may not completely mimic those in clinical trials,” one of the authors, MeiLan Han, MD, a professor of medicine in the division of pulmonary and critical care at the University of Michigan, Ann Arbor, told this news organization. Dr. Han, a volunteer medical spokesperson for the American Lung Association, added that patients “may not be as adherent to medications in real life as they are in clinical trials.”

Randomized controlled trials that support regulatory drug approvals typically enroll patients who do not have comorbid conditions, who are younger than the average patient with COPD, and who typically are male. Patients are seen in resource-abundant settings designed to maximize adherence to treatment, with supports such as free medication and frequent monitoring – settings far different from those in which most primary care physicians practice.

The authors of the new article said trials conducted with typical patients in primary care settings could help physicians to optimize treatment.

Real-world evidence can shed light on physicians’ intent and on barriers to following guidelines, as well as important patient factors, such as adherence and good inhaler technique, Barbara Yawn, MD, an adjunct professor in the department of family and community health at the University of Minnesota, Minneapolis, and a coauthor of the study, said in an interview.
 

A window onto patient burden

According to the Centers for Disease Control and Prevention, an estimated $15 million Americans have COPD. Annual costs to the health care system approach $50 billion a year. The death rate for COPD has increased since 1969 as death rates of other major killers in the United States, such as heart disease and cancer, declined, according to a 2015 analysis of death records.

The new study, published in the July/August issue of the Annals of Family Medicine, provides a snapshot of COPD’s toll on patients.

Researchers examined electronic health records of 17,192 patients treated at primary care clinics in five states using a dataset maintained by DARTNet Institute, a nonprofit organization that supports research and quality improvement. They also analyzed self-reported assessments from 1,354 patients in the dataset who are in a registry called Advancing the Patient Experience in COPD.

Over half (56%) of patients were female, White (64%), aged 55-84 years (81%), and current or exsmokers (80%). The vast majority had three or more comorbidities, including hypertension, diabetes, and depression.

Serious flare-ups were common; 38% of patients had experienced one or more exacerbations in the previous year. Of registry respondents, half said they had had at least one exacerbation, and 20% said they had been hospitalized for COPD during that period.

Among patients in the registry, 43% reported that COPD had a high or very high impact on their health, and 45% could not walk at a normal pace without losing their breath.

Almost 90% of patients were receiving a maintenance therapy regimen. The number of exacerbations was “somewhat surprising,” the authors say. They write that the findings may indicate that patients were not receiving appropriate treatment or were not complying with their medication regimens and that there may be a need for nonpharmacologic interventions, such as smoking cessation. They also write that physician education is needed to support earlier diagnosis and treatment so as to delay declines in lung function.

The researchers say their findings highlight “the need for more real-life effectiveness trials to better support decision-making at the primary care level.”

Dr. Yawn is a coinvestigator of one such study, called CAPTURE, which is assessing a screening tool for COPD in primary care practices.

At the University of Illinois, Chicago, Jerry Krishnan, MD, PhD, pulmonologist and professor of medicine and public health, is running the RELIANCE study, which is comparing the use of azithromycin and roflumilast in preventing hospitalization and death among patients with COPD who continue to have exacerbations.

Although RELIANCE involves pulmonologists, Dr. Krishnan told this news organization, it offers a model for building real-world evidence on questions relevant to primary care. “We don’t really know if medications used by patients in my clinic are as effective as reported in clinical trials that were used to obtain regulatory approvals by the U.S. Food and Drug Administration,” he said.

Wilson Pace, MD, a family physician and chief medical officer and chief technology officer of DARTNet, said funders of research are becoming aware of the need for real-world studies along with “gold standard” efficacy trials.

Dr. Pace, who helped conduct the new study, said a remaining obstacle to improving care is “a defeatist attitude of clinicians” who are skeptical about the ability of therapy to have an effect.

Real-world evidence could remedy clinician frustrations, he said. When clinicians are shown that they can improve patients’ quality of life and maybe even reduce the cost of care, “then they will hopefully pay attention,” he said.

Some experts who were not involved in the study said the findings offer an illuminating, although incomplete, picture. Nonpharmacologic interventions, the management of other health problems, and access to specialty care are not addressed, and the researchers didn’t have data on treatment adherence, inhaler technique, and patients’ peak inspiratory flow – factors that influence the effectiveness of medications. The study also lacked information on whether patients received pulmonary rehabilitation to help their heart and lungs work better.

Nicola Hanania, MD, a professor of medicine and director of the Airways Clinical Research Center at Baylor College of Medicine, Houston, said the study “adds a lot to what we have known” but pointed out that COPD is grossly underdiagnosed.

According to one analysis of National Health and Nutrition Examination Surveys, 72% of individuals with COPD don’t know they have the condition. Such patients were not included in the study, Dr. Hanania noted.

“We need pragmatic studies over multiple years to better understand” the condition, Dr. Yawn said. Real-world evidence “based in an academic setting or specialty practices is not sufficient,” she added. “We need to see results from patients and clinics that look like what we have.”

The registry was established and funded by Optimum Patient Care Global, a nonprofit organization, and Boehringer Ingelheim. Dr. Han has consulted for Boehringer Ingelheim, GlaxoSmithKline, and AstraZeneca and has received research support from Novartis and Sunovion. Dr. Yawn has served on advisory boards for GlaxoSmithKline, Astra-Zeneca, Novartis, and Boehringer Ingelheim and has received research funds from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, and Novartis. Dr. Krishnan has disclosed no relevant financial relationshps. Dr. Hanania has received honoraria for serving as consultant or advisory board member for GSK, Boehringer Ingelheim, Novartis, Sanofi, AstraZeneca, Teva, Genentech, and Amgen. His institution has received research grant support on his behalf from GSK, Sanofi, Boehringer Ingelheim, AstraZeneca, Genentech, Teva, and Novartis. Dr. Pace is on the advisory board for Mylan and has received stock from Novo Nordisk, Pfizer, Novartis, Johnson & Johnson, Stryker, Amgen, Gilead, and Sanofi.

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

Summer, since 1975, is traditionally a time for the BIG blockbusters to hit theaters. Some are new, others are sequels in successful franchises. Some anticipated, some not as much.

And, in summer 2022, we have the least-wanted sequel in modern history – Polio II: The Return.

Of course, this sequel isn’t in the theaters (unless the concessions staff isn’t washing their hands), definitely isn’t funny, and could potentially cost a lot more money than the latest Marvel Cinematic Universe flick.

Personally and professionally, I’m in the middle generation on the disease. I’m young enough that I never had to worry about catching it or having afflicted classmates. But, as a doctor, I’m old enough to still see the consequences. Like most neurologists, I have a handful of patients who had childhood polio, and still deal with the chronic weakness (and consequent pain and orthopedic issues it brings). Signing off on braces and other mobility aids for them is still commonplace.

One of my attendings in residency was the renowned Parkinson’s disease expert Abraham Lieberman. On rounds it was impossible not to notice his marked limp, a consequence of childhood polio, and he’d tell us what it was like, being a 6-year-old boy and dealing with the disease. You learn as much from hearing firsthand experiences as you do from textbooks.

And now the virus is showing up again. A few victims, a lot of virions circulating in waste water, but it shouldn’t be there at all.

We aren’t in the era when schoolchildren died or were crippled by it. Elementary school kids today don’t see classmates catch polio and never return to school, or see their grieving parents.

To take 1 year: More than 3,000 American children died of polio in 1952, and more than 21,000 were left with lifelong paralysis – many of them still among us.

When you think of an iron lung, you think of polio.

Those were the casualties in a war to save future generations from this, along with smallpox and other horrors.

But today, that war is mostly forgotten. And now scientific evidence is drowned out by whatever’s on Facebook and the hard-earned miracle of vaccination is ignored in favor of a nonmedical “social influencer” on YouTube.

So polio is back. The majority of the population likely has nothing to worry about. But there may be segments that are hit hard, and when they are they will never accept the obvious reasons why. It will be part of a cover-up, or a conspiracy, or whatever the guy on Parler told them it was.

As doctors, we’re in the middle. We have to give patients the best recommendations we can, based on learning, evidence, and experience, but at the same time have to recognize their autonomy. I’m not following someone around to make sure they get vaccinated, or take the medication I prescribed.

But we’re also the ones who can be held legally responsible for bad outcomes, regardless of the actual facts of the matter. On the flip side, you don’t hear about someone suing a Facebook “influencer” for doling out inaccurate, potentially fatal, medical advice.

So cracks appear in herd immunity, and leaks will happen.

A few generations of neurologists, including mine, have completed training without considering polio in a differential diagnosis. It would, of course, get bandied about in grand rounds or at the conference table, but none of us really took it seriously. To us residents it was more of historical note. “Gone with the Wind” and the “Wizard of Oz” both came out in 1939, and while we all knew of them, none of us were going to be watching them at the theaters.

Unlike them, though, polio is trying make it back to prime time. It’s a sequel nobody wanted.

But here it is.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Summer, since 1975, is traditionally a time for the BIG blockbusters to hit theaters. Some are new, others are sequels in successful franchises. Some anticipated, some not as much.

And, in summer 2022, we have the least-wanted sequel in modern history – Polio II: The Return.

Of course, this sequel isn’t in the theaters (unless the concessions staff isn’t washing their hands), definitely isn’t funny, and could potentially cost a lot more money than the latest Marvel Cinematic Universe flick.

Personally and professionally, I’m in the middle generation on the disease. I’m young enough that I never had to worry about catching it or having afflicted classmates. But, as a doctor, I’m old enough to still see the consequences. Like most neurologists, I have a handful of patients who had childhood polio, and still deal with the chronic weakness (and consequent pain and orthopedic issues it brings). Signing off on braces and other mobility aids for them is still commonplace.

One of my attendings in residency was the renowned Parkinson’s disease expert Abraham Lieberman. On rounds it was impossible not to notice his marked limp, a consequence of childhood polio, and he’d tell us what it was like, being a 6-year-old boy and dealing with the disease. You learn as much from hearing firsthand experiences as you do from textbooks.

And now the virus is showing up again. A few victims, a lot of virions circulating in waste water, but it shouldn’t be there at all.

We aren’t in the era when schoolchildren died or were crippled by it. Elementary school kids today don’t see classmates catch polio and never return to school, or see their grieving parents.

To take 1 year: More than 3,000 American children died of polio in 1952, and more than 21,000 were left with lifelong paralysis – many of them still among us.

When you think of an iron lung, you think of polio.

Those were the casualties in a war to save future generations from this, along with smallpox and other horrors.

But today, that war is mostly forgotten. And now scientific evidence is drowned out by whatever’s on Facebook and the hard-earned miracle of vaccination is ignored in favor of a nonmedical “social influencer” on YouTube.

So polio is back. The majority of the population likely has nothing to worry about. But there may be segments that are hit hard, and when they are they will never accept the obvious reasons why. It will be part of a cover-up, or a conspiracy, or whatever the guy on Parler told them it was.

As doctors, we’re in the middle. We have to give patients the best recommendations we can, based on learning, evidence, and experience, but at the same time have to recognize their autonomy. I’m not following someone around to make sure they get vaccinated, or take the medication I prescribed.

But we’re also the ones who can be held legally responsible for bad outcomes, regardless of the actual facts of the matter. On the flip side, you don’t hear about someone suing a Facebook “influencer” for doling out inaccurate, potentially fatal, medical advice.

So cracks appear in herd immunity, and leaks will happen.

A few generations of neurologists, including mine, have completed training without considering polio in a differential diagnosis. It would, of course, get bandied about in grand rounds or at the conference table, but none of us really took it seriously. To us residents it was more of historical note. “Gone with the Wind” and the “Wizard of Oz” both came out in 1939, and while we all knew of them, none of us were going to be watching them at the theaters.

Unlike them, though, polio is trying make it back to prime time. It’s a sequel nobody wanted.

But here it is.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Summer, since 1975, is traditionally a time for the BIG blockbusters to hit theaters. Some are new, others are sequels in successful franchises. Some anticipated, some not as much.

And, in summer 2022, we have the least-wanted sequel in modern history – Polio II: The Return.

Of course, this sequel isn’t in the theaters (unless the concessions staff isn’t washing their hands), definitely isn’t funny, and could potentially cost a lot more money than the latest Marvel Cinematic Universe flick.

Personally and professionally, I’m in the middle generation on the disease. I’m young enough that I never had to worry about catching it or having afflicted classmates. But, as a doctor, I’m old enough to still see the consequences. Like most neurologists, I have a handful of patients who had childhood polio, and still deal with the chronic weakness (and consequent pain and orthopedic issues it brings). Signing off on braces and other mobility aids for them is still commonplace.

One of my attendings in residency was the renowned Parkinson’s disease expert Abraham Lieberman. On rounds it was impossible not to notice his marked limp, a consequence of childhood polio, and he’d tell us what it was like, being a 6-year-old boy and dealing with the disease. You learn as much from hearing firsthand experiences as you do from textbooks.

And now the virus is showing up again. A few victims, a lot of virions circulating in waste water, but it shouldn’t be there at all.

We aren’t in the era when schoolchildren died or were crippled by it. Elementary school kids today don’t see classmates catch polio and never return to school, or see their grieving parents.

To take 1 year: More than 3,000 American children died of polio in 1952, and more than 21,000 were left with lifelong paralysis – many of them still among us.

When you think of an iron lung, you think of polio.

Those were the casualties in a war to save future generations from this, along with smallpox and other horrors.

But today, that war is mostly forgotten. And now scientific evidence is drowned out by whatever’s on Facebook and the hard-earned miracle of vaccination is ignored in favor of a nonmedical “social influencer” on YouTube.

So polio is back. The majority of the population likely has nothing to worry about. But there may be segments that are hit hard, and when they are they will never accept the obvious reasons why. It will be part of a cover-up, or a conspiracy, or whatever the guy on Parler told them it was.

As doctors, we’re in the middle. We have to give patients the best recommendations we can, based on learning, evidence, and experience, but at the same time have to recognize their autonomy. I’m not following someone around to make sure they get vaccinated, or take the medication I prescribed.

But we’re also the ones who can be held legally responsible for bad outcomes, regardless of the actual facts of the matter. On the flip side, you don’t hear about someone suing a Facebook “influencer” for doling out inaccurate, potentially fatal, medical advice.

So cracks appear in herd immunity, and leaks will happen.

A few generations of neurologists, including mine, have completed training without considering polio in a differential diagnosis. It would, of course, get bandied about in grand rounds or at the conference table, but none of us really took it seriously. To us residents it was more of historical note. “Gone with the Wind” and the “Wizard of Oz” both came out in 1939, and while we all knew of them, none of us were going to be watching them at the theaters.

Unlike them, though, polio is trying make it back to prime time. It’s a sequel nobody wanted.

But here it is.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

My group in Rochester, N.Y., examined the current pneumococcal serotypes causing AOM in children. From our data, we can determine the PCV13 vaccine types that escape prevention and cause AOM and understand what effect to expect from the new pneumococcal conjugate vaccines (PCVs) that will be coming soon. There are limited data from middle ear fluid (MEF) cultures on which to base such analyses. Tympanocentesis is the preferred method for securing MEF for culture and our group is unique in providing such data to the Centers for Disease Control and publishing our results on a periodic basis to inform clinicians.

Pneumococci are the second most common cause of acute otitis media (AOM) since the introduction of pneumococcal conjugate vaccines (PCVs) more than 2 decades ago.^1,2 Pneumococcal AOM causes more severe acute disease and more often causes suppurative complications than Haemophilus influenzae, which is the most common cause of AOM. Prevention of pneumococcal AOM will be a highly relevant contributor to cost-effectiveness analyses for the anticipated introduction of PCV15 (Merck) and PCV20 (Pfizer). Both PCV15 and PCV20 have been licensed for adult use; PCV15 licensure for infants and children occurred in June 2022 for invasive pneumococcal disease and is anticipated in the near future for PCV20. They are improvements over PCV13 because they add serotypes that cause invasive pneumococcal diseases, although less so for prevention of AOM, on the basis of our data.

Nasopharyngeal colonization is a necessary pathogenic step in progression to pneumococcal disease. However, not all strains of pneumococci expressing different capsular serotypes are equally virulent and likely to cause disease. In PCV-vaccinated populations, vaccine pressure and antibiotic resistance drive PCV serotype replacement with nonvaccine serotypes (NVTs), gradually reducing the net effectiveness of the vaccines. Therefore, knowledge of prevalent NVTs colonizing the nasopharynx identifies future pneumococcal serotypes most likely to emerge as pathogenic.

We published an effectiveness study of PCV13.³ A relative reduction of 86% in AOM caused by strains expressing PCV13 serotypes was observed in the first few years after PCV13 introduction. The greatest reduction in MEF samples was in serotype 19A, with a relative reduction of 91%. However, over time the vaccine type efficacy of PCV13 against MEF-positive pneumococcal AOM has eroded. There was no clear efficacy against serotype 3, and we still observed cases of serotype 19A and 19F. PCV13 vaccine failures have been even more frequent in Europe (nearly 30% of pneumococcal AOM in Europe is caused by vaccine serotypes) than our data indicate, where about 10% of AOM is caused by PCV13 serotypes.

In our most recent publication covering 2015-2019, we described results from 589 children, aged 6-36 months, from whom we collected 2,042 nasopharyngeal samples.^2,4 During AOM, 495 MEF samples from 319 AOM-infected children were collected (during bilateral infections, tympanocentesis was performed in both ears). Whether bacteria were isolated was based per AOM case, not per tap. The average age of children with AOM was 15 months (range 6-31 months). The three most prevalent nasopharyngeal pneumococcal serotypes were 35B, 23B, and 15B/C. Serotype 35B was the most common at AOM visits in both the nasopharynx and MEF samples followed by serotype 15B/C. Nonsusceptibility among pneumococci to penicillin, azithromycin, and multiple other antibiotics was high. Increasing resistance to ceftriaxone was also observed.

Based on our results, if PCV15 (PCV13 + 22F and 33F) effectiveness is identical to PCV13 for the included serotypes and 100% efficacy for the added serotypes is presumed, PCV15 will reduce pneumococcal AOMs by 8%, pneumococcal nasopharyngeal colonization events at onset of AOM by 6%, and pneumococcal nasopharyngeal colonization events during health by 3%. As for the projected reductions brought about by PCV20 (PCV15 + 8, 10A, 11A, 12F, and 15B), presuming serotype 15B is efficacious against serotype 15C and 100% efficacy for the added serotypes, PCV20 will reduce pneumococcal AOMs by 22%, pneumococcal nasopharyngeal colonization events at onset of AOM by 20%, and pneumococcal nasopharyngeal colonization events during health by 3% (Figure).

The CDC estimated that, in 2004, pneumococcal disease in the United States caused 4 million illness episodes, 22,000 deaths, 445,000 hospitalizations, 774,000 emergency department visits, 5 million outpatient visits, and 4.1 million outpatient antibiotic prescriptions. Direct medical costs totaled $3.5 billion. Pneumonia (866,000 cases) accounted for 22% of all cases and 72% of pneumococcal costs. AOM and sinusitis (1.5 million cases each) composed 75% of cases and 16% of direct medical costs.⁵ However, if indirect costs are taken into account, such as work loss by parents of young children, the cost of pneumococcal disease caused by AOM alone may exceed $6 billion annually⁶ and become dominant in the cost-effectiveness analysis in high-income countries.

Despite widespread use of PCV13, Pneumococcus has shown its resilience under vaccine pressure such that the organism remains a very common AOM pathogen. All-cause AOM has declined modestly and pneumococcal AOM caused by the specific serotypes in PCVs has declined dramatically since the introduction of PCVs. However, the burden of pneumococcal AOM disease is still considerable.

The notion that strains expressing serotypes that were not included in PCV7 were less virulent was proven wrong within a few years after introduction of PCV7, with the emergence of strains expressing serotype 19A, and others. The same cycle occurred after introduction of PCV13. It appears to take about 4 years after introduction of a PCV before peak effectiveness is achieved – which then begins to erode with emergence of NVTs. First, the NVTs are observed to colonize the nasopharynx as commensals and then from among those strains new disease-causing strains emerge.

At the most recent meeting of the International Society of Pneumococci and Pneumococcal Diseases in Toronto in June, many presentations focused on the fact that PCVs elicit highly effective protective serotype-specific antibodies to the capsular polysaccharides of included types. However, 100 serotypes are known. The limitations of PCVs are becoming increasingly apparent. They are costly and consume a large portion of the Vaccines for Children budget. Children in the developing world remain largely unvaccinated because of the high cost. NVTs that have emerged to cause disease vary by country, vary by adult vs. pediatric populations, and are dynamically changing year to year. Forthcoming PCVs of 15 and 20 serotypes will be even more costly than PCV13, will not include many newly emerged serotypes, and will probably likewise encounter “serotype replacement” because of high immune evasion by pneumococci.

When Merck and Pfizer made their decisions on serotype composition for PCV15 and PCV20, respectively, they were based on available data at the time regarding predominant serotypes causing invasive pneumococcal disease in countries that had the best data and would be the market for their products. However, from the time of the decision to licensure of vaccine is many years, and during that time the pneumococcal serotypes have changed, more so for AOM, and I predict more change will occur in the future.

In the past 3 years, Dr. Pichichero has received honoraria from Merck to attend 1-day consulting meetings and his institution has received investigator-initiated research grants to study aspects of PCV15. In the past 3 years, he was reimbursed for expenses to attend the ISPPD meeting in Toronto to present a poster on potential efficacy of PCV20 to prevent complicated AOM.

Dr. Pichichero is a specialist in pediatric infectious diseases, Center for Infectious Diseases and Immunology, and director of the Research Institute, at Rochester (N.Y.) General Hospital.

References

1. Kaur R et al. Pediatrics. 2017;140(3).

2. Kaur R et al. Eur J Clin Microbiol Infect Dis. 2021;41:37-44..

3. Pichichero M et al. Lancet Child Adolesc Health. 2018;2(8):561-8.

4. Zhou F et al. Pediatrics. 2008;121(2):253-60.

5. Huang SS et al. Vaccine. 2011;29(18):3398-412.

6. Casey JR and Pichichero ME. Clin Pediatr (Phila). 2014;53(9):865-73. .
 

My group in Rochester, N.Y., examined the current pneumococcal serotypes causing AOM in children. From our data, we can determine the PCV13 vaccine types that escape prevention and cause AOM and understand what effect to expect from the new pneumococcal conjugate vaccines (PCVs) that will be coming soon. There are limited data from middle ear fluid (MEF) cultures on which to base such analyses. Tympanocentesis is the preferred method for securing MEF for culture and our group is unique in providing such data to the Centers for Disease Control and publishing our results on a periodic basis to inform clinicians.

Pneumococci are the second most common cause of acute otitis media (AOM) since the introduction of pneumococcal conjugate vaccines (PCVs) more than 2 decades ago.^1,2 Pneumococcal AOM causes more severe acute disease and more often causes suppurative complications than Haemophilus influenzae, which is the most common cause of AOM. Prevention of pneumococcal AOM will be a highly relevant contributor to cost-effectiveness analyses for the anticipated introduction of PCV15 (Merck) and PCV20 (Pfizer). Both PCV15 and PCV20 have been licensed for adult use; PCV15 licensure for infants and children occurred in June 2022 for invasive pneumococcal disease and is anticipated in the near future for PCV20. They are improvements over PCV13 because they add serotypes that cause invasive pneumococcal diseases, although less so for prevention of AOM, on the basis of our data.

Nasopharyngeal colonization is a necessary pathogenic step in progression to pneumococcal disease. However, not all strains of pneumococci expressing different capsular serotypes are equally virulent and likely to cause disease. In PCV-vaccinated populations, vaccine pressure and antibiotic resistance drive PCV serotype replacement with nonvaccine serotypes (NVTs), gradually reducing the net effectiveness of the vaccines. Therefore, knowledge of prevalent NVTs colonizing the nasopharynx identifies future pneumococcal serotypes most likely to emerge as pathogenic.

We published an effectiveness study of PCV13.³ A relative reduction of 86% in AOM caused by strains expressing PCV13 serotypes was observed in the first few years after PCV13 introduction. The greatest reduction in MEF samples was in serotype 19A, with a relative reduction of 91%. However, over time the vaccine type efficacy of PCV13 against MEF-positive pneumococcal AOM has eroded. There was no clear efficacy against serotype 3, and we still observed cases of serotype 19A and 19F. PCV13 vaccine failures have been even more frequent in Europe (nearly 30% of pneumococcal AOM in Europe is caused by vaccine serotypes) than our data indicate, where about 10% of AOM is caused by PCV13 serotypes.

In our most recent publication covering 2015-2019, we described results from 589 children, aged 6-36 months, from whom we collected 2,042 nasopharyngeal samples.^2,4 During AOM, 495 MEF samples from 319 AOM-infected children were collected (during bilateral infections, tympanocentesis was performed in both ears). Whether bacteria were isolated was based per AOM case, not per tap. The average age of children with AOM was 15 months (range 6-31 months). The three most prevalent nasopharyngeal pneumococcal serotypes were 35B, 23B, and 15B/C. Serotype 35B was the most common at AOM visits in both the nasopharynx and MEF samples followed by serotype 15B/C. Nonsusceptibility among pneumococci to penicillin, azithromycin, and multiple other antibiotics was high. Increasing resistance to ceftriaxone was also observed.

Based on our results, if PCV15 (PCV13 + 22F and 33F) effectiveness is identical to PCV13 for the included serotypes and 100% efficacy for the added serotypes is presumed, PCV15 will reduce pneumococcal AOMs by 8%, pneumococcal nasopharyngeal colonization events at onset of AOM by 6%, and pneumococcal nasopharyngeal colonization events during health by 3%. As for the projected reductions brought about by PCV20 (PCV15 + 8, 10A, 11A, 12F, and 15B), presuming serotype 15B is efficacious against serotype 15C and 100% efficacy for the added serotypes, PCV20 will reduce pneumococcal AOMs by 22%, pneumococcal nasopharyngeal colonization events at onset of AOM by 20%, and pneumococcal nasopharyngeal colonization events during health by 3% (Figure).

The CDC estimated that, in 2004, pneumococcal disease in the United States caused 4 million illness episodes, 22,000 deaths, 445,000 hospitalizations, 774,000 emergency department visits, 5 million outpatient visits, and 4.1 million outpatient antibiotic prescriptions. Direct medical costs totaled $3.5 billion. Pneumonia (866,000 cases) accounted for 22% of all cases and 72% of pneumococcal costs. AOM and sinusitis (1.5 million cases each) composed 75% of cases and 16% of direct medical costs.⁵ However, if indirect costs are taken into account, such as work loss by parents of young children, the cost of pneumococcal disease caused by AOM alone may exceed $6 billion annually⁶ and become dominant in the cost-effectiveness analysis in high-income countries.

Despite widespread use of PCV13, Pneumococcus has shown its resilience under vaccine pressure such that the organism remains a very common AOM pathogen. All-cause AOM has declined modestly and pneumococcal AOM caused by the specific serotypes in PCVs has declined dramatically since the introduction of PCVs. However, the burden of pneumococcal AOM disease is still considerable.

The notion that strains expressing serotypes that were not included in PCV7 were less virulent was proven wrong within a few years after introduction of PCV7, with the emergence of strains expressing serotype 19A, and others. The same cycle occurred after introduction of PCV13. It appears to take about 4 years after introduction of a PCV before peak effectiveness is achieved – which then begins to erode with emergence of NVTs. First, the NVTs are observed to colonize the nasopharynx as commensals and then from among those strains new disease-causing strains emerge.

At the most recent meeting of the International Society of Pneumococci and Pneumococcal Diseases in Toronto in June, many presentations focused on the fact that PCVs elicit highly effective protective serotype-specific antibodies to the capsular polysaccharides of included types. However, 100 serotypes are known. The limitations of PCVs are becoming increasingly apparent. They are costly and consume a large portion of the Vaccines for Children budget. Children in the developing world remain largely unvaccinated because of the high cost. NVTs that have emerged to cause disease vary by country, vary by adult vs. pediatric populations, and are dynamically changing year to year. Forthcoming PCVs of 15 and 20 serotypes will be even more costly than PCV13, will not include many newly emerged serotypes, and will probably likewise encounter “serotype replacement” because of high immune evasion by pneumococci.

When Merck and Pfizer made their decisions on serotype composition for PCV15 and PCV20, respectively, they were based on available data at the time regarding predominant serotypes causing invasive pneumococcal disease in countries that had the best data and would be the market for their products. However, from the time of the decision to licensure of vaccine is many years, and during that time the pneumococcal serotypes have changed, more so for AOM, and I predict more change will occur in the future.

In the past 3 years, Dr. Pichichero has received honoraria from Merck to attend 1-day consulting meetings and his institution has received investigator-initiated research grants to study aspects of PCV15. In the past 3 years, he was reimbursed for expenses to attend the ISPPD meeting in Toronto to present a poster on potential efficacy of PCV20 to prevent complicated AOM.

Dr. Pichichero is a specialist in pediatric infectious diseases, Center for Infectious Diseases and Immunology, and director of the Research Institute, at Rochester (N.Y.) General Hospital.

References

1. Kaur R et al. Pediatrics. 2017;140(3).

2. Kaur R et al. Eur J Clin Microbiol Infect Dis. 2021;41:37-44..

3. Pichichero M et al. Lancet Child Adolesc Health. 2018;2(8):561-8.

4. Zhou F et al. Pediatrics. 2008;121(2):253-60.

5. Huang SS et al. Vaccine. 2011;29(18):3398-412.

6. Casey JR and Pichichero ME. Clin Pediatr (Phila). 2014;53(9):865-73. .
 

My group in Rochester, N.Y., examined the current pneumococcal serotypes causing AOM in children. From our data, we can determine the PCV13 vaccine types that escape prevention and cause AOM and understand what effect to expect from the new pneumococcal conjugate vaccines (PCVs) that will be coming soon. There are limited data from middle ear fluid (MEF) cultures on which to base such analyses. Tympanocentesis is the preferred method for securing MEF for culture and our group is unique in providing such data to the Centers for Disease Control and publishing our results on a periodic basis to inform clinicians.

Pneumococci are the second most common cause of acute otitis media (AOM) since the introduction of pneumococcal conjugate vaccines (PCVs) more than 2 decades ago.^1,2 Pneumococcal AOM causes more severe acute disease and more often causes suppurative complications than Haemophilus influenzae, which is the most common cause of AOM. Prevention of pneumococcal AOM will be a highly relevant contributor to cost-effectiveness analyses for the anticipated introduction of PCV15 (Merck) and PCV20 (Pfizer). Both PCV15 and PCV20 have been licensed for adult use; PCV15 licensure for infants and children occurred in June 2022 for invasive pneumococcal disease and is anticipated in the near future for PCV20. They are improvements over PCV13 because they add serotypes that cause invasive pneumococcal diseases, although less so for prevention of AOM, on the basis of our data.

Nasopharyngeal colonization is a necessary pathogenic step in progression to pneumococcal disease. However, not all strains of pneumococci expressing different capsular serotypes are equally virulent and likely to cause disease. In PCV-vaccinated populations, vaccine pressure and antibiotic resistance drive PCV serotype replacement with nonvaccine serotypes (NVTs), gradually reducing the net effectiveness of the vaccines. Therefore, knowledge of prevalent NVTs colonizing the nasopharynx identifies future pneumococcal serotypes most likely to emerge as pathogenic.

We published an effectiveness study of PCV13.³ A relative reduction of 86% in AOM caused by strains expressing PCV13 serotypes was observed in the first few years after PCV13 introduction. The greatest reduction in MEF samples was in serotype 19A, with a relative reduction of 91%. However, over time the vaccine type efficacy of PCV13 against MEF-positive pneumococcal AOM has eroded. There was no clear efficacy against serotype 3, and we still observed cases of serotype 19A and 19F. PCV13 vaccine failures have been even more frequent in Europe (nearly 30% of pneumococcal AOM in Europe is caused by vaccine serotypes) than our data indicate, where about 10% of AOM is caused by PCV13 serotypes.

In our most recent publication covering 2015-2019, we described results from 589 children, aged 6-36 months, from whom we collected 2,042 nasopharyngeal samples.^2,4 During AOM, 495 MEF samples from 319 AOM-infected children were collected (during bilateral infections, tympanocentesis was performed in both ears). Whether bacteria were isolated was based per AOM case, not per tap. The average age of children with AOM was 15 months (range 6-31 months). The three most prevalent nasopharyngeal pneumococcal serotypes were 35B, 23B, and 15B/C. Serotype 35B was the most common at AOM visits in both the nasopharynx and MEF samples followed by serotype 15B/C. Nonsusceptibility among pneumococci to penicillin, azithromycin, and multiple other antibiotics was high. Increasing resistance to ceftriaxone was also observed.

Based on our results, if PCV15 (PCV13 + 22F and 33F) effectiveness is identical to PCV13 for the included serotypes and 100% efficacy for the added serotypes is presumed, PCV15 will reduce pneumococcal AOMs by 8%, pneumococcal nasopharyngeal colonization events at onset of AOM by 6%, and pneumococcal nasopharyngeal colonization events during health by 3%. As for the projected reductions brought about by PCV20 (PCV15 + 8, 10A, 11A, 12F, and 15B), presuming serotype 15B is efficacious against serotype 15C and 100% efficacy for the added serotypes, PCV20 will reduce pneumococcal AOMs by 22%, pneumococcal nasopharyngeal colonization events at onset of AOM by 20%, and pneumococcal nasopharyngeal colonization events during health by 3% (Figure).

The CDC estimated that, in 2004, pneumococcal disease in the United States caused 4 million illness episodes, 22,000 deaths, 445,000 hospitalizations, 774,000 emergency department visits, 5 million outpatient visits, and 4.1 million outpatient antibiotic prescriptions. Direct medical costs totaled $3.5 billion. Pneumonia (866,000 cases) accounted for 22% of all cases and 72% of pneumococcal costs. AOM and sinusitis (1.5 million cases each) composed 75% of cases and 16% of direct medical costs.⁵ However, if indirect costs are taken into account, such as work loss by parents of young children, the cost of pneumococcal disease caused by AOM alone may exceed $6 billion annually⁶ and become dominant in the cost-effectiveness analysis in high-income countries.

Despite widespread use of PCV13, Pneumococcus has shown its resilience under vaccine pressure such that the organism remains a very common AOM pathogen. All-cause AOM has declined modestly and pneumococcal AOM caused by the specific serotypes in PCVs has declined dramatically since the introduction of PCVs. However, the burden of pneumococcal AOM disease is still considerable.

The notion that strains expressing serotypes that were not included in PCV7 were less virulent was proven wrong within a few years after introduction of PCV7, with the emergence of strains expressing serotype 19A, and others. The same cycle occurred after introduction of PCV13. It appears to take about 4 years after introduction of a PCV before peak effectiveness is achieved – which then begins to erode with emergence of NVTs. First, the NVTs are observed to colonize the nasopharynx as commensals and then from among those strains new disease-causing strains emerge.

At the most recent meeting of the International Society of Pneumococci and Pneumococcal Diseases in Toronto in June, many presentations focused on the fact that PCVs elicit highly effective protective serotype-specific antibodies to the capsular polysaccharides of included types. However, 100 serotypes are known. The limitations of PCVs are becoming increasingly apparent. They are costly and consume a large portion of the Vaccines for Children budget. Children in the developing world remain largely unvaccinated because of the high cost. NVTs that have emerged to cause disease vary by country, vary by adult vs. pediatric populations, and are dynamically changing year to year. Forthcoming PCVs of 15 and 20 serotypes will be even more costly than PCV13, will not include many newly emerged serotypes, and will probably likewise encounter “serotype replacement” because of high immune evasion by pneumococci.

When Merck and Pfizer made their decisions on serotype composition for PCV15 and PCV20, respectively, they were based on available data at the time regarding predominant serotypes causing invasive pneumococcal disease in countries that had the best data and would be the market for their products. However, from the time of the decision to licensure of vaccine is many years, and during that time the pneumococcal serotypes have changed, more so for AOM, and I predict more change will occur in the future.

In the past 3 years, Dr. Pichichero has received honoraria from Merck to attend 1-day consulting meetings and his institution has received investigator-initiated research grants to study aspects of PCV15. In the past 3 years, he was reimbursed for expenses to attend the ISPPD meeting in Toronto to present a poster on potential efficacy of PCV20 to prevent complicated AOM.

Dr. Pichichero is a specialist in pediatric infectious diseases, Center for Infectious Diseases and Immunology, and director of the Research Institute, at Rochester (N.Y.) General Hospital.

References

1. Kaur R et al. Pediatrics. 2017;140(3).

2. Kaur R et al. Eur J Clin Microbiol Infect Dis. 2021;41:37-44..

3. Pichichero M et al. Lancet Child Adolesc Health. 2018;2(8):561-8.

4. Zhou F et al. Pediatrics. 2008;121(2):253-60.

5. Huang SS et al. Vaccine. 2011;29(18):3398-412.

6. Casey JR and Pichichero ME. Clin Pediatr (Phila). 2014;53(9):865-73. .
 

Lung cancer has been the leading cause of cancer-related mortality for decades. It is also predicted to remain as the leading cause of cancer-related mortality through 2030.¹ Platinum-based chemotherapy, including carboplatin and paclitaxel, was introduced 3 decades ago and revolutionized the management of advanced non–small cell lung cancer (NSCLC). A more recent advancement has been mutant epidermal growth factor receptor–tyrosine kinase (EGFR-TK) inhibitors.¹ EGFR is a transmembrane protein that functions by transducing essential growth factor signaling from the extracellular milieu to the cell. As 60% of the advanced NSCLC expresses this receptor, blocking the mutant EGFR receptor was a groundbreaking development in the management of advanced NSCLC.² Development of mutant EGFR-TK inhibitors has revolutionized the management of advanced NSCLC. This study was conducted to determine the safety profile of mutant EGFR-TK inhibitors in the management of advanced NSCLC.

Methods 

This meta-analysis was conducted according to Cochrane Collaboration guidelines and reported as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The findings are summarized in the PRISMA flow diagram (Figure 1). Two authors (MZ and MM) performed a systematic literature search using databases such as MEDLINE (via PubMed), Embase, and Cochrane Library using the medical search terms and their respective entry words with the following search strategy: safety, “mutant EGFR-TK inhibitors,” advanced, “non–small cell,” “lung cancer,” “adverse effect,” and literature. Additionally, unpublished trials were identified from clinicaltrials.gov, and references of all pertinent articles were also scrutinized to ensure the inclusion of all relevant studies. The search was completed on June 1, 2021, and we only included studies available in English. Two authors (MM and MZ) independently screened the search results in a 2-step process based on predetermined inclusion/exclusion criteria. First, 890 articles were evaluated for relevance on title and abstract level, followed by full-text screening of the final list of 140 articles. Any disagreements were resolved by discussion or third-party review, and a total of 9 articles were included in the study.

The following eligibility criteria were used: original articles reporting adverse effects (AEs) of mutant EGFR-TK inhibitors in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy. All the patients included in the study had an EGFR mutation but randomly assigned to either treatment or control group. All articles with subjective data on mutant EGFR-TK inhibitors AEs in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy were included in the analysis. Only 9 articles qualified the aforementioned selection criteria for eligibility. All qualifying studies were nationwide inpatient or pooled clinical trials data. The reasons for exclusion of the other 71 articles were irrelevant (n = 31), duplicate (n = 13), reviews (n = 14), and poor data reporting (n = 12). Out of the 9 included studies, 9 studies showed correlation of AEs, including rash, diarrhea, nausea, and fatigue. Seven studies showed correlation of AEs including neutropenia, anorexia, and vomiting. Six studies showed correlation of anemia, cough, and stomatitis. Five studies showed correlation of elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and leucopenia. Four studies showed correlation of fever between mutant EGFR-TK inhibitors and platinum-based chemotherapy.

The primary endpoints were reported AEs including rash, diarrhea, elevated ALT, elevated AST, stomatitis, nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever, respectively. Data on baseline characteristics and clinical outcomes were then extracted, and summary tables were created. Summary estimates of the clinical endpoints were then calculated with risk ratio (RR) and 95% confidence intervals (CIs) using the random-effects model. Heterogeneity between studies was examined with the Cochran Q I² statistic which can be defined as low (25% to 50%), moderate (50% to 75%), or high (> 75%). Statistical analysis was performed using Comprehensive Meta-Analysis Software CMA Version 3.0.

Results

A total of 9 studies including 3415 patients (1775 in EGFR-TK inhibitor treatment group while 1640 patients in platinum-based chemotherapy control group) were included in the study. All 9 studies were phase III randomized control clinical trials conducted to compare the safety profile of mutant EGFR-TK inhibitors in patients with advanced NSCLC. Mean age was 61 years in both treatment and control groups. Further details on study and participant characteristics and safety profile including AEs are summarized in Tables 1 and 2. No evidence of publication bias was found.

Rash developed in 45.8% of patients in the treatment group receiving mutant EGFR-TK inhibitors vs only 5.6% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 7.38 with the 95% CI noted, which was statistically significant, confirming higher rash event rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 2).

Diarrhea occurred in 33.6% of patients in the mutant EGFR-TK inhibitors treatment group vs 13.5% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 2.63 and 95% CI was noted, which was statistically significant, confirming higher diarrheal rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 3).

Discussion

Despite the advancement in the treatment of metastatic NSCLC, lung cancer stays as most common cause of cancer-related death in North America and European countries, as patients usually have an advanced disease at the time of diagnosis.³ In the past, platinum-based chemotherapy remained the standard of care for most of the patients affected with advanced NSCLC, but the higher recurrence rate and increase in frequency and intensity of AEs with platinum-based chemotherapy led to the development of targeted therapy for NSCLC, one of which includes mutant EGFR-TK inhibitors, including erlotinib, gefitinib, dacomitinib, lapatinib, and osimertinib.⁴

Smoking is the most common reversible risk factor associated with lung cancer. The EURTAC trial was the first perspective study in this regard, which compared safety and efficacy of mutant EGFR-TK inhibitors with platinum-based chemotherapy. Results analyzed in this study were in favor of mutant EGFR-TK inhibitors except in the group of former smokers.⁵ On the contrary, the OPTIMAL trial showed results in favor of mutant EGFR-TK inhibitors both in active and former smokers; this trial also confirmed the efficacy of mutant EGFR-TK inhibitors in European and Asian populations, confirming the rationale for routine testing of EGFR mutation in all the patients being diagnosed with advanced NSCLC.⁶ Similarly, osimertinib is one of the most recent mutant EGFR-TK inhibitors developed for the treatment of advanced NSCLC in patients with EGFR-positive receptors.

According to the FLAURA trial, patients receiving osimertinib showed significantly longer progression-free survival compared with platinum-based chemotherapy and early mutant EGFR-TK inhibitors. Median progression-free survival was noted to be 18.9 months, which showed 54% lower risk of disease progression in the treatment group receiving osimertinib.⁷ The ARCHER study emphasized a significant improvement in overall survival as well as progression-free survival among a patient population receiving dacomitinib compared with platinum-based chemotherapy.^8,9

Being a potent targeted therapy, mutant EGFR-TK inhibitors do come with some AEs including diarrhea, which was seen in 33.6% of the patients receiving mutant EGFR-TK inhibitors in our study vs 53% in the chemotherapy group, as was observed in the study conducted by Pless and colleagues.¹⁰ Similarly, only 16.5% of patients receiving mutant EGFR-TK inhibitors developed nausea compared with 66% being observed in patients receiving chemotherapy. Correspondingly, only a small fraction of patients (9.7%) receiving mutant EGFR-TK inhibitors developed leucopenia, which was 10 times less reported in mutant EGFR-TK inhibitors compared with patients receiving chemotherapy having a percentage of 100%. A similar trend was reported for neutropenia and anemia in mutant EGFR-TK inhibitors with an incidence of 6.1% and 8.7%, compared with the platinum-based chemotherapy group in which the incidence was found to be 80% and 100%, respectively. It was concluded that platinum-based chemotherapy had played a vital role in the treatment of advanced NSCLC but at an expense of serious and severe AEs which led to discontinuation or withdrawal of treatment, leading to relapse and recurrence of lung cancer.^10,11

Zhong and colleagues conducted a phase 2 randomized clinical trial comparing mutant EGFR-TK inhibitors with platinum-based chemotherapy. They concluded that in patients receiving platinum-based chemotherapy, incidence of rash, vomiting, anorexia, neutropenia, and nausea were 29.4%, 47%, 41.2%, 55.8%, and 32.4% compared with 45.8%, 11%, 21.3%, 6.1%, and 16.5%, respectively, reported in patients receiving mutant EGFR-TK inhibitors for their advanced NSCLC.¹²

Another study was conducted in 2019 by Noronha and colleagues to determine the impact of platinum-based chemotherapy combined with gefitinib on patients with advanced NSCLC.¹³ They concluded that 70% of the patients receiving combination treatment developed rash, which was significantly higher compared with 45.8% patients receiving the mutant EGFR-TK inhibitors alone in our study. Also, 56% of patients receiving combination therapy developed diarrhea vs 33.6% of patients receiving mutant EGFR-TK inhibitors only. Similarly, 96% of patients in the combination therapy group developed some degree of anemia compared with only 8.7% patients in the mutant EGFR-TK inhibitors group included in our study. In the same way, neutropenia was observed in 55% of patients receiving combination therapy vs 6.1% in patients receiving mutant EGFR-TK inhibitors solely. They concluded that mutant EGFR-TK inhibitors when combined with platinum-based chemotherapy increase the incidence of AEs of chemotherapy by many folds.^13,14

Kato and colleagues conducted a study to determine the impact on AEs when erlotinib was combined with anti–vascular endothelial growth factor (VEGF) inhibitors like bevacizumab, they stated that 98.7% of patient in combination therapy developed rash, the incidence of which was only 45.8% in patients receiving mutant EGFR-TK inhibitors as was observed in our study. Similar trends were noticed with other AEs, including diarrhea, fatigue, nausea, and elevated liver enzymes.¹⁵

Conclusions

Our study focused on the safety profile of mutant EGFR-TK inhibitors vs platinum-based chemotherapy in the treatment of advanced NSCLC. Mutant EGFR-TK inhibitors are safer than platinum-based chemotherapy when compared for nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever. On the other end, mutant EGFR-TK inhibitors cause slightly higher AEs, including rash, diarrhea, elevated AST and ALT levels, and stomatitis. However, considering that the development of mutant EGFR-TK inhibitors laid a foundation of targeted therapy, we recommend continuing using mutant EGFR-TK inhibitors in patients with advanced NSCLC especially in patients having mutant EGFR receptors. AEs caused by mutant EGFR-TK inhibitors are significant but are usually tolerable and can be avoided by reducing the dosage of it with each cycle or by skipping or delaying the dose until the patient is symptomatic.

Lung cancer has been the leading cause of cancer-related mortality for decades. It is also predicted to remain as the leading cause of cancer-related mortality through 2030.¹ Platinum-based chemotherapy, including carboplatin and paclitaxel, was introduced 3 decades ago and revolutionized the management of advanced non–small cell lung cancer (NSCLC). A more recent advancement has been mutant epidermal growth factor receptor–tyrosine kinase (EGFR-TK) inhibitors.¹ EGFR is a transmembrane protein that functions by transducing essential growth factor signaling from the extracellular milieu to the cell. As 60% of the advanced NSCLC expresses this receptor, blocking the mutant EGFR receptor was a groundbreaking development in the management of advanced NSCLC.² Development of mutant EGFR-TK inhibitors has revolutionized the management of advanced NSCLC. This study was conducted to determine the safety profile of mutant EGFR-TK inhibitors in the management of advanced NSCLC.

Methods 

This meta-analysis was conducted according to Cochrane Collaboration guidelines and reported as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The findings are summarized in the PRISMA flow diagram (Figure 1). Two authors (MZ and MM) performed a systematic literature search using databases such as MEDLINE (via PubMed), Embase, and Cochrane Library using the medical search terms and their respective entry words with the following search strategy: safety, “mutant EGFR-TK inhibitors,” advanced, “non–small cell,” “lung cancer,” “adverse effect,” and literature. Additionally, unpublished trials were identified from clinicaltrials.gov, and references of all pertinent articles were also scrutinized to ensure the inclusion of all relevant studies. The search was completed on June 1, 2021, and we only included studies available in English. Two authors (MM and MZ) independently screened the search results in a 2-step process based on predetermined inclusion/exclusion criteria. First, 890 articles were evaluated for relevance on title and abstract level, followed by full-text screening of the final list of 140 articles. Any disagreements were resolved by discussion or third-party review, and a total of 9 articles were included in the study.

The following eligibility criteria were used: original articles reporting adverse effects (AEs) of mutant EGFR-TK inhibitors in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy. All the patients included in the study had an EGFR mutation but randomly assigned to either treatment or control group. All articles with subjective data on mutant EGFR-TK inhibitors AEs in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy were included in the analysis. Only 9 articles qualified the aforementioned selection criteria for eligibility. All qualifying studies were nationwide inpatient or pooled clinical trials data. The reasons for exclusion of the other 71 articles were irrelevant (n = 31), duplicate (n = 13), reviews (n = 14), and poor data reporting (n = 12). Out of the 9 included studies, 9 studies showed correlation of AEs, including rash, diarrhea, nausea, and fatigue. Seven studies showed correlation of AEs including neutropenia, anorexia, and vomiting. Six studies showed correlation of anemia, cough, and stomatitis. Five studies showed correlation of elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and leucopenia. Four studies showed correlation of fever between mutant EGFR-TK inhibitors and platinum-based chemotherapy.

The primary endpoints were reported AEs including rash, diarrhea, elevated ALT, elevated AST, stomatitis, nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever, respectively. Data on baseline characteristics and clinical outcomes were then extracted, and summary tables were created. Summary estimates of the clinical endpoints were then calculated with risk ratio (RR) and 95% confidence intervals (CIs) using the random-effects model. Heterogeneity between studies was examined with the Cochran Q I² statistic which can be defined as low (25% to 50%), moderate (50% to 75%), or high (> 75%). Statistical analysis was performed using Comprehensive Meta-Analysis Software CMA Version 3.0.

Results

A total of 9 studies including 3415 patients (1775 in EGFR-TK inhibitor treatment group while 1640 patients in platinum-based chemotherapy control group) were included in the study. All 9 studies were phase III randomized control clinical trials conducted to compare the safety profile of mutant EGFR-TK inhibitors in patients with advanced NSCLC. Mean age was 61 years in both treatment and control groups. Further details on study and participant characteristics and safety profile including AEs are summarized in Tables 1 and 2. No evidence of publication bias was found.

Rash developed in 45.8% of patients in the treatment group receiving mutant EGFR-TK inhibitors vs only 5.6% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 7.38 with the 95% CI noted, which was statistically significant, confirming higher rash event rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 2).

Diarrhea occurred in 33.6% of patients in the mutant EGFR-TK inhibitors treatment group vs 13.5% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 2.63 and 95% CI was noted, which was statistically significant, confirming higher diarrheal rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 3).

Discussion

Despite the advancement in the treatment of metastatic NSCLC, lung cancer stays as most common cause of cancer-related death in North America and European countries, as patients usually have an advanced disease at the time of diagnosis.³ In the past, platinum-based chemotherapy remained the standard of care for most of the patients affected with advanced NSCLC, but the higher recurrence rate and increase in frequency and intensity of AEs with platinum-based chemotherapy led to the development of targeted therapy for NSCLC, one of which includes mutant EGFR-TK inhibitors, including erlotinib, gefitinib, dacomitinib, lapatinib, and osimertinib.⁴

Smoking is the most common reversible risk factor associated with lung cancer. The EURTAC trial was the first perspective study in this regard, which compared safety and efficacy of mutant EGFR-TK inhibitors with platinum-based chemotherapy. Results analyzed in this study were in favor of mutant EGFR-TK inhibitors except in the group of former smokers.⁵ On the contrary, the OPTIMAL trial showed results in favor of mutant EGFR-TK inhibitors both in active and former smokers; this trial also confirmed the efficacy of mutant EGFR-TK inhibitors in European and Asian populations, confirming the rationale for routine testing of EGFR mutation in all the patients being diagnosed with advanced NSCLC.⁶ Similarly, osimertinib is one of the most recent mutant EGFR-TK inhibitors developed for the treatment of advanced NSCLC in patients with EGFR-positive receptors.

According to the FLAURA trial, patients receiving osimertinib showed significantly longer progression-free survival compared with platinum-based chemotherapy and early mutant EGFR-TK inhibitors. Median progression-free survival was noted to be 18.9 months, which showed 54% lower risk of disease progression in the treatment group receiving osimertinib.⁷ The ARCHER study emphasized a significant improvement in overall survival as well as progression-free survival among a patient population receiving dacomitinib compared with platinum-based chemotherapy.^8,9

Being a potent targeted therapy, mutant EGFR-TK inhibitors do come with some AEs including diarrhea, which was seen in 33.6% of the patients receiving mutant EGFR-TK inhibitors in our study vs 53% in the chemotherapy group, as was observed in the study conducted by Pless and colleagues.¹⁰ Similarly, only 16.5% of patients receiving mutant EGFR-TK inhibitors developed nausea compared with 66% being observed in patients receiving chemotherapy. Correspondingly, only a small fraction of patients (9.7%) receiving mutant EGFR-TK inhibitors developed leucopenia, which was 10 times less reported in mutant EGFR-TK inhibitors compared with patients receiving chemotherapy having a percentage of 100%. A similar trend was reported for neutropenia and anemia in mutant EGFR-TK inhibitors with an incidence of 6.1% and 8.7%, compared with the platinum-based chemotherapy group in which the incidence was found to be 80% and 100%, respectively. It was concluded that platinum-based chemotherapy had played a vital role in the treatment of advanced NSCLC but at an expense of serious and severe AEs which led to discontinuation or withdrawal of treatment, leading to relapse and recurrence of lung cancer.^10,11

Zhong and colleagues conducted a phase 2 randomized clinical trial comparing mutant EGFR-TK inhibitors with platinum-based chemotherapy. They concluded that in patients receiving platinum-based chemotherapy, incidence of rash, vomiting, anorexia, neutropenia, and nausea were 29.4%, 47%, 41.2%, 55.8%, and 32.4% compared with 45.8%, 11%, 21.3%, 6.1%, and 16.5%, respectively, reported in patients receiving mutant EGFR-TK inhibitors for their advanced NSCLC.¹²

Another study was conducted in 2019 by Noronha and colleagues to determine the impact of platinum-based chemotherapy combined with gefitinib on patients with advanced NSCLC.¹³ They concluded that 70% of the patients receiving combination treatment developed rash, which was significantly higher compared with 45.8% patients receiving the mutant EGFR-TK inhibitors alone in our study. Also, 56% of patients receiving combination therapy developed diarrhea vs 33.6% of patients receiving mutant EGFR-TK inhibitors only. Similarly, 96% of patients in the combination therapy group developed some degree of anemia compared with only 8.7% patients in the mutant EGFR-TK inhibitors group included in our study. In the same way, neutropenia was observed in 55% of patients receiving combination therapy vs 6.1% in patients receiving mutant EGFR-TK inhibitors solely. They concluded that mutant EGFR-TK inhibitors when combined with platinum-based chemotherapy increase the incidence of AEs of chemotherapy by many folds.^13,14

Kato and colleagues conducted a study to determine the impact on AEs when erlotinib was combined with anti–vascular endothelial growth factor (VEGF) inhibitors like bevacizumab, they stated that 98.7% of patient in combination therapy developed rash, the incidence of which was only 45.8% in patients receiving mutant EGFR-TK inhibitors as was observed in our study. Similar trends were noticed with other AEs, including diarrhea, fatigue, nausea, and elevated liver enzymes.¹⁵

Conclusions

Our study focused on the safety profile of mutant EGFR-TK inhibitors vs platinum-based chemotherapy in the treatment of advanced NSCLC. Mutant EGFR-TK inhibitors are safer than platinum-based chemotherapy when compared for nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever. On the other end, mutant EGFR-TK inhibitors cause slightly higher AEs, including rash, diarrhea, elevated AST and ALT levels, and stomatitis. However, considering that the development of mutant EGFR-TK inhibitors laid a foundation of targeted therapy, we recommend continuing using mutant EGFR-TK inhibitors in patients with advanced NSCLC especially in patients having mutant EGFR receptors. AEs caused by mutant EGFR-TK inhibitors are significant but are usually tolerable and can be avoided by reducing the dosage of it with each cycle or by skipping or delaying the dose until the patient is symptomatic.

Lung cancer has been the leading cause of cancer-related mortality for decades. It is also predicted to remain as the leading cause of cancer-related mortality through 2030.¹ Platinum-based chemotherapy, including carboplatin and paclitaxel, was introduced 3 decades ago and revolutionized the management of advanced non–small cell lung cancer (NSCLC). A more recent advancement has been mutant epidermal growth factor receptor–tyrosine kinase (EGFR-TK) inhibitors.¹ EGFR is a transmembrane protein that functions by transducing essential growth factor signaling from the extracellular milieu to the cell. As 60% of the advanced NSCLC expresses this receptor, blocking the mutant EGFR receptor was a groundbreaking development in the management of advanced NSCLC.² Development of mutant EGFR-TK inhibitors has revolutionized the management of advanced NSCLC. This study was conducted to determine the safety profile of mutant EGFR-TK inhibitors in the management of advanced NSCLC.

Methods 

This meta-analysis was conducted according to Cochrane Collaboration guidelines and reported as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The findings are summarized in the PRISMA flow diagram (Figure 1). Two authors (MZ and MM) performed a systematic literature search using databases such as MEDLINE (via PubMed), Embase, and Cochrane Library using the medical search terms and their respective entry words with the following search strategy: safety, “mutant EGFR-TK inhibitors,” advanced, “non–small cell,” “lung cancer,” “adverse effect,” and literature. Additionally, unpublished trials were identified from clinicaltrials.gov, and references of all pertinent articles were also scrutinized to ensure the inclusion of all relevant studies. The search was completed on June 1, 2021, and we only included studies available in English. Two authors (MM and MZ) independently screened the search results in a 2-step process based on predetermined inclusion/exclusion criteria. First, 890 articles were evaluated for relevance on title and abstract level, followed by full-text screening of the final list of 140 articles. Any disagreements were resolved by discussion or third-party review, and a total of 9 articles were included in the study.

The following eligibility criteria were used: original articles reporting adverse effects (AEs) of mutant EGFR-TK inhibitors in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy. All the patients included in the study had an EGFR mutation but randomly assigned to either treatment or control group. All articles with subjective data on mutant EGFR-TK inhibitors AEs in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy were included in the analysis. Only 9 articles qualified the aforementioned selection criteria for eligibility. All qualifying studies were nationwide inpatient or pooled clinical trials data. The reasons for exclusion of the other 71 articles were irrelevant (n = 31), duplicate (n = 13), reviews (n = 14), and poor data reporting (n = 12). Out of the 9 included studies, 9 studies showed correlation of AEs, including rash, diarrhea, nausea, and fatigue. Seven studies showed correlation of AEs including neutropenia, anorexia, and vomiting. Six studies showed correlation of anemia, cough, and stomatitis. Five studies showed correlation of elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and leucopenia. Four studies showed correlation of fever between mutant EGFR-TK inhibitors and platinum-based chemotherapy.

The primary endpoints were reported AEs including rash, diarrhea, elevated ALT, elevated AST, stomatitis, nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever, respectively. Data on baseline characteristics and clinical outcomes were then extracted, and summary tables were created. Summary estimates of the clinical endpoints were then calculated with risk ratio (RR) and 95% confidence intervals (CIs) using the random-effects model. Heterogeneity between studies was examined with the Cochran Q I² statistic which can be defined as low (25% to 50%), moderate (50% to 75%), or high (> 75%). Statistical analysis was performed using Comprehensive Meta-Analysis Software CMA Version 3.0.

Results

A total of 9 studies including 3415 patients (1775 in EGFR-TK inhibitor treatment group while 1640 patients in platinum-based chemotherapy control group) were included in the study. All 9 studies were phase III randomized control clinical trials conducted to compare the safety profile of mutant EGFR-TK inhibitors in patients with advanced NSCLC. Mean age was 61 years in both treatment and control groups. Further details on study and participant characteristics and safety profile including AEs are summarized in Tables 1 and 2. No evidence of publication bias was found.

Rash developed in 45.8% of patients in the treatment group receiving mutant EGFR-TK inhibitors vs only 5.6% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 7.38 with the 95% CI noted, which was statistically significant, confirming higher rash event rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 2).

Diarrhea occurred in 33.6% of patients in the mutant EGFR-TK inhibitors treatment group vs 13.5% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 2.63 and 95% CI was noted, which was statistically significant, confirming higher diarrheal rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 3).

Discussion

Despite the advancement in the treatment of metastatic NSCLC, lung cancer stays as most common cause of cancer-related death in North America and European countries, as patients usually have an advanced disease at the time of diagnosis.³ In the past, platinum-based chemotherapy remained the standard of care for most of the patients affected with advanced NSCLC, but the higher recurrence rate and increase in frequency and intensity of AEs with platinum-based chemotherapy led to the development of targeted therapy for NSCLC, one of which includes mutant EGFR-TK inhibitors, including erlotinib, gefitinib, dacomitinib, lapatinib, and osimertinib.⁴

Smoking is the most common reversible risk factor associated with lung cancer. The EURTAC trial was the first perspective study in this regard, which compared safety and efficacy of mutant EGFR-TK inhibitors with platinum-based chemotherapy. Results analyzed in this study were in favor of mutant EGFR-TK inhibitors except in the group of former smokers.⁵ On the contrary, the OPTIMAL trial showed results in favor of mutant EGFR-TK inhibitors both in active and former smokers; this trial also confirmed the efficacy of mutant EGFR-TK inhibitors in European and Asian populations, confirming the rationale for routine testing of EGFR mutation in all the patients being diagnosed with advanced NSCLC.⁶ Similarly, osimertinib is one of the most recent mutant EGFR-TK inhibitors developed for the treatment of advanced NSCLC in patients with EGFR-positive receptors.

According to the FLAURA trial, patients receiving osimertinib showed significantly longer progression-free survival compared with platinum-based chemotherapy and early mutant EGFR-TK inhibitors. Median progression-free survival was noted to be 18.9 months, which showed 54% lower risk of disease progression in the treatment group receiving osimertinib.⁷ The ARCHER study emphasized a significant improvement in overall survival as well as progression-free survival among a patient population receiving dacomitinib compared with platinum-based chemotherapy.^8,9

Being a potent targeted therapy, mutant EGFR-TK inhibitors do come with some AEs including diarrhea, which was seen in 33.6% of the patients receiving mutant EGFR-TK inhibitors in our study vs 53% in the chemotherapy group, as was observed in the study conducted by Pless and colleagues.¹⁰ Similarly, only 16.5% of patients receiving mutant EGFR-TK inhibitors developed nausea compared with 66% being observed in patients receiving chemotherapy. Correspondingly, only a small fraction of patients (9.7%) receiving mutant EGFR-TK inhibitors developed leucopenia, which was 10 times less reported in mutant EGFR-TK inhibitors compared with patients receiving chemotherapy having a percentage of 100%. A similar trend was reported for neutropenia and anemia in mutant EGFR-TK inhibitors with an incidence of 6.1% and 8.7%, compared with the platinum-based chemotherapy group in which the incidence was found to be 80% and 100%, respectively. It was concluded that platinum-based chemotherapy had played a vital role in the treatment of advanced NSCLC but at an expense of serious and severe AEs which led to discontinuation or withdrawal of treatment, leading to relapse and recurrence of lung cancer.^10,11

Zhong and colleagues conducted a phase 2 randomized clinical trial comparing mutant EGFR-TK inhibitors with platinum-based chemotherapy. They concluded that in patients receiving platinum-based chemotherapy, incidence of rash, vomiting, anorexia, neutropenia, and nausea were 29.4%, 47%, 41.2%, 55.8%, and 32.4% compared with 45.8%, 11%, 21.3%, 6.1%, and 16.5%, respectively, reported in patients receiving mutant EGFR-TK inhibitors for their advanced NSCLC.¹²

Another study was conducted in 2019 by Noronha and colleagues to determine the impact of platinum-based chemotherapy combined with gefitinib on patients with advanced NSCLC.¹³ They concluded that 70% of the patients receiving combination treatment developed rash, which was significantly higher compared with 45.8% patients receiving the mutant EGFR-TK inhibitors alone in our study. Also, 56% of patients receiving combination therapy developed diarrhea vs 33.6% of patients receiving mutant EGFR-TK inhibitors only. Similarly, 96% of patients in the combination therapy group developed some degree of anemia compared with only 8.7% patients in the mutant EGFR-TK inhibitors group included in our study. In the same way, neutropenia was observed in 55% of patients receiving combination therapy vs 6.1% in patients receiving mutant EGFR-TK inhibitors solely. They concluded that mutant EGFR-TK inhibitors when combined with platinum-based chemotherapy increase the incidence of AEs of chemotherapy by many folds.^13,14

Kato and colleagues conducted a study to determine the impact on AEs when erlotinib was combined with anti–vascular endothelial growth factor (VEGF) inhibitors like bevacizumab, they stated that 98.7% of patient in combination therapy developed rash, the incidence of which was only 45.8% in patients receiving mutant EGFR-TK inhibitors as was observed in our study. Similar trends were noticed with other AEs, including diarrhea, fatigue, nausea, and elevated liver enzymes.¹⁵

Conclusions

Our study focused on the safety profile of mutant EGFR-TK inhibitors vs platinum-based chemotherapy in the treatment of advanced NSCLC. Mutant EGFR-TK inhibitors are safer than platinum-based chemotherapy when compared for nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever. On the other end, mutant EGFR-TK inhibitors cause slightly higher AEs, including rash, diarrhea, elevated AST and ALT levels, and stomatitis. However, considering that the development of mutant EGFR-TK inhibitors laid a foundation of targeted therapy, we recommend continuing using mutant EGFR-TK inhibitors in patients with advanced NSCLC especially in patients having mutant EGFR receptors. AEs caused by mutant EGFR-TK inhibitors are significant but are usually tolerable and can be avoided by reducing the dosage of it with each cycle or by skipping or delaying the dose until the patient is symptomatic.

Gun attacks in classrooms across the nation have led principals and other school leaders to implement “active shooter” drills to try to increase the safety of their students and faculty.

The drills can range from staging lockdowns and sheltering in place to quasi dramas with mock shooters roaming the halls. Although the goals of these training exercises are important, equally important are the potential negative effects of drills on students’ mental health, according to doctors with expertise in pediatrics and mental health.

“Dramatic simulation of an active shooter event at school would be expected to provoke the same stress response as the real thing,” said Peter L. Loper Jr., MD, a pediatrician and psychiatrist, in an interview. “While ensuring their physical safety is very important, we must be intentional about making sure that we are not doing so at the expense of their psychosocial or emotional safety.”

“Children may not be able to differentiate a dramatic drill from a real event,” emphasized Dr. Loper, of the neuropsychiatry and behavioral science departments at the University of South Carolina, Columbia. “The parts of the brain responsible for our flight-fight-or-freeze response would interpret both simulated and real events identically and produce the same neurohormonal stress-response.”

Indeed, a study published in the journal Humanities & Social Sciences Communications suggested children experienced mental health problems related to participating in active shooter drills. In the large study, a team of statisticians from the Georgia Institute of Technology found that students reported a 42% increase in stress and anxiety and a 38.7% increase in depression during the 90 days following active shooter drills, compared with the 90 days before the drills.

The authors of this study, including Mai ElSherief, PhD, drew these conclusions after analyzing 54 million social media posts before and after drills in 114 schools across 33 states. The researchers analyzed the language of the social media posts by teachers, parents, and students and found increased use of the words hope, love, home, school, kids, community, support, and help after the drills. The researchers considered posting with these terms in the aftermath of the drills to be indicative of having high anxiety.

They included examples of how high stress, anxiety, and depression manifested in specific posts from parents in their report. The following is an example of a poster expressing high anxiety and stress: “are we really gonna normalize school shooter drills?! holy sh* there has to be a real way to avoid these tragedies. sh*t like this cannot be normalized. teachers injured after being shot with plastic pellets ‘execution style’ in active shooter drill.”

The authors also shared this post to serve as an example of a person who seems depressed: “and now we are revisiting the trauma on our kids, forcing them to act out school drills monthly. i don’t get why gen x parents buy into this concept wholeheartedly. things need to change.”

The published material did not include posts from students, but the researchers’ analysis of the content of posts overall showed increased concerns for health and increased concerns about death during the period after drills, compared with before drills.

The authors also conducted focus groups in communities in which drills occurred, and many teachers and parents reported anecdotal evidence of children who were nervous long after the drills were over, with some showing extreme reactions such as panic over a standard fire alarm at school. Overall, the results show that school shooter drills can negatively affect school communities over prolonged periods of time, they concluded.

According to a statement from the American Academy of Pediatrics, “there is a need to be cautious about the potential psychological risks and other unintended consequences of directly involving children in live exercises and drills.”

“These risks and consequences are especially a concern when children are deceived and led to believe there is an actual attack and not a drill,” wrote David Schonfeld, MD, the lead author of the statement on Participation of Children and Adolescents in Live Crisis Drills and Exercises, and colleagues.
 

Managing the fallout

Physicians can help students experiencing mental health problems from these drills, according to doctors interviewed for this piece.

It’s important for providers to know that stress will show up differently in children than in adults, said Chelsea Younghans, MD, a psychiatrist and military officer in Bethesda, Md., in an interview.

“They may see children with headaches, stomach aches, or nonspecific complaints. They may also see children who have not had difficulty with sleep present with nightmares or bed wetting,” she added.

For teens and preteens, validated tools such as the Child PTSD Symptom Scale (CPSS-5) and Child and Adolescent Trauma Screen (CATS) to assess PTSD in youth, may help serve as a starting point for a conversation between providers and their older child population, she noted.

Children who exhibit avoidance or withdrawal behaviors including consistent school refusal, an increase in reassurance-seeking behaviors, or somatic symptoms like vague abdominal pain or headaches that prevent school attendance after participating in a drill, may need more robust mental health services, Dr. Loper noted.

Dr. Schonfeld, who is also director of the National Center for School Crisis and Bereavement at Children’s Hospital Los Angeles, called for health care providers to be available to help children process traumatic reactions to these exercises.

Agreeing with Dr. Schonfeld, Dr. Younghans said: “It is vital to debrief with students and staff after drills, making sure that students have a safe space and ample time to speak with trusted staff. As children will undoubtedly have questions and concerns, creating open lines of communication will help alleviate any traumatic effect these drills may have.”
 

Communicating with various stakeholders

Experts also gave recommendations for how clinicians communicate with leaders in their area’s school districts and other members of their communities about these training exercises.

“For primary care providers, it is important to establish meaningful relationships within your community and patient population as much as possible,” Dr. Younghans said. “Having a good relationship with the local schools and being part of the conversation can help increase school and community awareness on the impact these drills can have on students and staff,” she added.

For those pediatricians or other health care providers who serve as consultants to schools, Dr. Schonfeld advised they ask about policies related to exercises and drills, such as what are the limits to what children might be exposed to in a drill, and what requirements there might be at the local and state level in terms of frequency and what the drills will and will not involve.

He also noted that clinicians should encourage school leaders to consider the fact that kids may have personal histories of trauma that are completely unknown to the school when they design these exercises.

School staff and health care providers should explain the nature and reasons for drills, invite family members to express concerns, and make accommodations if necessary for some children to participate in drills in a more limited way, noted Dr. Schonfeld, who is also clinical professor of pediatrics at the University of Southern California, Los Angeles.

“I think health care providers should work with legislators, so that if they require a drill, it must be done in a way that is physically and emotionally safe,” he added.
 

Executing better drills for students’ mental health

Experts also advised on ways to execute these drills that will be least damaging to students.

The AAP statement on Participation of Children and Adolescents in Live Crisis Drills and Exercises, for example, advocates eliminating high-intensity drills, prohibiting deception in drills, and providing accommodations based on children’s vulnerabilities.

Dr. Schonfeld also emphasized, in an interview, that training for an attack need not be extremely realistic to be effective.

“When you are preparing for a crisis, the drills and exercises are for children to practice and develop mastery over something they don’t know how to do fully yet,” said Dr. Schonfeld.

Citing a suggestion from a 2020 report conducted by Everytown for Gun Safety on keeping schools safe from gun violence, Dr. Younghans said, “Schools should be in clear communication with communities and families regarding when drills will be happening,” and advised ensuring that the explanation of drills is developmentally appropriate to the age of the children participating.

The report also recommends conducting drills that do not simulate an actual incident, combining drills with trauma-informed approaches to address students’ well-being during and for a sustained period after the drills, and tracking data on the efficacy and effects of drills.

Dr. Loper suggested ways that clinicians and parents can help navigate the tricky territory of school safety drills.

In his view, they should not be random or unexpected, and anticipatory guidance should be given regarding any visual or auditory stimuli, such as flashing lights or sirens, alarms, or announcements.

“A preventive approach should be utilized to ensure that any child who is experiencing extreme drill-distress be excused from any future disaster drills to prevent retraumatization,” Dr. Loper said.

Physicians interviewed for this piece also provided tips on how to talk about these events with children in a way that is beneficial to their mental health.

“What we want to do is [have a] calm discussion [with kids] about what we are doing and why we are doing it” and guide them through the movements, Dr. Schonfeld said.

When teaching children how to respond to an emergency, some elements of uncertainty need to be discussed. Children need to anticipate “what you might do if you are not in the classroom if something occurs, such as being in the bathroom, or out at recess,” he continued.

Dr. Younghans recommended that parents and staff schedule time to prepare children for the drill and practice in advance, and that behavioral health providers, counselors, and/or primary care providers should be involved in the planning and execution of the drill.

The Georgia Tech study was supported through a grant from Everytown for Gun Safety.

The study authors and experts interviewed for this piece had no financial conflicts to disclose.

Gun attacks in classrooms across the nation have led principals and other school leaders to implement “active shooter” drills to try to increase the safety of their students and faculty.

The drills can range from staging lockdowns and sheltering in place to quasi dramas with mock shooters roaming the halls. Although the goals of these training exercises are important, equally important are the potential negative effects of drills on students’ mental health, according to doctors with expertise in pediatrics and mental health.

“Dramatic simulation of an active shooter event at school would be expected to provoke the same stress response as the real thing,” said Peter L. Loper Jr., MD, a pediatrician and psychiatrist, in an interview. “While ensuring their physical safety is very important, we must be intentional about making sure that we are not doing so at the expense of their psychosocial or emotional safety.”

“Children may not be able to differentiate a dramatic drill from a real event,” emphasized Dr. Loper, of the neuropsychiatry and behavioral science departments at the University of South Carolina, Columbia. “The parts of the brain responsible for our flight-fight-or-freeze response would interpret both simulated and real events identically and produce the same neurohormonal stress-response.”

Indeed, a study published in the journal Humanities & Social Sciences Communications suggested children experienced mental health problems related to participating in active shooter drills. In the large study, a team of statisticians from the Georgia Institute of Technology found that students reported a 42% increase in stress and anxiety and a 38.7% increase in depression during the 90 days following active shooter drills, compared with the 90 days before the drills.

The authors of this study, including Mai ElSherief, PhD, drew these conclusions after analyzing 54 million social media posts before and after drills in 114 schools across 33 states. The researchers analyzed the language of the social media posts by teachers, parents, and students and found increased use of the words hope, love, home, school, kids, community, support, and help after the drills. The researchers considered posting with these terms in the aftermath of the drills to be indicative of having high anxiety.

They included examples of how high stress, anxiety, and depression manifested in specific posts from parents in their report. The following is an example of a poster expressing high anxiety and stress: “are we really gonna normalize school shooter drills?! holy sh* there has to be a real way to avoid these tragedies. sh*t like this cannot be normalized. teachers injured after being shot with plastic pellets ‘execution style’ in active shooter drill.”

The authors also shared this post to serve as an example of a person who seems depressed: “and now we are revisiting the trauma on our kids, forcing them to act out school drills monthly. i don’t get why gen x parents buy into this concept wholeheartedly. things need to change.”

The published material did not include posts from students, but the researchers’ analysis of the content of posts overall showed increased concerns for health and increased concerns about death during the period after drills, compared with before drills.

The authors also conducted focus groups in communities in which drills occurred, and many teachers and parents reported anecdotal evidence of children who were nervous long after the drills were over, with some showing extreme reactions such as panic over a standard fire alarm at school. Overall, the results show that school shooter drills can negatively affect school communities over prolonged periods of time, they concluded.

According to a statement from the American Academy of Pediatrics, “there is a need to be cautious about the potential psychological risks and other unintended consequences of directly involving children in live exercises and drills.”

“These risks and consequences are especially a concern when children are deceived and led to believe there is an actual attack and not a drill,” wrote David Schonfeld, MD, the lead author of the statement on Participation of Children and Adolescents in Live Crisis Drills and Exercises, and colleagues.
 

Managing the fallout

Physicians can help students experiencing mental health problems from these drills, according to doctors interviewed for this piece.

It’s important for providers to know that stress will show up differently in children than in adults, said Chelsea Younghans, MD, a psychiatrist and military officer in Bethesda, Md., in an interview.

“They may see children with headaches, stomach aches, or nonspecific complaints. They may also see children who have not had difficulty with sleep present with nightmares or bed wetting,” she added.

For teens and preteens, validated tools such as the Child PTSD Symptom Scale (CPSS-5) and Child and Adolescent Trauma Screen (CATS) to assess PTSD in youth, may help serve as a starting point for a conversation between providers and their older child population, she noted.

Children who exhibit avoidance or withdrawal behaviors including consistent school refusal, an increase in reassurance-seeking behaviors, or somatic symptoms like vague abdominal pain or headaches that prevent school attendance after participating in a drill, may need more robust mental health services, Dr. Loper noted.

Dr. Schonfeld, who is also director of the National Center for School Crisis and Bereavement at Children’s Hospital Los Angeles, called for health care providers to be available to help children process traumatic reactions to these exercises.

Agreeing with Dr. Schonfeld, Dr. Younghans said: “It is vital to debrief with students and staff after drills, making sure that students have a safe space and ample time to speak with trusted staff. As children will undoubtedly have questions and concerns, creating open lines of communication will help alleviate any traumatic effect these drills may have.”
 

Communicating with various stakeholders

Experts also gave recommendations for how clinicians communicate with leaders in their area’s school districts and other members of their communities about these training exercises.

“For primary care providers, it is important to establish meaningful relationships within your community and patient population as much as possible,” Dr. Younghans said. “Having a good relationship with the local schools and being part of the conversation can help increase school and community awareness on the impact these drills can have on students and staff,” she added.

For those pediatricians or other health care providers who serve as consultants to schools, Dr. Schonfeld advised they ask about policies related to exercises and drills, such as what are the limits to what children might be exposed to in a drill, and what requirements there might be at the local and state level in terms of frequency and what the drills will and will not involve.

He also noted that clinicians should encourage school leaders to consider the fact that kids may have personal histories of trauma that are completely unknown to the school when they design these exercises.

School staff and health care providers should explain the nature and reasons for drills, invite family members to express concerns, and make accommodations if necessary for some children to participate in drills in a more limited way, noted Dr. Schonfeld, who is also clinical professor of pediatrics at the University of Southern California, Los Angeles.

“I think health care providers should work with legislators, so that if they require a drill, it must be done in a way that is physically and emotionally safe,” he added.
 

Executing better drills for students’ mental health

Experts also advised on ways to execute these drills that will be least damaging to students.

The AAP statement on Participation of Children and Adolescents in Live Crisis Drills and Exercises, for example, advocates eliminating high-intensity drills, prohibiting deception in drills, and providing accommodations based on children’s vulnerabilities.

Dr. Schonfeld also emphasized, in an interview, that training for an attack need not be extremely realistic to be effective.

“When you are preparing for a crisis, the drills and exercises are for children to practice and develop mastery over something they don’t know how to do fully yet,” said Dr. Schonfeld.

Citing a suggestion from a 2020 report conducted by Everytown for Gun Safety on keeping schools safe from gun violence, Dr. Younghans said, “Schools should be in clear communication with communities and families regarding when drills will be happening,” and advised ensuring that the explanation of drills is developmentally appropriate to the age of the children participating.

The report also recommends conducting drills that do not simulate an actual incident, combining drills with trauma-informed approaches to address students’ well-being during and for a sustained period after the drills, and tracking data on the efficacy and effects of drills.

Dr. Loper suggested ways that clinicians and parents can help navigate the tricky territory of school safety drills.

In his view, they should not be random or unexpected, and anticipatory guidance should be given regarding any visual or auditory stimuli, such as flashing lights or sirens, alarms, or announcements.

“A preventive approach should be utilized to ensure that any child who is experiencing extreme drill-distress be excused from any future disaster drills to prevent retraumatization,” Dr. Loper said.

Physicians interviewed for this piece also provided tips on how to talk about these events with children in a way that is beneficial to their mental health.

“What we want to do is [have a] calm discussion [with kids] about what we are doing and why we are doing it” and guide them through the movements, Dr. Schonfeld said.

When teaching children how to respond to an emergency, some elements of uncertainty need to be discussed. Children need to anticipate “what you might do if you are not in the classroom if something occurs, such as being in the bathroom, or out at recess,” he continued.

Dr. Younghans recommended that parents and staff schedule time to prepare children for the drill and practice in advance, and that behavioral health providers, counselors, and/or primary care providers should be involved in the planning and execution of the drill.

The Georgia Tech study was supported through a grant from Everytown for Gun Safety.

The study authors and experts interviewed for this piece had no financial conflicts to disclose.

Gun attacks in classrooms across the nation have led principals and other school leaders to implement “active shooter” drills to try to increase the safety of their students and faculty.

The drills can range from staging lockdowns and sheltering in place to quasi dramas with mock shooters roaming the halls. Although the goals of these training exercises are important, equally important are the potential negative effects of drills on students’ mental health, according to doctors with expertise in pediatrics and mental health.

“Dramatic simulation of an active shooter event at school would be expected to provoke the same stress response as the real thing,” said Peter L. Loper Jr., MD, a pediatrician and psychiatrist, in an interview. “While ensuring their physical safety is very important, we must be intentional about making sure that we are not doing so at the expense of their psychosocial or emotional safety.”

“Children may not be able to differentiate a dramatic drill from a real event,” emphasized Dr. Loper, of the neuropsychiatry and behavioral science departments at the University of South Carolina, Columbia. “The parts of the brain responsible for our flight-fight-or-freeze response would interpret both simulated and real events identically and produce the same neurohormonal stress-response.”

Indeed, a study published in the journal Humanities & Social Sciences Communications suggested children experienced mental health problems related to participating in active shooter drills. In the large study, a team of statisticians from the Georgia Institute of Technology found that students reported a 42% increase in stress and anxiety and a 38.7% increase in depression during the 90 days following active shooter drills, compared with the 90 days before the drills.

The authors of this study, including Mai ElSherief, PhD, drew these conclusions after analyzing 54 million social media posts before and after drills in 114 schools across 33 states. The researchers analyzed the language of the social media posts by teachers, parents, and students and found increased use of the words hope, love, home, school, kids, community, support, and help after the drills. The researchers considered posting with these terms in the aftermath of the drills to be indicative of having high anxiety.

They included examples of how high stress, anxiety, and depression manifested in specific posts from parents in their report. The following is an example of a poster expressing high anxiety and stress: “are we really gonna normalize school shooter drills?! holy sh* there has to be a real way to avoid these tragedies. sh*t like this cannot be normalized. teachers injured after being shot with plastic pellets ‘execution style’ in active shooter drill.”

The authors also shared this post to serve as an example of a person who seems depressed: “and now we are revisiting the trauma on our kids, forcing them to act out school drills monthly. i don’t get why gen x parents buy into this concept wholeheartedly. things need to change.”

The published material did not include posts from students, but the researchers’ analysis of the content of posts overall showed increased concerns for health and increased concerns about death during the period after drills, compared with before drills.

The authors also conducted focus groups in communities in which drills occurred, and many teachers and parents reported anecdotal evidence of children who were nervous long after the drills were over, with some showing extreme reactions such as panic over a standard fire alarm at school. Overall, the results show that school shooter drills can negatively affect school communities over prolonged periods of time, they concluded.

According to a statement from the American Academy of Pediatrics, “there is a need to be cautious about the potential psychological risks and other unintended consequences of directly involving children in live exercises and drills.”

“These risks and consequences are especially a concern when children are deceived and led to believe there is an actual attack and not a drill,” wrote David Schonfeld, MD, the lead author of the statement on Participation of Children and Adolescents in Live Crisis Drills and Exercises, and colleagues.
 

Managing the fallout

Physicians can help students experiencing mental health problems from these drills, according to doctors interviewed for this piece.

It’s important for providers to know that stress will show up differently in children than in adults, said Chelsea Younghans, MD, a psychiatrist and military officer in Bethesda, Md., in an interview.

“They may see children with headaches, stomach aches, or nonspecific complaints. They may also see children who have not had difficulty with sleep present with nightmares or bed wetting,” she added.

For teens and preteens, validated tools such as the Child PTSD Symptom Scale (CPSS-5) and Child and Adolescent Trauma Screen (CATS) to assess PTSD in youth, may help serve as a starting point for a conversation between providers and their older child population, she noted.

Children who exhibit avoidance or withdrawal behaviors including consistent school refusal, an increase in reassurance-seeking behaviors, or somatic symptoms like vague abdominal pain or headaches that prevent school attendance after participating in a drill, may need more robust mental health services, Dr. Loper noted.

Dr. Schonfeld, who is also director of the National Center for School Crisis and Bereavement at Children’s Hospital Los Angeles, called for health care providers to be available to help children process traumatic reactions to these exercises.

Agreeing with Dr. Schonfeld, Dr. Younghans said: “It is vital to debrief with students and staff after drills, making sure that students have a safe space and ample time to speak with trusted staff. As children will undoubtedly have questions and concerns, creating open lines of communication will help alleviate any traumatic effect these drills may have.”
 

Communicating with various stakeholders

Experts also gave recommendations for how clinicians communicate with leaders in their area’s school districts and other members of their communities about these training exercises.

“For primary care providers, it is important to establish meaningful relationships within your community and patient population as much as possible,” Dr. Younghans said. “Having a good relationship with the local schools and being part of the conversation can help increase school and community awareness on the impact these drills can have on students and staff,” she added.

For those pediatricians or other health care providers who serve as consultants to schools, Dr. Schonfeld advised they ask about policies related to exercises and drills, such as what are the limits to what children might be exposed to in a drill, and what requirements there might be at the local and state level in terms of frequency and what the drills will and will not involve.

He also noted that clinicians should encourage school leaders to consider the fact that kids may have personal histories of trauma that are completely unknown to the school when they design these exercises.

School staff and health care providers should explain the nature and reasons for drills, invite family members to express concerns, and make accommodations if necessary for some children to participate in drills in a more limited way, noted Dr. Schonfeld, who is also clinical professor of pediatrics at the University of Southern California, Los Angeles.

“I think health care providers should work with legislators, so that if they require a drill, it must be done in a way that is physically and emotionally safe,” he added.
 

Executing better drills for students’ mental health

Experts also advised on ways to execute these drills that will be least damaging to students.

The AAP statement on Participation of Children and Adolescents in Live Crisis Drills and Exercises, for example, advocates eliminating high-intensity drills, prohibiting deception in drills, and providing accommodations based on children’s vulnerabilities.

Dr. Schonfeld also emphasized, in an interview, that training for an attack need not be extremely realistic to be effective.

“When you are preparing for a crisis, the drills and exercises are for children to practice and develop mastery over something they don’t know how to do fully yet,” said Dr. Schonfeld.

Citing a suggestion from a 2020 report conducted by Everytown for Gun Safety on keeping schools safe from gun violence, Dr. Younghans said, “Schools should be in clear communication with communities and families regarding when drills will be happening,” and advised ensuring that the explanation of drills is developmentally appropriate to the age of the children participating.

The report also recommends conducting drills that do not simulate an actual incident, combining drills with trauma-informed approaches to address students’ well-being during and for a sustained period after the drills, and tracking data on the efficacy and effects of drills.

Dr. Loper suggested ways that clinicians and parents can help navigate the tricky territory of school safety drills.

In his view, they should not be random or unexpected, and anticipatory guidance should be given regarding any visual or auditory stimuli, such as flashing lights or sirens, alarms, or announcements.

“A preventive approach should be utilized to ensure that any child who is experiencing extreme drill-distress be excused from any future disaster drills to prevent retraumatization,” Dr. Loper said.

Physicians interviewed for this piece also provided tips on how to talk about these events with children in a way that is beneficial to their mental health.

“What we want to do is [have a] calm discussion [with kids] about what we are doing and why we are doing it” and guide them through the movements, Dr. Schonfeld said.

When teaching children how to respond to an emergency, some elements of uncertainty need to be discussed. Children need to anticipate “what you might do if you are not in the classroom if something occurs, such as being in the bathroom, or out at recess,” he continued.

Dr. Younghans recommended that parents and staff schedule time to prepare children for the drill and practice in advance, and that behavioral health providers, counselors, and/or primary care providers should be involved in the planning and execution of the drill.

The Georgia Tech study was supported through a grant from Everytown for Gun Safety.

The study authors and experts interviewed for this piece had no financial conflicts to disclose.