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Brain connectivity patterns reliably identify ADHD
Functional brain connectivity patterns are a stable biomarker of attention-deficit/hyperactivity disorder, new research suggests.
By applying a machine-learning approach to brain-imaging data, investigators were able to identify with 99% accuracy the adult study participants who had been diagnosed with ADHD in childhood.
“Even though the symptoms of ADHD may be less apparent in adulthood, the brain-wiring signature seems to be persistent,” study investigator Christopher McNorgan, PhD, of the department of psychology, State University of New York at Buffalo told this news organization.
The findings were published online Dec. 17, 2020, in Frontiers of Psychology.
Deep-learning neural networks
The researchers analyzed archived functional magnetic resonance imaging (fMRI) and behavioral data for 80 adults (mean age, 24 years; 64 male). Of these participants, 55 were diagnosed with ADHD in childhood and 25 were not.
The fMRI data were obtained during a response inhibition task that tested the individual’s ability to not respond automatically; for example, not saying “Simon Says” after someone else makes the comment.
The behavioral data included scores on the Iowa Gambling Task (IGT), which is used to measure impulsivity and risk taking.
“Usually, but not always, people with ADHD make riskier choices on this task,” Dr. McNorgan noted.
The investigators measured the amount of interconnectedness among different brain regions during the response inhibition task, which was repeated four times.
Patterns of interconnectivity were then fed into a deep-learning neural network that learned which patterns belonged to the ADHD group vs. those without ADHD (control group) and which patterns belonged to the high vs. low scorers on the IGT.
Caveats, cautionary notes
“The trained models are then tested on brain patterns they had never seen before, and we found the models would make the correct ADHD diagnosis and could tell apart the high and low scorers on the IGT 99% of the time,” Dr. McNorgan reported.
“The trained classifiers make predictions by calculating probabilities, and the neural networks learned how each of the brain connections contributes towards the final classification probability. We identified the set of brain connections that had the greatest influence on these probability calculations,” he noted.
Because the network classified both ADHD diagnosis and gambling task performance, the researchers were able to distinguish between connections that predicted ADHD when gambling performance was poor, as is typical for patients with ADHD, and those predicting ADHD when gambling performance was uncharacteristically good.
While more work is needed, the findings have potential clinical relevance, Dr. McNorgan said.
“ADHD can be difficult to diagnose reliably. If expense wasn’t an issue, fMRI may be able to help make diagnosis more reliable and objective,” he added.
However, because individuals with ADHD have different behavioral profiles, such as scoring atypically well on the IGT, additional studies using this approach may help identify brain networks “that are more or less active in those with ADHD that show a particular diagnostic trait,” he said.
“This could help inform what treatments might be more effective for those individuals,” Dr. McNorgan said.
Of course, he added, “clinicians’ diagnostic expertise is still required, as I would not base an ADHD diagnosis solely on the results of a single brain scan.”
No cross-validation
Commenting on the findings for this news organization, Vince Calhoun, PhD, neuroscientist and founding director of the Center for Translational Research in Neuroimaging and Data Science, Atlanta, a joint effort between Georgia State, Georgia Tech, and Emory University, noted some study limitations.
One cautionary note is that the investigators “appear to select relevant regions to include in the model based on activation to the task, then computed the predictions using the subset of regions that showed strong activation. The issue is this was done on the same data, so there was no cross-validation of this ‘feature selection’ step,” said Dr. Calhoun, who was not involved with the research. “This is a type of circularity which can lead to inflated accuracies,” he added.
Dr. Calhoun also noted that “multiple ADHD classification studies” have reported accuracies above 90%. In addition, there were only 80 participants in the current dataset.
“That’s relatively small for making strong claims about high accuracies as has been reported elsewhere,” he said.
Dr. McNorgan and Dr. Calhoun have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Functional brain connectivity patterns are a stable biomarker of attention-deficit/hyperactivity disorder, new research suggests.
By applying a machine-learning approach to brain-imaging data, investigators were able to identify with 99% accuracy the adult study participants who had been diagnosed with ADHD in childhood.
“Even though the symptoms of ADHD may be less apparent in adulthood, the brain-wiring signature seems to be persistent,” study investigator Christopher McNorgan, PhD, of the department of psychology, State University of New York at Buffalo told this news organization.
The findings were published online Dec. 17, 2020, in Frontiers of Psychology.
Deep-learning neural networks
The researchers analyzed archived functional magnetic resonance imaging (fMRI) and behavioral data for 80 adults (mean age, 24 years; 64 male). Of these participants, 55 were diagnosed with ADHD in childhood and 25 were not.
The fMRI data were obtained during a response inhibition task that tested the individual’s ability to not respond automatically; for example, not saying “Simon Says” after someone else makes the comment.
The behavioral data included scores on the Iowa Gambling Task (IGT), which is used to measure impulsivity and risk taking.
“Usually, but not always, people with ADHD make riskier choices on this task,” Dr. McNorgan noted.
The investigators measured the amount of interconnectedness among different brain regions during the response inhibition task, which was repeated four times.
Patterns of interconnectivity were then fed into a deep-learning neural network that learned which patterns belonged to the ADHD group vs. those without ADHD (control group) and which patterns belonged to the high vs. low scorers on the IGT.
Caveats, cautionary notes
“The trained models are then tested on brain patterns they had never seen before, and we found the models would make the correct ADHD diagnosis and could tell apart the high and low scorers on the IGT 99% of the time,” Dr. McNorgan reported.
“The trained classifiers make predictions by calculating probabilities, and the neural networks learned how each of the brain connections contributes towards the final classification probability. We identified the set of brain connections that had the greatest influence on these probability calculations,” he noted.
Because the network classified both ADHD diagnosis and gambling task performance, the researchers were able to distinguish between connections that predicted ADHD when gambling performance was poor, as is typical for patients with ADHD, and those predicting ADHD when gambling performance was uncharacteristically good.
While more work is needed, the findings have potential clinical relevance, Dr. McNorgan said.
“ADHD can be difficult to diagnose reliably. If expense wasn’t an issue, fMRI may be able to help make diagnosis more reliable and objective,” he added.
However, because individuals with ADHD have different behavioral profiles, such as scoring atypically well on the IGT, additional studies using this approach may help identify brain networks “that are more or less active in those with ADHD that show a particular diagnostic trait,” he said.
“This could help inform what treatments might be more effective for those individuals,” Dr. McNorgan said.
Of course, he added, “clinicians’ diagnostic expertise is still required, as I would not base an ADHD diagnosis solely on the results of a single brain scan.”
No cross-validation
Commenting on the findings for this news organization, Vince Calhoun, PhD, neuroscientist and founding director of the Center for Translational Research in Neuroimaging and Data Science, Atlanta, a joint effort between Georgia State, Georgia Tech, and Emory University, noted some study limitations.
One cautionary note is that the investigators “appear to select relevant regions to include in the model based on activation to the task, then computed the predictions using the subset of regions that showed strong activation. The issue is this was done on the same data, so there was no cross-validation of this ‘feature selection’ step,” said Dr. Calhoun, who was not involved with the research. “This is a type of circularity which can lead to inflated accuracies,” he added.
Dr. Calhoun also noted that “multiple ADHD classification studies” have reported accuracies above 90%. In addition, there were only 80 participants in the current dataset.
“That’s relatively small for making strong claims about high accuracies as has been reported elsewhere,” he said.
Dr. McNorgan and Dr. Calhoun have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Functional brain connectivity patterns are a stable biomarker of attention-deficit/hyperactivity disorder, new research suggests.
By applying a machine-learning approach to brain-imaging data, investigators were able to identify with 99% accuracy the adult study participants who had been diagnosed with ADHD in childhood.
“Even though the symptoms of ADHD may be less apparent in adulthood, the brain-wiring signature seems to be persistent,” study investigator Christopher McNorgan, PhD, of the department of psychology, State University of New York at Buffalo told this news organization.
The findings were published online Dec. 17, 2020, in Frontiers of Psychology.
Deep-learning neural networks
The researchers analyzed archived functional magnetic resonance imaging (fMRI) and behavioral data for 80 adults (mean age, 24 years; 64 male). Of these participants, 55 were diagnosed with ADHD in childhood and 25 were not.
The fMRI data were obtained during a response inhibition task that tested the individual’s ability to not respond automatically; for example, not saying “Simon Says” after someone else makes the comment.
The behavioral data included scores on the Iowa Gambling Task (IGT), which is used to measure impulsivity and risk taking.
“Usually, but not always, people with ADHD make riskier choices on this task,” Dr. McNorgan noted.
The investigators measured the amount of interconnectedness among different brain regions during the response inhibition task, which was repeated four times.
Patterns of interconnectivity were then fed into a deep-learning neural network that learned which patterns belonged to the ADHD group vs. those without ADHD (control group) and which patterns belonged to the high vs. low scorers on the IGT.
Caveats, cautionary notes
“The trained models are then tested on brain patterns they had never seen before, and we found the models would make the correct ADHD diagnosis and could tell apart the high and low scorers on the IGT 99% of the time,” Dr. McNorgan reported.
“The trained classifiers make predictions by calculating probabilities, and the neural networks learned how each of the brain connections contributes towards the final classification probability. We identified the set of brain connections that had the greatest influence on these probability calculations,” he noted.
Because the network classified both ADHD diagnosis and gambling task performance, the researchers were able to distinguish between connections that predicted ADHD when gambling performance was poor, as is typical for patients with ADHD, and those predicting ADHD when gambling performance was uncharacteristically good.
While more work is needed, the findings have potential clinical relevance, Dr. McNorgan said.
“ADHD can be difficult to diagnose reliably. If expense wasn’t an issue, fMRI may be able to help make diagnosis more reliable and objective,” he added.
However, because individuals with ADHD have different behavioral profiles, such as scoring atypically well on the IGT, additional studies using this approach may help identify brain networks “that are more or less active in those with ADHD that show a particular diagnostic trait,” he said.
“This could help inform what treatments might be more effective for those individuals,” Dr. McNorgan said.
Of course, he added, “clinicians’ diagnostic expertise is still required, as I would not base an ADHD diagnosis solely on the results of a single brain scan.”
No cross-validation
Commenting on the findings for this news organization, Vince Calhoun, PhD, neuroscientist and founding director of the Center for Translational Research in Neuroimaging and Data Science, Atlanta, a joint effort between Georgia State, Georgia Tech, and Emory University, noted some study limitations.
One cautionary note is that the investigators “appear to select relevant regions to include in the model based on activation to the task, then computed the predictions using the subset of regions that showed strong activation. The issue is this was done on the same data, so there was no cross-validation of this ‘feature selection’ step,” said Dr. Calhoun, who was not involved with the research. “This is a type of circularity which can lead to inflated accuracies,” he added.
Dr. Calhoun also noted that “multiple ADHD classification studies” have reported accuracies above 90%. In addition, there were only 80 participants in the current dataset.
“That’s relatively small for making strong claims about high accuracies as has been reported elsewhere,” he said.
Dr. McNorgan and Dr. Calhoun have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Updated WIC in pregnancy boosts infant outcomes
Developmental outcomes in the first 2 years of life improved in children whose mothers received the revised Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) while pregnant, based on data from approximately 1,200 women.
Maternal nutrition is essential to healthy fetal development, and the WIC was revised in 2009 to align with current dietary guidelines and to support the health of women and children in low-income households, wrote Alice Guan, MPH, of the University of California, San Francisco, and colleagues.
“However, no researchers, to our knowledge, have evaluated effects of this revision on downstream child health or development,” they said.
In a study published in Pediatrics, the researchers reviewed data from mothers and their children who participated in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) longitudinal cohort study conducted in Tennessee between 2006 and 2011. Their quasi-experimental analysis included 700 women who received WIC during pregnancy and 525 women who did not.
The researchers considered core developmental outcomes of child growth, cognitive development, and socioemotional development at age 12 months and 24 months, and age 4-6 years.
Overall, infants of women who received the WIC food package showed significant increases in length-for-age z scores at 12 months of age (.33, representing approximately one-fifth of a standard deviation), compared to infants of women who did not receive the revised WIC package.
In addition, the Bayley Scales of Infant Development cognitive composite score showed a 4.3-point increase at 24 months of age (approximately one-third of a standard deviation) compared to infants of women who did not receive the revised WIC package.
No effects on growth at age 24 months or on cognitive development at age 4-6 years were noted, which suggests that the impact of the WIC program during pregnancy may fade over time, the researchers said.
“The magnitude of the findings in this study represents clinically relevant effect sizes and provides evidence that one of the largest U.S. safety net policies improves developmental outcomes among low-income and marginalized children,” they noted.
The study findings were limited by several factors including the statistical, quasi-experimental design; the reliance on self-reports for information on income, receipt of WIC, and other variables; and a potential lack of generalizability to other states, the researchers noted. However, the results support findings from previous studies and were strengthened by the review of multiple outcomes and use of a longitudinal database, they said.
“These findings provide timely and critical evidence for the role that WIC plays in improving the health of the nation’s most vulnerable populations, suggesting meaningful impacts of the revised WIC food package on child development,” the researchers said. In addition, “considering the relatively modest scope of the 2009 revision, more substantial updates to the program based on up-to-date nutritional guidance may have substantial effects on improving the health of WIC recipients,” they concluded.
Findings support program’s value
“Pediatrics has always had a commitment to reducing disparities in health care, and we are the main clinicians to see many Medicaid patients on a regular basis,” Herschel Lessin, MD, of Children’s Medical Group, Poughkeepsie, N.Y., said in an interview.
“We all know that pregnant women eating nutritiously ought to help child outcomes, but the current study provides an evidence base for something that seems like common sense,” he noted.
Having such an evidence base is helpful to reinforce the value of the WIC program for its intended recipients, especially in the wake of the COVID-19 pandemic when many funding sources are stretched thin, Dr. Lessin said.
The WIC is intended to try to reduce racial and socioeconomic disparities in the most basic form possible, by helping people who are disadvantaged get enough high-quality food to eat, but results of the program’s impact have not been well studied, he said.
“Outcomes are fiendishly difficult to measure,” and the study is subject to the limitations of its statistical nature, he said. But the large sample size adds support to the findings, which are encouraging, Dr. Lessin noted.
Other potential areas for research include comparing the quality of WIC programs in different states, but such research is very difficult, Dr. Lessin noted. However, the findings might encourage states with less robust WIC programs to consider increasing support, he said.
The study was funded by the National Institutes of Health (National Heart, Lung, and Blood Institute); the National Institute on Aging; the University of California, San Francisco, National Center of Excellence in Women’s Health; and the Urban Child Institute. The researchers had no financial conflicts to disclose. Dr. Lessin serves on the editorial advisory board of Pediatric News and had no relevant financial conflicts to disclose.
Developmental outcomes in the first 2 years of life improved in children whose mothers received the revised Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) while pregnant, based on data from approximately 1,200 women.
Maternal nutrition is essential to healthy fetal development, and the WIC was revised in 2009 to align with current dietary guidelines and to support the health of women and children in low-income households, wrote Alice Guan, MPH, of the University of California, San Francisco, and colleagues.
“However, no researchers, to our knowledge, have evaluated effects of this revision on downstream child health or development,” they said.
In a study published in Pediatrics, the researchers reviewed data from mothers and their children who participated in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) longitudinal cohort study conducted in Tennessee between 2006 and 2011. Their quasi-experimental analysis included 700 women who received WIC during pregnancy and 525 women who did not.
The researchers considered core developmental outcomes of child growth, cognitive development, and socioemotional development at age 12 months and 24 months, and age 4-6 years.
Overall, infants of women who received the WIC food package showed significant increases in length-for-age z scores at 12 months of age (.33, representing approximately one-fifth of a standard deviation), compared to infants of women who did not receive the revised WIC package.
In addition, the Bayley Scales of Infant Development cognitive composite score showed a 4.3-point increase at 24 months of age (approximately one-third of a standard deviation) compared to infants of women who did not receive the revised WIC package.
No effects on growth at age 24 months or on cognitive development at age 4-6 years were noted, which suggests that the impact of the WIC program during pregnancy may fade over time, the researchers said.
“The magnitude of the findings in this study represents clinically relevant effect sizes and provides evidence that one of the largest U.S. safety net policies improves developmental outcomes among low-income and marginalized children,” they noted.
The study findings were limited by several factors including the statistical, quasi-experimental design; the reliance on self-reports for information on income, receipt of WIC, and other variables; and a potential lack of generalizability to other states, the researchers noted. However, the results support findings from previous studies and were strengthened by the review of multiple outcomes and use of a longitudinal database, they said.
“These findings provide timely and critical evidence for the role that WIC plays in improving the health of the nation’s most vulnerable populations, suggesting meaningful impacts of the revised WIC food package on child development,” the researchers said. In addition, “considering the relatively modest scope of the 2009 revision, more substantial updates to the program based on up-to-date nutritional guidance may have substantial effects on improving the health of WIC recipients,” they concluded.
Findings support program’s value
“Pediatrics has always had a commitment to reducing disparities in health care, and we are the main clinicians to see many Medicaid patients on a regular basis,” Herschel Lessin, MD, of Children’s Medical Group, Poughkeepsie, N.Y., said in an interview.
“We all know that pregnant women eating nutritiously ought to help child outcomes, but the current study provides an evidence base for something that seems like common sense,” he noted.
Having such an evidence base is helpful to reinforce the value of the WIC program for its intended recipients, especially in the wake of the COVID-19 pandemic when many funding sources are stretched thin, Dr. Lessin said.
The WIC is intended to try to reduce racial and socioeconomic disparities in the most basic form possible, by helping people who are disadvantaged get enough high-quality food to eat, but results of the program’s impact have not been well studied, he said.
“Outcomes are fiendishly difficult to measure,” and the study is subject to the limitations of its statistical nature, he said. But the large sample size adds support to the findings, which are encouraging, Dr. Lessin noted.
Other potential areas for research include comparing the quality of WIC programs in different states, but such research is very difficult, Dr. Lessin noted. However, the findings might encourage states with less robust WIC programs to consider increasing support, he said.
The study was funded by the National Institutes of Health (National Heart, Lung, and Blood Institute); the National Institute on Aging; the University of California, San Francisco, National Center of Excellence in Women’s Health; and the Urban Child Institute. The researchers had no financial conflicts to disclose. Dr. Lessin serves on the editorial advisory board of Pediatric News and had no relevant financial conflicts to disclose.
Developmental outcomes in the first 2 years of life improved in children whose mothers received the revised Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) while pregnant, based on data from approximately 1,200 women.
Maternal nutrition is essential to healthy fetal development, and the WIC was revised in 2009 to align with current dietary guidelines and to support the health of women and children in low-income households, wrote Alice Guan, MPH, of the University of California, San Francisco, and colleagues.
“However, no researchers, to our knowledge, have evaluated effects of this revision on downstream child health or development,” they said.
In a study published in Pediatrics, the researchers reviewed data from mothers and their children who participated in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) longitudinal cohort study conducted in Tennessee between 2006 and 2011. Their quasi-experimental analysis included 700 women who received WIC during pregnancy and 525 women who did not.
The researchers considered core developmental outcomes of child growth, cognitive development, and socioemotional development at age 12 months and 24 months, and age 4-6 years.
Overall, infants of women who received the WIC food package showed significant increases in length-for-age z scores at 12 months of age (.33, representing approximately one-fifth of a standard deviation), compared to infants of women who did not receive the revised WIC package.
In addition, the Bayley Scales of Infant Development cognitive composite score showed a 4.3-point increase at 24 months of age (approximately one-third of a standard deviation) compared to infants of women who did not receive the revised WIC package.
No effects on growth at age 24 months or on cognitive development at age 4-6 years were noted, which suggests that the impact of the WIC program during pregnancy may fade over time, the researchers said.
“The magnitude of the findings in this study represents clinically relevant effect sizes and provides evidence that one of the largest U.S. safety net policies improves developmental outcomes among low-income and marginalized children,” they noted.
The study findings were limited by several factors including the statistical, quasi-experimental design; the reliance on self-reports for information on income, receipt of WIC, and other variables; and a potential lack of generalizability to other states, the researchers noted. However, the results support findings from previous studies and were strengthened by the review of multiple outcomes and use of a longitudinal database, they said.
“These findings provide timely and critical evidence for the role that WIC plays in improving the health of the nation’s most vulnerable populations, suggesting meaningful impacts of the revised WIC food package on child development,” the researchers said. In addition, “considering the relatively modest scope of the 2009 revision, more substantial updates to the program based on up-to-date nutritional guidance may have substantial effects on improving the health of WIC recipients,” they concluded.
Findings support program’s value
“Pediatrics has always had a commitment to reducing disparities in health care, and we are the main clinicians to see many Medicaid patients on a regular basis,” Herschel Lessin, MD, of Children’s Medical Group, Poughkeepsie, N.Y., said in an interview.
“We all know that pregnant women eating nutritiously ought to help child outcomes, but the current study provides an evidence base for something that seems like common sense,” he noted.
Having such an evidence base is helpful to reinforce the value of the WIC program for its intended recipients, especially in the wake of the COVID-19 pandemic when many funding sources are stretched thin, Dr. Lessin said.
The WIC is intended to try to reduce racial and socioeconomic disparities in the most basic form possible, by helping people who are disadvantaged get enough high-quality food to eat, but results of the program’s impact have not been well studied, he said.
“Outcomes are fiendishly difficult to measure,” and the study is subject to the limitations of its statistical nature, he said. But the large sample size adds support to the findings, which are encouraging, Dr. Lessin noted.
Other potential areas for research include comparing the quality of WIC programs in different states, but such research is very difficult, Dr. Lessin noted. However, the findings might encourage states with less robust WIC programs to consider increasing support, he said.
The study was funded by the National Institutes of Health (National Heart, Lung, and Blood Institute); the National Institute on Aging; the University of California, San Francisco, National Center of Excellence in Women’s Health; and the Urban Child Institute. The researchers had no financial conflicts to disclose. Dr. Lessin serves on the editorial advisory board of Pediatric News and had no relevant financial conflicts to disclose.
FROM PEDIATRICS
Molecular insights suggest novel therapies for hidradenitis suppurativa
at the virtual annual congress of the European Academy of Dermatology and Venereology.
He presented highlights of a multicenter translational study, which utilized whole transcriptome analysis of lesional and nonlesional skin from patients with HS and normal controls along with quantitative real-time PCR and immunohistochemistry. The purpose was to further define the molecular taxonomy of this inflammatory disease. And while this objective was achieved, the results also underscored a truism regarding the painful and scarring disease: “HS is characterized by an ever-growing complexity, which translates into multiple potential mechanistic drivers,” observed Dr. da Costa, head of immunology precision medicine at AstraZeneca in Gothenburg, Sweden.
Indeed, the study identified a panel of immune-related drivers in HS that influence innate immunity and cell differentiation in follicular and epidermal keratinocytes. The research by Dr. da Costa and coinvestigators identified a broad array of promising novel therapeutic targets in HS.
“Our findings provide evidence of an inflammatory process coupled with impaired barrier function, altered epidermal cell differentiation, and possibly abnormal microbiome activity which can be seen at the follicular and epidermal keratinocytes and also to a minor degree at the level of the skin glands,” Dr. da Costa said.
There is a huge unmet need for new therapies for HS, since at present adalimumab (Humira) is the only approved medication for this debilitating inflammatory disease. Some good news that emerged from this translational study is that some of the novel molecular mediators implicated in HS are targeted by multiple Food and Drug Administration–approved therapies that have other indications. From a drug development standpoint, repurposing a commercially available drug for a novel indication is a much more efficient and less costly endeavor than is necessary to establish the safety and efficacy of an unproven new agent.
The translational work demonstrated that the proteins calgranulin-A and -B and serpin-B4 were strongly expressed in the hair root sheaths of patients with HS. Connexin-32 and koebnerisin were present in stratum granulosum, matrix metallopeptidase-9 was strongly expressed in resident monocytes, small prolin-rich protein 3 in apocrine sweat glands and ducts as well as in sebaceous glands and ducts, and transcobalamin-1 was prominent in stratum spinosum.
Of the 19 key molecular mediators of HS identified in the study, FDA-approved agents are already available that target 12 of them. For example, apremilast (Otezla) targets interferon-gamma and tumor necrosis factor–alpha. Gentamicin targets growth arrest-specific 6 (GAS6) and interleukin-17 (IL-17). Secukinumab (Cosentyx) and ixekizumab (Taltz) target IL-17A, and brodalumab (Siliq) more broadly targets IL-17A as well as all the other IL-17 receptors. Thalidomide targets hepatocyte growth factor (HGF) and TNF-alpha. Spironolactone targets androgen receptor (AR) and TNF-alpha. Colchicine targets tubulin. Anakinra (Kineret) homes in on the IL-1 receptor. And prednisone targets NFxB.
Other key molecular mediators of HS, which are targeted by commercially available drugs, include epidermal growth factor (EGF), macrophage colony-stimulating factor (MCSF), epiregulin (EREG), fibroblast growth factor 1 (FGF1), FGF2, insulin-like growth factor 2 (IGF2), and IL-6, according to Dr. da Costa.
In addition, clinical trials are underway in HS involving totally investigational agents, including several Janus kinase inhibitors and tyrosine kinase 2 inhibitors.
The work described by Dr. da Costa had multiple funding sources, including the European Hidradenitis Suppurativa Foundation, the University of Copenhagen, the Icahn School of Medicine at Mount Sinai, AstraZeneca, and the German Federal Ministry of Education and Research. Dr. da Costa is an employee of AstraZeneca, Gothenburg, Sweden.
at the virtual annual congress of the European Academy of Dermatology and Venereology.
He presented highlights of a multicenter translational study, which utilized whole transcriptome analysis of lesional and nonlesional skin from patients with HS and normal controls along with quantitative real-time PCR and immunohistochemistry. The purpose was to further define the molecular taxonomy of this inflammatory disease. And while this objective was achieved, the results also underscored a truism regarding the painful and scarring disease: “HS is characterized by an ever-growing complexity, which translates into multiple potential mechanistic drivers,” observed Dr. da Costa, head of immunology precision medicine at AstraZeneca in Gothenburg, Sweden.
Indeed, the study identified a panel of immune-related drivers in HS that influence innate immunity and cell differentiation in follicular and epidermal keratinocytes. The research by Dr. da Costa and coinvestigators identified a broad array of promising novel therapeutic targets in HS.
“Our findings provide evidence of an inflammatory process coupled with impaired barrier function, altered epidermal cell differentiation, and possibly abnormal microbiome activity which can be seen at the follicular and epidermal keratinocytes and also to a minor degree at the level of the skin glands,” Dr. da Costa said.
There is a huge unmet need for new therapies for HS, since at present adalimumab (Humira) is the only approved medication for this debilitating inflammatory disease. Some good news that emerged from this translational study is that some of the novel molecular mediators implicated in HS are targeted by multiple Food and Drug Administration–approved therapies that have other indications. From a drug development standpoint, repurposing a commercially available drug for a novel indication is a much more efficient and less costly endeavor than is necessary to establish the safety and efficacy of an unproven new agent.
The translational work demonstrated that the proteins calgranulin-A and -B and serpin-B4 were strongly expressed in the hair root sheaths of patients with HS. Connexin-32 and koebnerisin were present in stratum granulosum, matrix metallopeptidase-9 was strongly expressed in resident monocytes, small prolin-rich protein 3 in apocrine sweat glands and ducts as well as in sebaceous glands and ducts, and transcobalamin-1 was prominent in stratum spinosum.
Of the 19 key molecular mediators of HS identified in the study, FDA-approved agents are already available that target 12 of them. For example, apremilast (Otezla) targets interferon-gamma and tumor necrosis factor–alpha. Gentamicin targets growth arrest-specific 6 (GAS6) and interleukin-17 (IL-17). Secukinumab (Cosentyx) and ixekizumab (Taltz) target IL-17A, and brodalumab (Siliq) more broadly targets IL-17A as well as all the other IL-17 receptors. Thalidomide targets hepatocyte growth factor (HGF) and TNF-alpha. Spironolactone targets androgen receptor (AR) and TNF-alpha. Colchicine targets tubulin. Anakinra (Kineret) homes in on the IL-1 receptor. And prednisone targets NFxB.
Other key molecular mediators of HS, which are targeted by commercially available drugs, include epidermal growth factor (EGF), macrophage colony-stimulating factor (MCSF), epiregulin (EREG), fibroblast growth factor 1 (FGF1), FGF2, insulin-like growth factor 2 (IGF2), and IL-6, according to Dr. da Costa.
In addition, clinical trials are underway in HS involving totally investigational agents, including several Janus kinase inhibitors and tyrosine kinase 2 inhibitors.
The work described by Dr. da Costa had multiple funding sources, including the European Hidradenitis Suppurativa Foundation, the University of Copenhagen, the Icahn School of Medicine at Mount Sinai, AstraZeneca, and the German Federal Ministry of Education and Research. Dr. da Costa is an employee of AstraZeneca, Gothenburg, Sweden.
at the virtual annual congress of the European Academy of Dermatology and Venereology.
He presented highlights of a multicenter translational study, which utilized whole transcriptome analysis of lesional and nonlesional skin from patients with HS and normal controls along with quantitative real-time PCR and immunohistochemistry. The purpose was to further define the molecular taxonomy of this inflammatory disease. And while this objective was achieved, the results also underscored a truism regarding the painful and scarring disease: “HS is characterized by an ever-growing complexity, which translates into multiple potential mechanistic drivers,” observed Dr. da Costa, head of immunology precision medicine at AstraZeneca in Gothenburg, Sweden.
Indeed, the study identified a panel of immune-related drivers in HS that influence innate immunity and cell differentiation in follicular and epidermal keratinocytes. The research by Dr. da Costa and coinvestigators identified a broad array of promising novel therapeutic targets in HS.
“Our findings provide evidence of an inflammatory process coupled with impaired barrier function, altered epidermal cell differentiation, and possibly abnormal microbiome activity which can be seen at the follicular and epidermal keratinocytes and also to a minor degree at the level of the skin glands,” Dr. da Costa said.
There is a huge unmet need for new therapies for HS, since at present adalimumab (Humira) is the only approved medication for this debilitating inflammatory disease. Some good news that emerged from this translational study is that some of the novel molecular mediators implicated in HS are targeted by multiple Food and Drug Administration–approved therapies that have other indications. From a drug development standpoint, repurposing a commercially available drug for a novel indication is a much more efficient and less costly endeavor than is necessary to establish the safety and efficacy of an unproven new agent.
The translational work demonstrated that the proteins calgranulin-A and -B and serpin-B4 were strongly expressed in the hair root sheaths of patients with HS. Connexin-32 and koebnerisin were present in stratum granulosum, matrix metallopeptidase-9 was strongly expressed in resident monocytes, small prolin-rich protein 3 in apocrine sweat glands and ducts as well as in sebaceous glands and ducts, and transcobalamin-1 was prominent in stratum spinosum.
Of the 19 key molecular mediators of HS identified in the study, FDA-approved agents are already available that target 12 of them. For example, apremilast (Otezla) targets interferon-gamma and tumor necrosis factor–alpha. Gentamicin targets growth arrest-specific 6 (GAS6) and interleukin-17 (IL-17). Secukinumab (Cosentyx) and ixekizumab (Taltz) target IL-17A, and brodalumab (Siliq) more broadly targets IL-17A as well as all the other IL-17 receptors. Thalidomide targets hepatocyte growth factor (HGF) and TNF-alpha. Spironolactone targets androgen receptor (AR) and TNF-alpha. Colchicine targets tubulin. Anakinra (Kineret) homes in on the IL-1 receptor. And prednisone targets NFxB.
Other key molecular mediators of HS, which are targeted by commercially available drugs, include epidermal growth factor (EGF), macrophage colony-stimulating factor (MCSF), epiregulin (EREG), fibroblast growth factor 1 (FGF1), FGF2, insulin-like growth factor 2 (IGF2), and IL-6, according to Dr. da Costa.
In addition, clinical trials are underway in HS involving totally investigational agents, including several Janus kinase inhibitors and tyrosine kinase 2 inhibitors.
The work described by Dr. da Costa had multiple funding sources, including the European Hidradenitis Suppurativa Foundation, the University of Copenhagen, the Icahn School of Medicine at Mount Sinai, AstraZeneca, and the German Federal Ministry of Education and Research. Dr. da Costa is an employee of AstraZeneca, Gothenburg, Sweden.
FROM THE EADV CONGRESS
Puppy love: Is losing a pet too hard for children?
The big news in the Wilkoff household is that Marilyn and I will be celebrating the arrival of a granddog into our nuclear family. Our younger daughter and her husband will be welcoming into their home a golden retriever puppy the first week in March. This may not seem like big news to some families and is certainly a step down on the priority list to the arrival of the four grandchildren that we already claim on our resume. But, you must understand that no one in our family has ever owned a dog.
Although my wife’s family had a dog, she apparently never really bonded with the canine. My pleas and occasional whining from our three children to get a dog were always met with my wife’s concerns about cleanliness and hygiene. We did have an antisocial cat who lived under a bed in the guest room or in the basement. His passing after 16 years when the kids were in college was not an event marked with any emotion beyond relief.
I think I harbored an unspoken concern about how I and our children might respond emotionally and psychologically to the inevitable death of what would likely have become our family’s best friend. Dispatching a belly-up goldfish after a month or two is small potatoes compared to putting down a tail-wagging, frisbee-catching, four-footed member of the family.
It turns out that my concerns about the mental health of our children may not have been unfounded. A recently published study from the Harvard Medical School and Massachusetts General Hospital found that children who had experienced the death of a loved pet were more likely to exhibit symptoms of psychopathology than were those who had loved a pet who was still alive (Crawford et al. Eur Child Adolesc Psychiatry. 2020 Sep 10. doi: 10.1007/s00787-020-01594-5). The observed effect of the loss was more pronounced in boys. There was also no statistical difference between the psychopathology symptoms of those children who had loved and lost and those children who had never loved a pet.
By the time I left for college I had grown up with five different dogs. I had endured the loss of sweet Mary, the boxer, when we moved to a small apartment and had to send her to a “farm.” I had watched 2-year-old Blackie experience a seizure that heralded his fatal bout with distemper. I shared the struggle with my parents as we made the decision to send my much loved inveterate car chasing “Butch” back to the pound.
However, I survived these losses and wonder whether they in some way prepared me for some of the emotional challenges that would come later in life. This study from Harvard sampled only children from birth to age 8 years. For those of us in primary care a more interesting study might be one that looked for any long-term associations between pet loss as a young child with adolescent and adult mental health. With the surge in pet ownership that has surfaced during the pandemic, there should be an abundance of clinical material to mine. The Harvard researchers’ findings should make us aware of the potential for psychopathology in a child who has suffered the loss of a pet. Each family must decide whether the plusses of pet ownership are worth the risk. However, I side with Tennyson who said it is better to have loved and lost than never to have loved at all.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.
The big news in the Wilkoff household is that Marilyn and I will be celebrating the arrival of a granddog into our nuclear family. Our younger daughter and her husband will be welcoming into their home a golden retriever puppy the first week in March. This may not seem like big news to some families and is certainly a step down on the priority list to the arrival of the four grandchildren that we already claim on our resume. But, you must understand that no one in our family has ever owned a dog.
Although my wife’s family had a dog, she apparently never really bonded with the canine. My pleas and occasional whining from our three children to get a dog were always met with my wife’s concerns about cleanliness and hygiene. We did have an antisocial cat who lived under a bed in the guest room or in the basement. His passing after 16 years when the kids were in college was not an event marked with any emotion beyond relief.
I think I harbored an unspoken concern about how I and our children might respond emotionally and psychologically to the inevitable death of what would likely have become our family’s best friend. Dispatching a belly-up goldfish after a month or two is small potatoes compared to putting down a tail-wagging, frisbee-catching, four-footed member of the family.
It turns out that my concerns about the mental health of our children may not have been unfounded. A recently published study from the Harvard Medical School and Massachusetts General Hospital found that children who had experienced the death of a loved pet were more likely to exhibit symptoms of psychopathology than were those who had loved a pet who was still alive (Crawford et al. Eur Child Adolesc Psychiatry. 2020 Sep 10. doi: 10.1007/s00787-020-01594-5). The observed effect of the loss was more pronounced in boys. There was also no statistical difference between the psychopathology symptoms of those children who had loved and lost and those children who had never loved a pet.
By the time I left for college I had grown up with five different dogs. I had endured the loss of sweet Mary, the boxer, when we moved to a small apartment and had to send her to a “farm.” I had watched 2-year-old Blackie experience a seizure that heralded his fatal bout with distemper. I shared the struggle with my parents as we made the decision to send my much loved inveterate car chasing “Butch” back to the pound.
However, I survived these losses and wonder whether they in some way prepared me for some of the emotional challenges that would come later in life. This study from Harvard sampled only children from birth to age 8 years. For those of us in primary care a more interesting study might be one that looked for any long-term associations between pet loss as a young child with adolescent and adult mental health. With the surge in pet ownership that has surfaced during the pandemic, there should be an abundance of clinical material to mine. The Harvard researchers’ findings should make us aware of the potential for psychopathology in a child who has suffered the loss of a pet. Each family must decide whether the plusses of pet ownership are worth the risk. However, I side with Tennyson who said it is better to have loved and lost than never to have loved at all.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.
The big news in the Wilkoff household is that Marilyn and I will be celebrating the arrival of a granddog into our nuclear family. Our younger daughter and her husband will be welcoming into their home a golden retriever puppy the first week in March. This may not seem like big news to some families and is certainly a step down on the priority list to the arrival of the four grandchildren that we already claim on our resume. But, you must understand that no one in our family has ever owned a dog.
Although my wife’s family had a dog, she apparently never really bonded with the canine. My pleas and occasional whining from our three children to get a dog were always met with my wife’s concerns about cleanliness and hygiene. We did have an antisocial cat who lived under a bed in the guest room or in the basement. His passing after 16 years when the kids were in college was not an event marked with any emotion beyond relief.
I think I harbored an unspoken concern about how I and our children might respond emotionally and psychologically to the inevitable death of what would likely have become our family’s best friend. Dispatching a belly-up goldfish after a month or two is small potatoes compared to putting down a tail-wagging, frisbee-catching, four-footed member of the family.
It turns out that my concerns about the mental health of our children may not have been unfounded. A recently published study from the Harvard Medical School and Massachusetts General Hospital found that children who had experienced the death of a loved pet were more likely to exhibit symptoms of psychopathology than were those who had loved a pet who was still alive (Crawford et al. Eur Child Adolesc Psychiatry. 2020 Sep 10. doi: 10.1007/s00787-020-01594-5). The observed effect of the loss was more pronounced in boys. There was also no statistical difference between the psychopathology symptoms of those children who had loved and lost and those children who had never loved a pet.
By the time I left for college I had grown up with five different dogs. I had endured the loss of sweet Mary, the boxer, when we moved to a small apartment and had to send her to a “farm.” I had watched 2-year-old Blackie experience a seizure that heralded his fatal bout with distemper. I shared the struggle with my parents as we made the decision to send my much loved inveterate car chasing “Butch” back to the pound.
However, I survived these losses and wonder whether they in some way prepared me for some of the emotional challenges that would come later in life. This study from Harvard sampled only children from birth to age 8 years. For those of us in primary care a more interesting study might be one that looked for any long-term associations between pet loss as a young child with adolescent and adult mental health. With the surge in pet ownership that has surfaced during the pandemic, there should be an abundance of clinical material to mine. The Harvard researchers’ findings should make us aware of the potential for psychopathology in a child who has suffered the loss of a pet. Each family must decide whether the plusses of pet ownership are worth the risk. However, I side with Tennyson who said it is better to have loved and lost than never to have loved at all.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.
Study: COVID cases have been ‘severely undercounted’
Large numbers of COVID-19 cases have been undetected and unreported, which has resulted in severe undercounting of the total number of people who have been infected during the pandemic, according to a new study published Monday in the journal PLOS ONE.
In the United States, the number of COVID-19 cases is likely three times that of reported cases. According to the study, more than 71 million Americans have contracted the virus during the pandemic, and 7 million were infected or potentially contagious last week.
Public health officials rely on case counts to guide decisions, so the undercounting should be considered while trying to end the pandemic.
“The estimates of actual infections reveal for the first time the true severity of COVID-19 across the U.S. and in countries worldwide,” Jungsik Noh, PhD, a bioinformatics professor at the University of Texas Southwestern Medical Center, said in a statement.
Dr. Noh and colleague Gaudenz Danuser created a computational model that uses machine-learning strategies to estimate the actual number of daily cases in the United States and the 50 most-infected countries.
The model pulls data from the Johns Hopkins University database and the COVID Tracking Project, as well as large-scale surveys conducted by the CDC and several states. The algorithm uses the number of reported deaths, which is thought to be more accurate than the number of lab-confirmed cases, as the basis for calculations.
In 25 of the 50 countries, the “actual” cumulative cases were estimated to be 5-20 times greater than the confirmed cases. In the United States, Belgium, and Brazil, about 10% of the population has contracted the coronavirus, according to the model. At the beginning of February, about 11% of the population in Pennsylvania had current infections, which was the highest rate of any state. About 0.15% of residents in Minnesota had infections, and about 2.5% of residents in New York and Texas had infections.
“Knowing the true severity in different regions will help us effectively fight against the virus spreading,” Dr. Noh said. “The currently infected population is the cause of future infections and deaths. Its actual size in a region is a crucial variable required when determining the severity of COVID-19 and building strategies against regional outbreaks.”
A version of this article first appeared on WebMD.com.
Large numbers of COVID-19 cases have been undetected and unreported, which has resulted in severe undercounting of the total number of people who have been infected during the pandemic, according to a new study published Monday in the journal PLOS ONE.
In the United States, the number of COVID-19 cases is likely three times that of reported cases. According to the study, more than 71 million Americans have contracted the virus during the pandemic, and 7 million were infected or potentially contagious last week.
Public health officials rely on case counts to guide decisions, so the undercounting should be considered while trying to end the pandemic.
“The estimates of actual infections reveal for the first time the true severity of COVID-19 across the U.S. and in countries worldwide,” Jungsik Noh, PhD, a bioinformatics professor at the University of Texas Southwestern Medical Center, said in a statement.
Dr. Noh and colleague Gaudenz Danuser created a computational model that uses machine-learning strategies to estimate the actual number of daily cases in the United States and the 50 most-infected countries.
The model pulls data from the Johns Hopkins University database and the COVID Tracking Project, as well as large-scale surveys conducted by the CDC and several states. The algorithm uses the number of reported deaths, which is thought to be more accurate than the number of lab-confirmed cases, as the basis for calculations.
In 25 of the 50 countries, the “actual” cumulative cases were estimated to be 5-20 times greater than the confirmed cases. In the United States, Belgium, and Brazil, about 10% of the population has contracted the coronavirus, according to the model. At the beginning of February, about 11% of the population in Pennsylvania had current infections, which was the highest rate of any state. About 0.15% of residents in Minnesota had infections, and about 2.5% of residents in New York and Texas had infections.
“Knowing the true severity in different regions will help us effectively fight against the virus spreading,” Dr. Noh said. “The currently infected population is the cause of future infections and deaths. Its actual size in a region is a crucial variable required when determining the severity of COVID-19 and building strategies against regional outbreaks.”
A version of this article first appeared on WebMD.com.
Large numbers of COVID-19 cases have been undetected and unreported, which has resulted in severe undercounting of the total number of people who have been infected during the pandemic, according to a new study published Monday in the journal PLOS ONE.
In the United States, the number of COVID-19 cases is likely three times that of reported cases. According to the study, more than 71 million Americans have contracted the virus during the pandemic, and 7 million were infected or potentially contagious last week.
Public health officials rely on case counts to guide decisions, so the undercounting should be considered while trying to end the pandemic.
“The estimates of actual infections reveal for the first time the true severity of COVID-19 across the U.S. and in countries worldwide,” Jungsik Noh, PhD, a bioinformatics professor at the University of Texas Southwestern Medical Center, said in a statement.
Dr. Noh and colleague Gaudenz Danuser created a computational model that uses machine-learning strategies to estimate the actual number of daily cases in the United States and the 50 most-infected countries.
The model pulls data from the Johns Hopkins University database and the COVID Tracking Project, as well as large-scale surveys conducted by the CDC and several states. The algorithm uses the number of reported deaths, which is thought to be more accurate than the number of lab-confirmed cases, as the basis for calculations.
In 25 of the 50 countries, the “actual” cumulative cases were estimated to be 5-20 times greater than the confirmed cases. In the United States, Belgium, and Brazil, about 10% of the population has contracted the coronavirus, according to the model. At the beginning of February, about 11% of the population in Pennsylvania had current infections, which was the highest rate of any state. About 0.15% of residents in Minnesota had infections, and about 2.5% of residents in New York and Texas had infections.
“Knowing the true severity in different regions will help us effectively fight against the virus spreading,” Dr. Noh said. “The currently infected population is the cause of future infections and deaths. Its actual size in a region is a crucial variable required when determining the severity of COVID-19 and building strategies against regional outbreaks.”
A version of this article first appeared on WebMD.com.
COVID-19: Peginterferon lambda may prevent clinical deterioration, shorten viral shedding
and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).
Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
Fewer side effects
To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.
Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.
The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
Greater benefit with higher baseline load
A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
More patients SARS-CoV-2 RNA negative
By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
Respiratory symptoms improved faster
Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).
Laboratory adverse events, similar for both groups, were mild.
“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.
“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.
Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.
“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.
The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.
Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.
and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).
Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
Fewer side effects
To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.
Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.
The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
Greater benefit with higher baseline load
A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
More patients SARS-CoV-2 RNA negative
By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
Respiratory symptoms improved faster
Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).
Laboratory adverse events, similar for both groups, were mild.
“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.
“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.
Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.
“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.
The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.
Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.
and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).
Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
Fewer side effects
To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.
Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.
The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
Greater benefit with higher baseline load
A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
More patients SARS-CoV-2 RNA negative
By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
Respiratory symptoms improved faster
Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).
Laboratory adverse events, similar for both groups, were mild.
“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.
“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.
Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.
“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.
The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.
Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.
FROM THE LANCET RESPIRATORY MEDICINE
Teenagers get in the queue for COVID-19 vaccines
The vaccinations can’t come soon enough for parents like Stacy Hillenburg, a developmental therapist in Aurora, Ill., whose 9-year-old son takes immunosuppressants because he had a heart transplant when he was 7 weeks old. Although school-age children aren’t yet included in clinical trials, if her 12- and 13-year-old daughters could get vaccinated, along with both parents, then the family could relax some of the protocols they currently follow to prevent infection.
Whenever they are around other people, even masked and socially distanced, they come home and immediately shower and change their clothes. So far, no one in the family has been infected with COVID, but the anxiety is ever-present. “I can’t wait for it to come out,” Ms. Hillenburg said of a pediatric COVID vaccine. “It will ease my mind so much.”
She isn’t alone in that anticipation. In the fall, the American Academy of Pediatrics and other pediatric vaccine experts urged faster action on pediatric vaccine trials and worried that children would be left behind as adults gained protection from COVID. But recent developments have eased those concerns.
“Over the next couple of months, we will be doing trials in an age-deescalation manner,” with studies moving gradually to younger children, Anthony S. Fauci, MD, chief medical adviser on COVID-19 to the president, said in a coronavirus response team briefing on Jan. 29. “So that hopefully, as we get to the late spring and summer, we will have children being able to be vaccinated.”
Pfizer completed enrollment of 2,259 teens aged 12-15 years in late January and expects to move forward with a separate pediatric trial of children aged 5-11 years by this spring, Keanna Ghazvini, senior associate for global media relations at Pfizer, said in an interview.
Enrollment in Moderna’s TeenCove study of adolescents ages 12-17 years began slowly in late December, but the pace has since picked up, said company spokesperson Colleen Hussey. “We continue to bring clinical trial sites online, and we are on track to provide updated data around mid-year 2021.” A trial extension in children 11 years and younger is expected to begin later in 2021.
Johnson & Johnson and AstraZeneca said they expect to begin adolescent trials in early 2021, according to data shared by the Advisory Committee on Immunization Practices. An interim analysis of J&J’s Janssen COVID-19 vaccine trial data, released on Jan. 29, showed it was 72% effective in US participants aged 18 years or older. AstraZeneca’s U.S. trial in adults is ongoing.
Easing the burden
Vaccination could lessen children’s risk of severe disease as well as the social and emotional burdens of the pandemic, says James Campbell, MD, a pediatric infectious disease specialist at the University of Maryland’s Center for Vaccine Development in Baltimore, which was involved in the Moderna and early-phase Pfizer trials. He coauthored a September 2020 article in Clinical Infectious Diseases titled: “Warp Speed for COVID-19 vaccines: Why are children stuck in neutral?”
The adolescent trials are a vital step to ensure timely vaccine access for teens and younger children. “It is reasonable, when you have limited vaccine, that your rollout goes to the highest priority and then moves to lower and lower priorities. In adults, we’re just saying: ‘Wait your turn,’ ” he said of the current vaccination effort. “If we didn’t have the [vaccine trial] data in children, we’d be saying: ‘You don’t have a turn.’ ”
As the pandemic has worn on, the burden on children has grown. As of Tuesday, 269 children had died of COVID-19. That is well above the highest annual death toll recorded during a regular flu season – 188 flu deaths among children and adolescents under 18 in the 2019-2020 and 2017-2018 flu seasons.
Children are less likely to transmit COVID-19 in their household than adults, according to a meta-analysis of 54 studies published in JAMA Network Open. But that does not necessarily mean children are less infectious, the authors said, noting that unmeasured factors could have affected the spread of infection among adults.
Moreover, children and adolescents need protection from COVID infection – and from the potential for severe disease or lingering effects – and, given that there are 74 million children and teens in the United States, their vaccination is an important part of stopping the pandemic, said Grace Lee, MD, professor of pediatrics at Stanford (Calif.) University, and cochair of ACIP’s COVID-19 Vaccine Safety Technical Subgroup.
“In order to interrupt transmission, I don’t see how we’re going to do that without vaccinating children and adolescents,” she said.
Dr. Lee said her 16-year-old daughter misses the normal teenage social life and is excited about getting the vaccine when she is eligible. (Adolescents without high-risk conditions are in the lowest vaccination tier, according to ACIP recommendations.) “There is truly individual protection to be gained,” Dr. Lee said.
She noted that researchers continue to assess the immune responses to the adult vaccines – even looking at immune characteristics of the small percentage of people who aren’t protected from infection – and that information helps in the evaluation of the pediatric immune responses. As the trials expand to younger children and infants, dosing will be a major focus. “How many doses do they need they need to receive the same immunity? Safety considerations will be critically important,” she said.
Teen trials underway
Pfizer/BioNTech extended its adult trial to 16- and 17-year-olds in October, which enabled older teens to be included in its emergency-use authorization. They and younger teens, ages 12-15, receive the same dose as adults.
The ongoing trials with Pfizer and Moderna vaccines are immunobridging trials, designed to study safety and immunogenicity. Investigators will compare the teens’ immune response with the findings from the larger adult trials. When the trials expand to school-age children (6-12 years), protocols call for testing the safety and immunogenicity of a half-dose vaccine as well as the full dose.
Children ages 2-5 years and infants and toddlers will be enrolled in future trials, studying safety and immunogenicity of full, half, or even quarter dosages. The Pediatric Research Equity Act of 2003 requires licensed vaccines to be tested for safety and efficacy in children, unless they are not appropriate for a pediatric population.
Demand for the teen trials has been strong. At Cincinnati Children’s Hospital Medical Center, 259 teenagers joined the Pfizer/BioNTech trial, but some teenagers were turned away when the trial’s national enrollment closed in late January.
“Many of the children are having no side effects, and if they are, they’re having the same [effects] as the young adults – local redness or pain, fatigue, and headaches,” said Robert Frenck, MD, director of the Cincinnati Children’s Gamble Program for Clinical Studies.
Parents may share some of the vaccine hesitancy that has affected adult vaccination. But that is balanced by the hope that vaccines will end the pandemic and usher in a new normal. “If it looks like [vaccines] will increase the likelihood of children returning to school safely, that may be a motivating factor,” Dr. Frenck said.
Cody Meissner, MD, chief of the pediatric infectious disease service at Tufts Medical Center, Boston, was initially cautious about the extension of vaccination to adolescents. A member of the Vaccine and Related Biological Products Advisory Committee, which evaluates data and makes recommendations to the Food and Drug Administration, Dr. Meissner initially abstained in the vote on the Pfizer/BioNTech emergency-use authorization for people 16 and older.
He noted that, at the time the committee reviewed the Pfizer vaccine, the company had data available for just 134 teenagers, half of whom received a placebo. But the vaccination of 34 million adults has provided robust data about the vaccine’s safety, and the trial expansion into adolescents is important.
“I’m comfortable with the way these trials are going now,” he said. “This is the way I was hoping they would go.”
Ms. Hillenburg is on the parent advisory board of Voices for Vaccines, an organization of parents supporting vaccination that is affiliated with the Task Force for Global Health, an Atlanta-based independent public health organization. Dr. Campbell’s institution has received funds to conduct clinical trials from the National Institutes of Health and several companies, including Merck, GlaxoSmithKline, Sanofi, Pfizer, and Moderna. He has served pro bono on many safety and data monitoring committees. Dr. Frenck’s institution is receiving funds to conduct the Pfizer trial. In the past 5 years, he has also participated in clinical trials for GlaxoSmithKline, Merck, and Meissa vaccines. Dr. Lee and Dr. Meissner disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The vaccinations can’t come soon enough for parents like Stacy Hillenburg, a developmental therapist in Aurora, Ill., whose 9-year-old son takes immunosuppressants because he had a heart transplant when he was 7 weeks old. Although school-age children aren’t yet included in clinical trials, if her 12- and 13-year-old daughters could get vaccinated, along with both parents, then the family could relax some of the protocols they currently follow to prevent infection.
Whenever they are around other people, even masked and socially distanced, they come home and immediately shower and change their clothes. So far, no one in the family has been infected with COVID, but the anxiety is ever-present. “I can’t wait for it to come out,” Ms. Hillenburg said of a pediatric COVID vaccine. “It will ease my mind so much.”
She isn’t alone in that anticipation. In the fall, the American Academy of Pediatrics and other pediatric vaccine experts urged faster action on pediatric vaccine trials and worried that children would be left behind as adults gained protection from COVID. But recent developments have eased those concerns.
“Over the next couple of months, we will be doing trials in an age-deescalation manner,” with studies moving gradually to younger children, Anthony S. Fauci, MD, chief medical adviser on COVID-19 to the president, said in a coronavirus response team briefing on Jan. 29. “So that hopefully, as we get to the late spring and summer, we will have children being able to be vaccinated.”
Pfizer completed enrollment of 2,259 teens aged 12-15 years in late January and expects to move forward with a separate pediatric trial of children aged 5-11 years by this spring, Keanna Ghazvini, senior associate for global media relations at Pfizer, said in an interview.
Enrollment in Moderna’s TeenCove study of adolescents ages 12-17 years began slowly in late December, but the pace has since picked up, said company spokesperson Colleen Hussey. “We continue to bring clinical trial sites online, and we are on track to provide updated data around mid-year 2021.” A trial extension in children 11 years and younger is expected to begin later in 2021.
Johnson & Johnson and AstraZeneca said they expect to begin adolescent trials in early 2021, according to data shared by the Advisory Committee on Immunization Practices. An interim analysis of J&J’s Janssen COVID-19 vaccine trial data, released on Jan. 29, showed it was 72% effective in US participants aged 18 years or older. AstraZeneca’s U.S. trial in adults is ongoing.
Easing the burden
Vaccination could lessen children’s risk of severe disease as well as the social and emotional burdens of the pandemic, says James Campbell, MD, a pediatric infectious disease specialist at the University of Maryland’s Center for Vaccine Development in Baltimore, which was involved in the Moderna and early-phase Pfizer trials. He coauthored a September 2020 article in Clinical Infectious Diseases titled: “Warp Speed for COVID-19 vaccines: Why are children stuck in neutral?”
The adolescent trials are a vital step to ensure timely vaccine access for teens and younger children. “It is reasonable, when you have limited vaccine, that your rollout goes to the highest priority and then moves to lower and lower priorities. In adults, we’re just saying: ‘Wait your turn,’ ” he said of the current vaccination effort. “If we didn’t have the [vaccine trial] data in children, we’d be saying: ‘You don’t have a turn.’ ”
As the pandemic has worn on, the burden on children has grown. As of Tuesday, 269 children had died of COVID-19. That is well above the highest annual death toll recorded during a regular flu season – 188 flu deaths among children and adolescents under 18 in the 2019-2020 and 2017-2018 flu seasons.
Children are less likely to transmit COVID-19 in their household than adults, according to a meta-analysis of 54 studies published in JAMA Network Open. But that does not necessarily mean children are less infectious, the authors said, noting that unmeasured factors could have affected the spread of infection among adults.
Moreover, children and adolescents need protection from COVID infection – and from the potential for severe disease or lingering effects – and, given that there are 74 million children and teens in the United States, their vaccination is an important part of stopping the pandemic, said Grace Lee, MD, professor of pediatrics at Stanford (Calif.) University, and cochair of ACIP’s COVID-19 Vaccine Safety Technical Subgroup.
“In order to interrupt transmission, I don’t see how we’re going to do that without vaccinating children and adolescents,” she said.
Dr. Lee said her 16-year-old daughter misses the normal teenage social life and is excited about getting the vaccine when she is eligible. (Adolescents without high-risk conditions are in the lowest vaccination tier, according to ACIP recommendations.) “There is truly individual protection to be gained,” Dr. Lee said.
She noted that researchers continue to assess the immune responses to the adult vaccines – even looking at immune characteristics of the small percentage of people who aren’t protected from infection – and that information helps in the evaluation of the pediatric immune responses. As the trials expand to younger children and infants, dosing will be a major focus. “How many doses do they need they need to receive the same immunity? Safety considerations will be critically important,” she said.
Teen trials underway
Pfizer/BioNTech extended its adult trial to 16- and 17-year-olds in October, which enabled older teens to be included in its emergency-use authorization. They and younger teens, ages 12-15, receive the same dose as adults.
The ongoing trials with Pfizer and Moderna vaccines are immunobridging trials, designed to study safety and immunogenicity. Investigators will compare the teens’ immune response with the findings from the larger adult trials. When the trials expand to school-age children (6-12 years), protocols call for testing the safety and immunogenicity of a half-dose vaccine as well as the full dose.
Children ages 2-5 years and infants and toddlers will be enrolled in future trials, studying safety and immunogenicity of full, half, or even quarter dosages. The Pediatric Research Equity Act of 2003 requires licensed vaccines to be tested for safety and efficacy in children, unless they are not appropriate for a pediatric population.
Demand for the teen trials has been strong. At Cincinnati Children’s Hospital Medical Center, 259 teenagers joined the Pfizer/BioNTech trial, but some teenagers were turned away when the trial’s national enrollment closed in late January.
“Many of the children are having no side effects, and if they are, they’re having the same [effects] as the young adults – local redness or pain, fatigue, and headaches,” said Robert Frenck, MD, director of the Cincinnati Children’s Gamble Program for Clinical Studies.
Parents may share some of the vaccine hesitancy that has affected adult vaccination. But that is balanced by the hope that vaccines will end the pandemic and usher in a new normal. “If it looks like [vaccines] will increase the likelihood of children returning to school safely, that may be a motivating factor,” Dr. Frenck said.
Cody Meissner, MD, chief of the pediatric infectious disease service at Tufts Medical Center, Boston, was initially cautious about the extension of vaccination to adolescents. A member of the Vaccine and Related Biological Products Advisory Committee, which evaluates data and makes recommendations to the Food and Drug Administration, Dr. Meissner initially abstained in the vote on the Pfizer/BioNTech emergency-use authorization for people 16 and older.
He noted that, at the time the committee reviewed the Pfizer vaccine, the company had data available for just 134 teenagers, half of whom received a placebo. But the vaccination of 34 million adults has provided robust data about the vaccine’s safety, and the trial expansion into adolescents is important.
“I’m comfortable with the way these trials are going now,” he said. “This is the way I was hoping they would go.”
Ms. Hillenburg is on the parent advisory board of Voices for Vaccines, an organization of parents supporting vaccination that is affiliated with the Task Force for Global Health, an Atlanta-based independent public health organization. Dr. Campbell’s institution has received funds to conduct clinical trials from the National Institutes of Health and several companies, including Merck, GlaxoSmithKline, Sanofi, Pfizer, and Moderna. He has served pro bono on many safety and data monitoring committees. Dr. Frenck’s institution is receiving funds to conduct the Pfizer trial. In the past 5 years, he has also participated in clinical trials for GlaxoSmithKline, Merck, and Meissa vaccines. Dr. Lee and Dr. Meissner disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The vaccinations can’t come soon enough for parents like Stacy Hillenburg, a developmental therapist in Aurora, Ill., whose 9-year-old son takes immunosuppressants because he had a heart transplant when he was 7 weeks old. Although school-age children aren’t yet included in clinical trials, if her 12- and 13-year-old daughters could get vaccinated, along with both parents, then the family could relax some of the protocols they currently follow to prevent infection.
Whenever they are around other people, even masked and socially distanced, they come home and immediately shower and change their clothes. So far, no one in the family has been infected with COVID, but the anxiety is ever-present. “I can’t wait for it to come out,” Ms. Hillenburg said of a pediatric COVID vaccine. “It will ease my mind so much.”
She isn’t alone in that anticipation. In the fall, the American Academy of Pediatrics and other pediatric vaccine experts urged faster action on pediatric vaccine trials and worried that children would be left behind as adults gained protection from COVID. But recent developments have eased those concerns.
“Over the next couple of months, we will be doing trials in an age-deescalation manner,” with studies moving gradually to younger children, Anthony S. Fauci, MD, chief medical adviser on COVID-19 to the president, said in a coronavirus response team briefing on Jan. 29. “So that hopefully, as we get to the late spring and summer, we will have children being able to be vaccinated.”
Pfizer completed enrollment of 2,259 teens aged 12-15 years in late January and expects to move forward with a separate pediatric trial of children aged 5-11 years by this spring, Keanna Ghazvini, senior associate for global media relations at Pfizer, said in an interview.
Enrollment in Moderna’s TeenCove study of adolescents ages 12-17 years began slowly in late December, but the pace has since picked up, said company spokesperson Colleen Hussey. “We continue to bring clinical trial sites online, and we are on track to provide updated data around mid-year 2021.” A trial extension in children 11 years and younger is expected to begin later in 2021.
Johnson & Johnson and AstraZeneca said they expect to begin adolescent trials in early 2021, according to data shared by the Advisory Committee on Immunization Practices. An interim analysis of J&J’s Janssen COVID-19 vaccine trial data, released on Jan. 29, showed it was 72% effective in US participants aged 18 years or older. AstraZeneca’s U.S. trial in adults is ongoing.
Easing the burden
Vaccination could lessen children’s risk of severe disease as well as the social and emotional burdens of the pandemic, says James Campbell, MD, a pediatric infectious disease specialist at the University of Maryland’s Center for Vaccine Development in Baltimore, which was involved in the Moderna and early-phase Pfizer trials. He coauthored a September 2020 article in Clinical Infectious Diseases titled: “Warp Speed for COVID-19 vaccines: Why are children stuck in neutral?”
The adolescent trials are a vital step to ensure timely vaccine access for teens and younger children. “It is reasonable, when you have limited vaccine, that your rollout goes to the highest priority and then moves to lower and lower priorities. In adults, we’re just saying: ‘Wait your turn,’ ” he said of the current vaccination effort. “If we didn’t have the [vaccine trial] data in children, we’d be saying: ‘You don’t have a turn.’ ”
As the pandemic has worn on, the burden on children has grown. As of Tuesday, 269 children had died of COVID-19. That is well above the highest annual death toll recorded during a regular flu season – 188 flu deaths among children and adolescents under 18 in the 2019-2020 and 2017-2018 flu seasons.
Children are less likely to transmit COVID-19 in their household than adults, according to a meta-analysis of 54 studies published in JAMA Network Open. But that does not necessarily mean children are less infectious, the authors said, noting that unmeasured factors could have affected the spread of infection among adults.
Moreover, children and adolescents need protection from COVID infection – and from the potential for severe disease or lingering effects – and, given that there are 74 million children and teens in the United States, their vaccination is an important part of stopping the pandemic, said Grace Lee, MD, professor of pediatrics at Stanford (Calif.) University, and cochair of ACIP’s COVID-19 Vaccine Safety Technical Subgroup.
“In order to interrupt transmission, I don’t see how we’re going to do that without vaccinating children and adolescents,” she said.
Dr. Lee said her 16-year-old daughter misses the normal teenage social life and is excited about getting the vaccine when she is eligible. (Adolescents without high-risk conditions are in the lowest vaccination tier, according to ACIP recommendations.) “There is truly individual protection to be gained,” Dr. Lee said.
She noted that researchers continue to assess the immune responses to the adult vaccines – even looking at immune characteristics of the small percentage of people who aren’t protected from infection – and that information helps in the evaluation of the pediatric immune responses. As the trials expand to younger children and infants, dosing will be a major focus. “How many doses do they need they need to receive the same immunity? Safety considerations will be critically important,” she said.
Teen trials underway
Pfizer/BioNTech extended its adult trial to 16- and 17-year-olds in October, which enabled older teens to be included in its emergency-use authorization. They and younger teens, ages 12-15, receive the same dose as adults.
The ongoing trials with Pfizer and Moderna vaccines are immunobridging trials, designed to study safety and immunogenicity. Investigators will compare the teens’ immune response with the findings from the larger adult trials. When the trials expand to school-age children (6-12 years), protocols call for testing the safety and immunogenicity of a half-dose vaccine as well as the full dose.
Children ages 2-5 years and infants and toddlers will be enrolled in future trials, studying safety and immunogenicity of full, half, or even quarter dosages. The Pediatric Research Equity Act of 2003 requires licensed vaccines to be tested for safety and efficacy in children, unless they are not appropriate for a pediatric population.
Demand for the teen trials has been strong. At Cincinnati Children’s Hospital Medical Center, 259 teenagers joined the Pfizer/BioNTech trial, but some teenagers were turned away when the trial’s national enrollment closed in late January.
“Many of the children are having no side effects, and if they are, they’re having the same [effects] as the young adults – local redness or pain, fatigue, and headaches,” said Robert Frenck, MD, director of the Cincinnati Children’s Gamble Program for Clinical Studies.
Parents may share some of the vaccine hesitancy that has affected adult vaccination. But that is balanced by the hope that vaccines will end the pandemic and usher in a new normal. “If it looks like [vaccines] will increase the likelihood of children returning to school safely, that may be a motivating factor,” Dr. Frenck said.
Cody Meissner, MD, chief of the pediatric infectious disease service at Tufts Medical Center, Boston, was initially cautious about the extension of vaccination to adolescents. A member of the Vaccine and Related Biological Products Advisory Committee, which evaluates data and makes recommendations to the Food and Drug Administration, Dr. Meissner initially abstained in the vote on the Pfizer/BioNTech emergency-use authorization for people 16 and older.
He noted that, at the time the committee reviewed the Pfizer vaccine, the company had data available for just 134 teenagers, half of whom received a placebo. But the vaccination of 34 million adults has provided robust data about the vaccine’s safety, and the trial expansion into adolescents is important.
“I’m comfortable with the way these trials are going now,” he said. “This is the way I was hoping they would go.”
Ms. Hillenburg is on the parent advisory board of Voices for Vaccines, an organization of parents supporting vaccination that is affiliated with the Task Force for Global Health, an Atlanta-based independent public health organization. Dr. Campbell’s institution has received funds to conduct clinical trials from the National Institutes of Health and several companies, including Merck, GlaxoSmithKline, Sanofi, Pfizer, and Moderna. He has served pro bono on many safety and data monitoring committees. Dr. Frenck’s institution is receiving funds to conduct the Pfizer trial. In the past 5 years, he has also participated in clinical trials for GlaxoSmithKline, Merck, and Meissa vaccines. Dr. Lee and Dr. Meissner disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
COVID-19 in children: New cases down for third straight week
New COVID-19 cases in children dropped for the third consecutive week, even as children continue to make up a larger share of all cases, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.
New child cases totaled almost 118,000 for the week of Jan. 29-Feb. 4, continuing the decline that began right after the United States topped 200,000 cases for the only time Jan. 8-14, the AAP and the CHA said in their weekly COVID-19 report.
For the latest week, however, children represented 16.0% of all new COVID-19 cases, continuing a 5-week increase that began in early December 2020, after the proportion had dropped to 12.6%, based on data collected from the health departments of 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam. During the week of Sept. 11-17, children made up 16.9% of all cases, the highest level seen during the pandemic.
The 2.93 million cases that have been reported in children make up 12.9% of all cases since the pandemic began, and the overall rate of pediatric coronavirus infection is 3,899 cases per 100,000 children in the population. Taking a step down from the national level, 30 states are above that rate and 18 are below it, along with D.C., New York City, Puerto Rico, and Guam (New York and Texas are excluded), the AAP and CHA reported.
There were 12 new COVID-19–related child deaths in the 43 states, along with New York City and Guam, that are reporting such data, bringing the total to 227. Nationally, 0.06% of all deaths have occurred in children, with rates ranging from 0.00% (11 states) to 0.26% (Nebraska) in the 45 jurisdictions, the AAP/CHA report shows.
Child hospitalizations rose to 1.9% of all hospitalizations after holding at 1.8% since mid-November in 25 reporting jurisdictions (24 states and New York City), but the hospitalization rate among children with COVID held at 0.8%, where it has been for the last 4 weeks. Hospitalization rates as high as 3.8% were recorded early in the pandemic, the AAP and CHA noted.
New COVID-19 cases in children dropped for the third consecutive week, even as children continue to make up a larger share of all cases, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.
New child cases totaled almost 118,000 for the week of Jan. 29-Feb. 4, continuing the decline that began right after the United States topped 200,000 cases for the only time Jan. 8-14, the AAP and the CHA said in their weekly COVID-19 report.
For the latest week, however, children represented 16.0% of all new COVID-19 cases, continuing a 5-week increase that began in early December 2020, after the proportion had dropped to 12.6%, based on data collected from the health departments of 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam. During the week of Sept. 11-17, children made up 16.9% of all cases, the highest level seen during the pandemic.
The 2.93 million cases that have been reported in children make up 12.9% of all cases since the pandemic began, and the overall rate of pediatric coronavirus infection is 3,899 cases per 100,000 children in the population. Taking a step down from the national level, 30 states are above that rate and 18 are below it, along with D.C., New York City, Puerto Rico, and Guam (New York and Texas are excluded), the AAP and CHA reported.
There were 12 new COVID-19–related child deaths in the 43 states, along with New York City and Guam, that are reporting such data, bringing the total to 227. Nationally, 0.06% of all deaths have occurred in children, with rates ranging from 0.00% (11 states) to 0.26% (Nebraska) in the 45 jurisdictions, the AAP/CHA report shows.
Child hospitalizations rose to 1.9% of all hospitalizations after holding at 1.8% since mid-November in 25 reporting jurisdictions (24 states and New York City), but the hospitalization rate among children with COVID held at 0.8%, where it has been for the last 4 weeks. Hospitalization rates as high as 3.8% were recorded early in the pandemic, the AAP and CHA noted.
New COVID-19 cases in children dropped for the third consecutive week, even as children continue to make up a larger share of all cases, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.
New child cases totaled almost 118,000 for the week of Jan. 29-Feb. 4, continuing the decline that began right after the United States topped 200,000 cases for the only time Jan. 8-14, the AAP and the CHA said in their weekly COVID-19 report.
For the latest week, however, children represented 16.0% of all new COVID-19 cases, continuing a 5-week increase that began in early December 2020, after the proportion had dropped to 12.6%, based on data collected from the health departments of 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam. During the week of Sept. 11-17, children made up 16.9% of all cases, the highest level seen during the pandemic.
The 2.93 million cases that have been reported in children make up 12.9% of all cases since the pandemic began, and the overall rate of pediatric coronavirus infection is 3,899 cases per 100,000 children in the population. Taking a step down from the national level, 30 states are above that rate and 18 are below it, along with D.C., New York City, Puerto Rico, and Guam (New York and Texas are excluded), the AAP and CHA reported.
There were 12 new COVID-19–related child deaths in the 43 states, along with New York City and Guam, that are reporting such data, bringing the total to 227. Nationally, 0.06% of all deaths have occurred in children, with rates ranging from 0.00% (11 states) to 0.26% (Nebraska) in the 45 jurisdictions, the AAP/CHA report shows.
Child hospitalizations rose to 1.9% of all hospitalizations after holding at 1.8% since mid-November in 25 reporting jurisdictions (24 states and New York City), but the hospitalization rate among children with COVID held at 0.8%, where it has been for the last 4 weeks. Hospitalization rates as high as 3.8% were recorded early in the pandemic, the AAP and CHA noted.
Study tests ways to increase autism screening and referrals
To improve autism screening rates, researchers in Utah tried a range of interventions.
They added automatic reminders to the electronic health record (EHR). They started using a shorter, more sensitive screening instrument. And they trained clinicians to perform autism-specific evaluations in a primary care clinic.
The researchers found that these interventions were associated with increased rates of autism screening and referrals.
At the same time, they looked at screening and referral rates at other community clinics in their health care system. These clinics incorporated EHR reminders but not all of the other changes.
“The community clinics had an increase in screening frequency with only automatic reminders,” the researchers reported. At the two intervention clinics, however, screening rates increased more than they did at the community clinics. Referrals did not significantly increase at the community clinics.
Kathleen Campbell, MD, MHSc, a pediatric resident at the University of Utah in Salt Lake City, and colleagues described their research in a study published in Pediatrics.
Three phases
They examined more than 12,000 well-child visits for children aged 16-30 months between July 2017 and June 2019.
In all, 4,155 visits occurred at the 2 intervention clinics, and 8,078 visits occurred at the 27 community clinics in the University of Utah health care system.
From baseline through the interventions, the proportion of visits with screening increased by 51% in the intervention clinics (from 58.6% to 88.8%), and by 21% in the community clinics (from 43.4% to 52.4%). The proportion of referrals increased 1.5-fold in intervention clinics, from 1.3% to 3.3%, the authors said.
The American Academy of Pediatrics (AAP) supports screening for autism in all children starting at age 18 months, but “only 44% of children with autism have had a comprehensive autism evaluation before age 36 months,” Dr. Campbell and colleagues wrote.
In their system, about half of the children were being screened for autism, and 0.5% had autism diagnosed.
In an effort to increase the proportion of visits with screening for autism and the proportion of visits with referrals for autism evaluation, Dr. Campbell and colleagues designed a quality improvement study.
Following a baseline period, they implemented interventions in three phases.
Initially, all clinics used the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) for autism screening. For the first phase starting in July 2018, the researchers changed the screening instrument at the two intervention clinics to the Parent’s Observation of Social Interaction (POSI). This instrument “is embedded in a broadband developmental screen, is shorter than the M-CHAT-R, and includes questions about the consistency of the child’s behavior,” the authors said. “The POSI has greater sensitivity than the M-CHAT-R ... and similar, although somewhat lower, specificity.”
In intervention phase 2 starting in November 2018, the researchers “added an automatic reminder for autism screening to the EHR health maintenance screen.” Both the intervention clinics and the community clinics received the automatic reminders.
In intervention phase 3 starting in February 2019, they “added a referral option that clinicians could use for rapid access to autism-specific evaluation ... for children who had a POSI result suggestive of autism and for whom the clinician had sufficient concerns about autism that would indicate the need for referral for autism evaluation,” the researchers said.
“Using an online tutorial, we trained three clinicians in the intervention clinics to administer an observational assessment known as the Screening Tool for Autism in Toddlers (STAT),” which requires a 30-minute visit, they said. “Children who had a STAT result suggestive of autism were referred for expedited autism diagnostic evaluation, which was performed by a multidisciplinary team in our university-based developmental assessment clinic. Children who had a STAT result that did not suggest autism did not receive further autism evaluations unless the clinician felt they still needed further evaluation at the developmental clinic.”
After the switch to POSI, the percentage of visits with a positive screen result increased from 4.7% to 13.5% in the intervention clinics.
Furthermore, referrals were 3.4 times more frequent for visits during phase 3 in the intervention clinics, relative to the baseline period.
Potential to overwhelm
“The change to a more sensitive screening instrument increased the frequency of screening results suggestive of autism and informed our improvement team of the need to implement autism evaluation in primary care to avoid overwhelming our referral system,” Dr. Campbell and coauthors reported.
Future studies may assess whether increased screening and referrals speed the time to diagnosis and treatment and improve long-term functional abilities of children with autism. Some children in the study have received an autism diagnosis, while others have not yet been evaluated.
The use of STAT in primary care may be limited by “the barriers of training providers and purchasing materials,” the authors noted. “However, the time-based billing for lengthier appointments and billing for developmental testing help to cover cost.”
The intervention clinics and community clinics were staffed by pediatric providers, including residents and attendings, said Dr. Campbell.
“The staffing is similar at the community and intervention clinics, with mostly pediatricians and some nurse practitioners,” Dr. Campbell said. “One difference is that there are a few family medicine physicians in the community clinics, but we did not study whether that made a difference in screening. At the beginning of the study the approach to screening was the same.”
From the start, the community clinics were screening for autism and referring for further autism evaluation less often than the intervention clinics. “I don’t know why they were screening less, but they did improve with the automatic reminders,” said Dr. Campbell. “We didn’t examine type of provider or type of practice in this study, but the literature suggests that family physicians do not screen for autism as often as pediatricians.”
Payment and referral challenges
In theory, the approach in the study is a great idea, but it may not be feasible to implement for many private practices, said Herschel Lessin, MD. Dr. Lessin is a senior partner of the Children’s Medical Group in New York.
“We desperately need autism screening in a primary care setting,” Dr. Lessin said. “These authors found that wasn’t being done as recommended by the AAP Bright Futures, which is a problem.”
However, the researchers incorporated the interventions in a health care system with “far more resources than most people in practice would ever have” and substituted a less familiar screening tool.
In addition, the ability to use confirmatory STAT for primary care evaluations may be limited. “Unless you can find pediatricians willing to commit 30 to 45 minutes on one of these evaluations ... few are going to do that,” he said.
“The whole problem is that there are no referrals available or very few referrals available, and that insurance payments so underpay for developmental screening and evaluation that it does not justify the time doing it, so a lot of doctors are unable to do it,” said Dr. Lessin. When a referral is warranted, developmental pediatricians may have 6- to 12-month waiting lists, he said.
“For people in clinical practice, this is not news,” Dr. Lessin said. “We know we should screen for autism. The problem is it’s time consuming. Nobody pays for it. We have no place to send them even when we are suspicious.”
From screening to diagnosis to treatment
“Autism screen approaches vary but with educational efforts on the part of the AAP, CDC, and family organizations the rates for autism screening have dramatically improved,” said Susan L. Hyman, MD, professor of pediatrics at the University of Rochester in New York. “I do not know if screening rates have been impacted by COVID.”
Dr. Hyman and coauthors wrote an AAP clinical report on the identification, evaluation, and management of children with autism spectrum disorder. The report was published in the January 2020 issue of Pediatrics.
After screening and diagnostic testing, patients most importantly need to be able to access “timely and equitable evidence-based intervention,” which should be available, said Dr. Hyman.
Although researchers have proposed training primary care providers in autism diagnostics, “older, more complex patients with co-occurring behavioral health or other developmental disorders may need more specialized diagnostic assessment than could be accomplished in a primary care setting,” Dr. Hyman added.
“However, it is very important to identify children with therapeutic needs as early as possible and move them through the continuum from screening to diagnosis to treatment in a timely fashion. It would be wonderful if symptoms could be addressed without the need for diagnosis in the very youngest children,” Dr. Hyman said. “Early symptoms, even if not autism, are likely to be appropriate for intervention – whether it is speech therapy, attention to food selectivity, sleep problems – things that impact quality of life and potential future symptoms.”
The research was supported by the Utah Stimulating Access to Research in Residency Transition Scholar award, which is funded by the National Institutes of Health.
Dr. Campbell is an inventor on a patent related to screening for autism. The study authors otherwise had no disclosures. Dr. Lessin is on the editorial advisory board for Pediatric News and is on an advisory board for Cognoa, which is developing a medical device to diagnose autism and he is also the co-editor of the AAP's current ADHD Toolkit. Dr. Hyman had no relevant financial disclosures.
*This story was updated on Feb. 11, 2021.
To improve autism screening rates, researchers in Utah tried a range of interventions.
They added automatic reminders to the electronic health record (EHR). They started using a shorter, more sensitive screening instrument. And they trained clinicians to perform autism-specific evaluations in a primary care clinic.
The researchers found that these interventions were associated with increased rates of autism screening and referrals.
At the same time, they looked at screening and referral rates at other community clinics in their health care system. These clinics incorporated EHR reminders but not all of the other changes.
“The community clinics had an increase in screening frequency with only automatic reminders,” the researchers reported. At the two intervention clinics, however, screening rates increased more than they did at the community clinics. Referrals did not significantly increase at the community clinics.
Kathleen Campbell, MD, MHSc, a pediatric resident at the University of Utah in Salt Lake City, and colleagues described their research in a study published in Pediatrics.
Three phases
They examined more than 12,000 well-child visits for children aged 16-30 months between July 2017 and June 2019.
In all, 4,155 visits occurred at the 2 intervention clinics, and 8,078 visits occurred at the 27 community clinics in the University of Utah health care system.
From baseline through the interventions, the proportion of visits with screening increased by 51% in the intervention clinics (from 58.6% to 88.8%), and by 21% in the community clinics (from 43.4% to 52.4%). The proportion of referrals increased 1.5-fold in intervention clinics, from 1.3% to 3.3%, the authors said.
The American Academy of Pediatrics (AAP) supports screening for autism in all children starting at age 18 months, but “only 44% of children with autism have had a comprehensive autism evaluation before age 36 months,” Dr. Campbell and colleagues wrote.
In their system, about half of the children were being screened for autism, and 0.5% had autism diagnosed.
In an effort to increase the proportion of visits with screening for autism and the proportion of visits with referrals for autism evaluation, Dr. Campbell and colleagues designed a quality improvement study.
Following a baseline period, they implemented interventions in three phases.
Initially, all clinics used the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) for autism screening. For the first phase starting in July 2018, the researchers changed the screening instrument at the two intervention clinics to the Parent’s Observation of Social Interaction (POSI). This instrument “is embedded in a broadband developmental screen, is shorter than the M-CHAT-R, and includes questions about the consistency of the child’s behavior,” the authors said. “The POSI has greater sensitivity than the M-CHAT-R ... and similar, although somewhat lower, specificity.”
In intervention phase 2 starting in November 2018, the researchers “added an automatic reminder for autism screening to the EHR health maintenance screen.” Both the intervention clinics and the community clinics received the automatic reminders.
In intervention phase 3 starting in February 2019, they “added a referral option that clinicians could use for rapid access to autism-specific evaluation ... for children who had a POSI result suggestive of autism and for whom the clinician had sufficient concerns about autism that would indicate the need for referral for autism evaluation,” the researchers said.
“Using an online tutorial, we trained three clinicians in the intervention clinics to administer an observational assessment known as the Screening Tool for Autism in Toddlers (STAT),” which requires a 30-minute visit, they said. “Children who had a STAT result suggestive of autism were referred for expedited autism diagnostic evaluation, which was performed by a multidisciplinary team in our university-based developmental assessment clinic. Children who had a STAT result that did not suggest autism did not receive further autism evaluations unless the clinician felt they still needed further evaluation at the developmental clinic.”
After the switch to POSI, the percentage of visits with a positive screen result increased from 4.7% to 13.5% in the intervention clinics.
Furthermore, referrals were 3.4 times more frequent for visits during phase 3 in the intervention clinics, relative to the baseline period.
Potential to overwhelm
“The change to a more sensitive screening instrument increased the frequency of screening results suggestive of autism and informed our improvement team of the need to implement autism evaluation in primary care to avoid overwhelming our referral system,” Dr. Campbell and coauthors reported.
Future studies may assess whether increased screening and referrals speed the time to diagnosis and treatment and improve long-term functional abilities of children with autism. Some children in the study have received an autism diagnosis, while others have not yet been evaluated.
The use of STAT in primary care may be limited by “the barriers of training providers and purchasing materials,” the authors noted. “However, the time-based billing for lengthier appointments and billing for developmental testing help to cover cost.”
The intervention clinics and community clinics were staffed by pediatric providers, including residents and attendings, said Dr. Campbell.
“The staffing is similar at the community and intervention clinics, with mostly pediatricians and some nurse practitioners,” Dr. Campbell said. “One difference is that there are a few family medicine physicians in the community clinics, but we did not study whether that made a difference in screening. At the beginning of the study the approach to screening was the same.”
From the start, the community clinics were screening for autism and referring for further autism evaluation less often than the intervention clinics. “I don’t know why they were screening less, but they did improve with the automatic reminders,” said Dr. Campbell. “We didn’t examine type of provider or type of practice in this study, but the literature suggests that family physicians do not screen for autism as often as pediatricians.”
Payment and referral challenges
In theory, the approach in the study is a great idea, but it may not be feasible to implement for many private practices, said Herschel Lessin, MD. Dr. Lessin is a senior partner of the Children’s Medical Group in New York.
“We desperately need autism screening in a primary care setting,” Dr. Lessin said. “These authors found that wasn’t being done as recommended by the AAP Bright Futures, which is a problem.”
However, the researchers incorporated the interventions in a health care system with “far more resources than most people in practice would ever have” and substituted a less familiar screening tool.
In addition, the ability to use confirmatory STAT for primary care evaluations may be limited. “Unless you can find pediatricians willing to commit 30 to 45 minutes on one of these evaluations ... few are going to do that,” he said.
“The whole problem is that there are no referrals available or very few referrals available, and that insurance payments so underpay for developmental screening and evaluation that it does not justify the time doing it, so a lot of doctors are unable to do it,” said Dr. Lessin. When a referral is warranted, developmental pediatricians may have 6- to 12-month waiting lists, he said.
“For people in clinical practice, this is not news,” Dr. Lessin said. “We know we should screen for autism. The problem is it’s time consuming. Nobody pays for it. We have no place to send them even when we are suspicious.”
From screening to diagnosis to treatment
“Autism screen approaches vary but with educational efforts on the part of the AAP, CDC, and family organizations the rates for autism screening have dramatically improved,” said Susan L. Hyman, MD, professor of pediatrics at the University of Rochester in New York. “I do not know if screening rates have been impacted by COVID.”
Dr. Hyman and coauthors wrote an AAP clinical report on the identification, evaluation, and management of children with autism spectrum disorder. The report was published in the January 2020 issue of Pediatrics.
After screening and diagnostic testing, patients most importantly need to be able to access “timely and equitable evidence-based intervention,” which should be available, said Dr. Hyman.
Although researchers have proposed training primary care providers in autism diagnostics, “older, more complex patients with co-occurring behavioral health or other developmental disorders may need more specialized diagnostic assessment than could be accomplished in a primary care setting,” Dr. Hyman added.
“However, it is very important to identify children with therapeutic needs as early as possible and move them through the continuum from screening to diagnosis to treatment in a timely fashion. It would be wonderful if symptoms could be addressed without the need for diagnosis in the very youngest children,” Dr. Hyman said. “Early symptoms, even if not autism, are likely to be appropriate for intervention – whether it is speech therapy, attention to food selectivity, sleep problems – things that impact quality of life and potential future symptoms.”
The research was supported by the Utah Stimulating Access to Research in Residency Transition Scholar award, which is funded by the National Institutes of Health.
Dr. Campbell is an inventor on a patent related to screening for autism. The study authors otherwise had no disclosures. Dr. Lessin is on the editorial advisory board for Pediatric News and is on an advisory board for Cognoa, which is developing a medical device to diagnose autism and he is also the co-editor of the AAP's current ADHD Toolkit. Dr. Hyman had no relevant financial disclosures.
*This story was updated on Feb. 11, 2021.
To improve autism screening rates, researchers in Utah tried a range of interventions.
They added automatic reminders to the electronic health record (EHR). They started using a shorter, more sensitive screening instrument. And they trained clinicians to perform autism-specific evaluations in a primary care clinic.
The researchers found that these interventions were associated with increased rates of autism screening and referrals.
At the same time, they looked at screening and referral rates at other community clinics in their health care system. These clinics incorporated EHR reminders but not all of the other changes.
“The community clinics had an increase in screening frequency with only automatic reminders,” the researchers reported. At the two intervention clinics, however, screening rates increased more than they did at the community clinics. Referrals did not significantly increase at the community clinics.
Kathleen Campbell, MD, MHSc, a pediatric resident at the University of Utah in Salt Lake City, and colleagues described their research in a study published in Pediatrics.
Three phases
They examined more than 12,000 well-child visits for children aged 16-30 months between July 2017 and June 2019.
In all, 4,155 visits occurred at the 2 intervention clinics, and 8,078 visits occurred at the 27 community clinics in the University of Utah health care system.
From baseline through the interventions, the proportion of visits with screening increased by 51% in the intervention clinics (from 58.6% to 88.8%), and by 21% in the community clinics (from 43.4% to 52.4%). The proportion of referrals increased 1.5-fold in intervention clinics, from 1.3% to 3.3%, the authors said.
The American Academy of Pediatrics (AAP) supports screening for autism in all children starting at age 18 months, but “only 44% of children with autism have had a comprehensive autism evaluation before age 36 months,” Dr. Campbell and colleagues wrote.
In their system, about half of the children were being screened for autism, and 0.5% had autism diagnosed.
In an effort to increase the proportion of visits with screening for autism and the proportion of visits with referrals for autism evaluation, Dr. Campbell and colleagues designed a quality improvement study.
Following a baseline period, they implemented interventions in three phases.
Initially, all clinics used the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) for autism screening. For the first phase starting in July 2018, the researchers changed the screening instrument at the two intervention clinics to the Parent’s Observation of Social Interaction (POSI). This instrument “is embedded in a broadband developmental screen, is shorter than the M-CHAT-R, and includes questions about the consistency of the child’s behavior,” the authors said. “The POSI has greater sensitivity than the M-CHAT-R ... and similar, although somewhat lower, specificity.”
In intervention phase 2 starting in November 2018, the researchers “added an automatic reminder for autism screening to the EHR health maintenance screen.” Both the intervention clinics and the community clinics received the automatic reminders.
In intervention phase 3 starting in February 2019, they “added a referral option that clinicians could use for rapid access to autism-specific evaluation ... for children who had a POSI result suggestive of autism and for whom the clinician had sufficient concerns about autism that would indicate the need for referral for autism evaluation,” the researchers said.
“Using an online tutorial, we trained three clinicians in the intervention clinics to administer an observational assessment known as the Screening Tool for Autism in Toddlers (STAT),” which requires a 30-minute visit, they said. “Children who had a STAT result suggestive of autism were referred for expedited autism diagnostic evaluation, which was performed by a multidisciplinary team in our university-based developmental assessment clinic. Children who had a STAT result that did not suggest autism did not receive further autism evaluations unless the clinician felt they still needed further evaluation at the developmental clinic.”
After the switch to POSI, the percentage of visits with a positive screen result increased from 4.7% to 13.5% in the intervention clinics.
Furthermore, referrals were 3.4 times more frequent for visits during phase 3 in the intervention clinics, relative to the baseline period.
Potential to overwhelm
“The change to a more sensitive screening instrument increased the frequency of screening results suggestive of autism and informed our improvement team of the need to implement autism evaluation in primary care to avoid overwhelming our referral system,” Dr. Campbell and coauthors reported.
Future studies may assess whether increased screening and referrals speed the time to diagnosis and treatment and improve long-term functional abilities of children with autism. Some children in the study have received an autism diagnosis, while others have not yet been evaluated.
The use of STAT in primary care may be limited by “the barriers of training providers and purchasing materials,” the authors noted. “However, the time-based billing for lengthier appointments and billing for developmental testing help to cover cost.”
The intervention clinics and community clinics were staffed by pediatric providers, including residents and attendings, said Dr. Campbell.
“The staffing is similar at the community and intervention clinics, with mostly pediatricians and some nurse practitioners,” Dr. Campbell said. “One difference is that there are a few family medicine physicians in the community clinics, but we did not study whether that made a difference in screening. At the beginning of the study the approach to screening was the same.”
From the start, the community clinics were screening for autism and referring for further autism evaluation less often than the intervention clinics. “I don’t know why they were screening less, but they did improve with the automatic reminders,” said Dr. Campbell. “We didn’t examine type of provider or type of practice in this study, but the literature suggests that family physicians do not screen for autism as often as pediatricians.”
Payment and referral challenges
In theory, the approach in the study is a great idea, but it may not be feasible to implement for many private practices, said Herschel Lessin, MD. Dr. Lessin is a senior partner of the Children’s Medical Group in New York.
“We desperately need autism screening in a primary care setting,” Dr. Lessin said. “These authors found that wasn’t being done as recommended by the AAP Bright Futures, which is a problem.”
However, the researchers incorporated the interventions in a health care system with “far more resources than most people in practice would ever have” and substituted a less familiar screening tool.
In addition, the ability to use confirmatory STAT for primary care evaluations may be limited. “Unless you can find pediatricians willing to commit 30 to 45 minutes on one of these evaluations ... few are going to do that,” he said.
“The whole problem is that there are no referrals available or very few referrals available, and that insurance payments so underpay for developmental screening and evaluation that it does not justify the time doing it, so a lot of doctors are unable to do it,” said Dr. Lessin. When a referral is warranted, developmental pediatricians may have 6- to 12-month waiting lists, he said.
“For people in clinical practice, this is not news,” Dr. Lessin said. “We know we should screen for autism. The problem is it’s time consuming. Nobody pays for it. We have no place to send them even when we are suspicious.”
From screening to diagnosis to treatment
“Autism screen approaches vary but with educational efforts on the part of the AAP, CDC, and family organizations the rates for autism screening have dramatically improved,” said Susan L. Hyman, MD, professor of pediatrics at the University of Rochester in New York. “I do not know if screening rates have been impacted by COVID.”
Dr. Hyman and coauthors wrote an AAP clinical report on the identification, evaluation, and management of children with autism spectrum disorder. The report was published in the January 2020 issue of Pediatrics.
After screening and diagnostic testing, patients most importantly need to be able to access “timely and equitable evidence-based intervention,” which should be available, said Dr. Hyman.
Although researchers have proposed training primary care providers in autism diagnostics, “older, more complex patients with co-occurring behavioral health or other developmental disorders may need more specialized diagnostic assessment than could be accomplished in a primary care setting,” Dr. Hyman added.
“However, it is very important to identify children with therapeutic needs as early as possible and move them through the continuum from screening to diagnosis to treatment in a timely fashion. It would be wonderful if symptoms could be addressed without the need for diagnosis in the very youngest children,” Dr. Hyman said. “Early symptoms, even if not autism, are likely to be appropriate for intervention – whether it is speech therapy, attention to food selectivity, sleep problems – things that impact quality of life and potential future symptoms.”
The research was supported by the Utah Stimulating Access to Research in Residency Transition Scholar award, which is funded by the National Institutes of Health.
Dr. Campbell is an inventor on a patent related to screening for autism. The study authors otherwise had no disclosures. Dr. Lessin is on the editorial advisory board for Pediatric News and is on an advisory board for Cognoa, which is developing a medical device to diagnose autism and he is also the co-editor of the AAP's current ADHD Toolkit. Dr. Hyman had no relevant financial disclosures.
*This story was updated on Feb. 11, 2021.
FROM PEDIATRICS
U.K. COVID-19 variant doubling every 10 days in the U.S.: Study
The SARS-CoV-2 variant first detected in the United Kingdom is rapidly becoming the dominant strain in several countries and is doubling every 10 days in the United States, according to new data.
The findings by Nicole L. Washington, PhD, associate director of research at the genomics company Helix, and colleagues were posted Feb. 7, 2021, on the preprint server medRxiv. The paper has not been peer-reviewed in a scientific journal.
The researchers also found that the transmission rate in the United States of the variant, labeled B.1.1.7, is 30%-40% higher than that of more common lineages.
While clinical outcomes initially were thought to be similar to those of other SARS-CoV-2 variants, early reports suggest that infection with the B.1.1.7 variant may increase death risk by about 30%.
A coauthor of the current study, Kristian Andersen, PhD, told the New York Times , “Nothing in this paper is surprising, but people need to see it.”
Dr. Andersen, a virologist at the Scripps Research Institute in La Jolla, Calif., added that “we should probably prepare for this being the predominant lineage in most places in the United States by March.”
The study of the B.1.1.7 variant adds support for the Centers for Disease Control and Prevention prediction in January that it would dominate by March.
“Our study shows that the U.S. is on a similar trajectory as other countries where B.1.1.7 rapidly became the dominant SARS-CoV-2 variant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality,” the researchers wrote.
The authors pointed out that the B.1.1.7 variant became the dominant SARS-CoV-2 strain in the United Kingdom within a couple of months of its detection.
“Since then, the variant has been increasingly observed across many European countries, including Portugal and Ireland, which, like the U.K., observed devastating waves of COVID-19 after B.1.1.7 became dominant,” the authors wrote.
“Category 5” storm
The B.1.1.7 variant has likely been spreading between U.S. states since at least December, they wrote.
This news organization reported on Jan. 15 that, as of Jan. 13, the B.1.1.7 variant was seen in 76 cases across 12 U.S. states, according to an early release of the CDC’s Morbidity and Mortality Weekly Report.
As of Feb. 7, there were 690 cases of the B.1.1.7 variant in the US in 33 states, according to the CDC.
Dr. Washington and colleagues examined more than 500,000 coronavirus test samples from cases across the United States that were tested at San Mateo, Calif.–based Helix facilities since July.
In the study, they found inconsistent prevalence of the variant across states. By the last week in January, the researchers estimated the proportion of B.1.1.7 in the U.S. population to be about 2.1% of all COVID-19 cases, though they found it made up about 2% of all COVID-19 cases in California and about 4.5% of cases in Florida. The authors acknowledged that their data is less robust outside of those two states.
Though that seems a relatively low frequency, “our estimates show that its growth rate is at least 35%-45% increased and doubling every week and a half,” the authors wrote.
“Because laboratories in the U.S. are only sequencing a small subset of SARS-CoV-2 samples, the true sequence diversity of SARS-CoV-2 in this country is still unknown,” they noted.
Michael Osterholm, PhD, MPH, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis, said last week that the United States is facing a “Category 5” storm with the spread of the B.1.1.7 variant as well as the variants first identified in South Africa and Brazil.
“We are going to see something like we have not seen yet in this country,” Dr. Osterholm said recently on NBC’s Meet the Press.
Lead author Nicole L. Washington and many of the coauthors are employees of Helix. Other coauthors are employees of Illumina. Three coauthors own stock in ILMN. The work was funded by Illumina, Helix, the Innovative Genomics Institute, and the New Frontiers in Research Fund provided by the Canadian Institutes of Health Research.
A version of this article first appeared on Medscape.com.
The SARS-CoV-2 variant first detected in the United Kingdom is rapidly becoming the dominant strain in several countries and is doubling every 10 days in the United States, according to new data.
The findings by Nicole L. Washington, PhD, associate director of research at the genomics company Helix, and colleagues were posted Feb. 7, 2021, on the preprint server medRxiv. The paper has not been peer-reviewed in a scientific journal.
The researchers also found that the transmission rate in the United States of the variant, labeled B.1.1.7, is 30%-40% higher than that of more common lineages.
While clinical outcomes initially were thought to be similar to those of other SARS-CoV-2 variants, early reports suggest that infection with the B.1.1.7 variant may increase death risk by about 30%.
A coauthor of the current study, Kristian Andersen, PhD, told the New York Times , “Nothing in this paper is surprising, but people need to see it.”
Dr. Andersen, a virologist at the Scripps Research Institute in La Jolla, Calif., added that “we should probably prepare for this being the predominant lineage in most places in the United States by March.”
The study of the B.1.1.7 variant adds support for the Centers for Disease Control and Prevention prediction in January that it would dominate by March.
“Our study shows that the U.S. is on a similar trajectory as other countries where B.1.1.7 rapidly became the dominant SARS-CoV-2 variant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality,” the researchers wrote.
The authors pointed out that the B.1.1.7 variant became the dominant SARS-CoV-2 strain in the United Kingdom within a couple of months of its detection.
“Since then, the variant has been increasingly observed across many European countries, including Portugal and Ireland, which, like the U.K., observed devastating waves of COVID-19 after B.1.1.7 became dominant,” the authors wrote.
“Category 5” storm
The B.1.1.7 variant has likely been spreading between U.S. states since at least December, they wrote.
This news organization reported on Jan. 15 that, as of Jan. 13, the B.1.1.7 variant was seen in 76 cases across 12 U.S. states, according to an early release of the CDC’s Morbidity and Mortality Weekly Report.
As of Feb. 7, there were 690 cases of the B.1.1.7 variant in the US in 33 states, according to the CDC.
Dr. Washington and colleagues examined more than 500,000 coronavirus test samples from cases across the United States that were tested at San Mateo, Calif.–based Helix facilities since July.
In the study, they found inconsistent prevalence of the variant across states. By the last week in January, the researchers estimated the proportion of B.1.1.7 in the U.S. population to be about 2.1% of all COVID-19 cases, though they found it made up about 2% of all COVID-19 cases in California and about 4.5% of cases in Florida. The authors acknowledged that their data is less robust outside of those two states.
Though that seems a relatively low frequency, “our estimates show that its growth rate is at least 35%-45% increased and doubling every week and a half,” the authors wrote.
“Because laboratories in the U.S. are only sequencing a small subset of SARS-CoV-2 samples, the true sequence diversity of SARS-CoV-2 in this country is still unknown,” they noted.
Michael Osterholm, PhD, MPH, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis, said last week that the United States is facing a “Category 5” storm with the spread of the B.1.1.7 variant as well as the variants first identified in South Africa and Brazil.
“We are going to see something like we have not seen yet in this country,” Dr. Osterholm said recently on NBC’s Meet the Press.
Lead author Nicole L. Washington and many of the coauthors are employees of Helix. Other coauthors are employees of Illumina. Three coauthors own stock in ILMN. The work was funded by Illumina, Helix, the Innovative Genomics Institute, and the New Frontiers in Research Fund provided by the Canadian Institutes of Health Research.
A version of this article first appeared on Medscape.com.
The SARS-CoV-2 variant first detected in the United Kingdom is rapidly becoming the dominant strain in several countries and is doubling every 10 days in the United States, according to new data.
The findings by Nicole L. Washington, PhD, associate director of research at the genomics company Helix, and colleagues were posted Feb. 7, 2021, on the preprint server medRxiv. The paper has not been peer-reviewed in a scientific journal.
The researchers also found that the transmission rate in the United States of the variant, labeled B.1.1.7, is 30%-40% higher than that of more common lineages.
While clinical outcomes initially were thought to be similar to those of other SARS-CoV-2 variants, early reports suggest that infection with the B.1.1.7 variant may increase death risk by about 30%.
A coauthor of the current study, Kristian Andersen, PhD, told the New York Times , “Nothing in this paper is surprising, but people need to see it.”
Dr. Andersen, a virologist at the Scripps Research Institute in La Jolla, Calif., added that “we should probably prepare for this being the predominant lineage in most places in the United States by March.”
The study of the B.1.1.7 variant adds support for the Centers for Disease Control and Prevention prediction in January that it would dominate by March.
“Our study shows that the U.S. is on a similar trajectory as other countries where B.1.1.7 rapidly became the dominant SARS-CoV-2 variant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality,” the researchers wrote.
The authors pointed out that the B.1.1.7 variant became the dominant SARS-CoV-2 strain in the United Kingdom within a couple of months of its detection.
“Since then, the variant has been increasingly observed across many European countries, including Portugal and Ireland, which, like the U.K., observed devastating waves of COVID-19 after B.1.1.7 became dominant,” the authors wrote.
“Category 5” storm
The B.1.1.7 variant has likely been spreading between U.S. states since at least December, they wrote.
This news organization reported on Jan. 15 that, as of Jan. 13, the B.1.1.7 variant was seen in 76 cases across 12 U.S. states, according to an early release of the CDC’s Morbidity and Mortality Weekly Report.
As of Feb. 7, there were 690 cases of the B.1.1.7 variant in the US in 33 states, according to the CDC.
Dr. Washington and colleagues examined more than 500,000 coronavirus test samples from cases across the United States that were tested at San Mateo, Calif.–based Helix facilities since July.
In the study, they found inconsistent prevalence of the variant across states. By the last week in January, the researchers estimated the proportion of B.1.1.7 in the U.S. population to be about 2.1% of all COVID-19 cases, though they found it made up about 2% of all COVID-19 cases in California and about 4.5% of cases in Florida. The authors acknowledged that their data is less robust outside of those two states.
Though that seems a relatively low frequency, “our estimates show that its growth rate is at least 35%-45% increased and doubling every week and a half,” the authors wrote.
“Because laboratories in the U.S. are only sequencing a small subset of SARS-CoV-2 samples, the true sequence diversity of SARS-CoV-2 in this country is still unknown,” they noted.
Michael Osterholm, PhD, MPH, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis, said last week that the United States is facing a “Category 5” storm with the spread of the B.1.1.7 variant as well as the variants first identified in South Africa and Brazil.
“We are going to see something like we have not seen yet in this country,” Dr. Osterholm said recently on NBC’s Meet the Press.
Lead author Nicole L. Washington and many of the coauthors are employees of Helix. Other coauthors are employees of Illumina. Three coauthors own stock in ILMN. The work was funded by Illumina, Helix, the Innovative Genomics Institute, and the New Frontiers in Research Fund provided by the Canadian Institutes of Health Research.
A version of this article first appeared on Medscape.com.