Pediatrics

An analysis of a large cohort of African American children with autism spectrum disorder (ASD) reveals a more than 3-year time lag between parental recognition of a development delay and an ASD diagnosis, reported John N. Constantino, MD, of the department of psychiatry at Washington University, St. Louis, and coauthors.

FreshSplash/E+

The analysis also highlights the need to further understand – and act on – the disproportionate burden of intellectual disability comorbidity among these children, the investigators say.

Their analysis, published in Pediatrics, builds on national community surveillance data from the Centers for Disease Control and Prevention published in 2018 showing near-equal rates of identification of ASD among African American (and other minorities) and non-Hispanic white children, but greater delays in diagnosis for African American children as well as twice the rate of comorbid intellectual disability, compared with non-Hispanic white children (44% vs. 22%).

To explore potential drivers of both diagnostic delays and the intellectual disability disparity, the investigators tapped into a repository of data on 584 African American children with ASD and their first-degree relatives who were consecutively enrolled in the National Institutes of Health–funded Autism Genetic Resource Exchange across four academic sites. The program aims to improve the representation of families of self-reported African ancestry in ASD genetics research.

The mean age of diagnosis was 65 months, which came at an average of more than 3 years after parents reported having concerns about their child’s language, behavior or development – and “the period when early developmental therapies (typically delivered through part C interventions in the United States) are initiated to ameliorate the disability associated with ASD,” Dr. Constantino and associates said.

Approximately 42% reported seeing multiple professionals before receiving an ASD diagnosis (14% saw six or more), and 31% said that a lack of available professionals had contributed to the delay. Almost all families – 98% – reported having some type of health insurance at the time of their first concerns (49% private, 46% public, and 5% others).

The data also show that excess intellectual disability comorbidity seen in African American children cannot be explained by familial or sociodemographic factors that have traditionally been associated with variation in IQ in the general population. Nor can it be explained by overclassification of intellectual disability, the authors said.

“The persistence of an unexplained excess of [intellectual disability] comorbidity of this magnitude in the [African American] population constitutes an urgent public health concern,” they wrote.

The NIH-funded program involved parental completion of “Diagnostic Odyssey” interviews (characterizing service-seeking experiences and obstacles to diagnosis, treatment, and care) and several in-person cognitive assessments and measurements of adaptive functioning. “These were in-depth [highly validated] intellectual assessments based on IQ measures that were tailored to the level of functioning of the children and backed by extensive assessments of adaptive functioning,” Dr. Constantino said in an interview.

Historically, autism has been underdiagnosed among minority children. Now that this is no longer the case, as demonstrated in the CDC’s 2018 report from its Autism and Developmental Disabilities Monitoring Network, the thought that higher rates of intellectual disability comorbidity among minority children are due to ascertainment bias – to “our only diagnosing the most serious cases” – “is no longer true,” he said.

And now, with use of data from the largest-available repository of diagnostic and phenotypic information on African American children with ASD, “we’ve dispelled other misperceptions, other factors that might be used to dismiss or explain away why Black children might have a high rate of intellectual disability,” Dr. Constantino said in the interview, referring to the absence of association between the IQ scores of children with ASD and those of their first-degree relatives as well as the lack of significant associations between the IQ of children with ASD and factors such as family income (above versus below the median income of the cohort), the mother having or not having a college degree, and the estimated gestational age at birth (before versus after 37 weeks).

“This kind of complication of autism lasts for the life of a child and profoundly impairs their functioning,” he said. “If anyone thinks there isn’t an opportunity to improve the timing of diagnosis and to improve access to services and appropriate developmental therapies, that’s wrong. There is opportunity – parents are raising the alarm, and we are not coming to these children’s rescue.”

In an accompanying editorial, Sarabeth Broder-Fingert, MD, MPH, of Boston University and Boston Medical Center, and associates wrote that the “confluence of findings [in this study] are suggestive of structural racism leading to inequity.”

For example, they said, “although the causes of delays from first parental concern to ASD diagnosis are complex, they can result from a number of issues, including racial bias and discrimination experienced by families, a lack of diversity in health professionals (impacting patient-provider relationships), and/or concentration of specialists in geographic areas with fewer minority residents.” Each of these issues, they wrote, can be linked to racism, both structural and individual.

Combined with previous research on inequity in ASD, the new data “necessitate an immediate evaluation of how issues of structural racism have impacted ASD diagnosis and, more importantly, an action plan to address inequity,” they said.

Issues of workforce capacity for ASD diagnosis need to be addressed by evaluating Medicaid reimbursement rates for ASD diagnosis, for instance, and removing restrictions on who is qualified to make a diagnosis, increasing adherence to evidence-based practices, “increasing workforce cultural humility, and recruiting a workforce that reflects the diverse communities they serve,” Dr. Broder-Fingert and associates said.

Jeremiah Dickerson, MD, a child and adolescent psychiatrist at the University of Vermont, Burlington, said he is hopeful that the inequities and structural obstacles that he sees in his patients are “being informed more and more by science” and that “we’re taking steps in exploring our own cultural humility and focusing on problems ... that have been under the surface for decades.”

Years of diagnostic delay and missed intervention for ASD can lead to increasing lifelong functional difficulties, which in turn can be compounded by enduring inequities and stigma, he said when asked to comment on the study.

“Diagnosing and teasing apart ID [intellectual disability] versus ASD, and ID co-occurring with ASD, can be very complicated, particularly in young children with significant language impairments,” he added. “If indeed there is a higher proportion of African American children with co-occurring ASD and ID ... we have to do a much better job with identifying those children earlier and providing longitudinal follow-up/assessment that can help provide diagnostic clarity and inform recommendations.”

Understanding better why this occurs “without repeating the history of assigning cause based upon racist thinking” is also important, said Dr. Dickerson, who directs the autism assessment clinic at the university’s Vermont Center for Children, Youth & Families.

Dr. Constantino, who has been involved in the CDC’s 11-site ASD surveillance network, said it is unclear to what extent broad implementation of early and high-quality interventions can reduce the proportion of African American children with autism and comorbid intellectual disability. “We may be only half-successful in closing the gap, or there may be other factors involved that we don’t understand yet,” he said. “But we haven’t even attempted to close the gap [through] reasonable application of an intervention strategy that is available and that we know can improve cognitive outcomes.”

“Some primary care doctors are reluctant to make the diagnosis in the first place because they have nothing to offer the families,” Dr. Constantino noted.

Continued research on the interactions between genetic background and specific biological susceptibilities to autism is an ongoing objective of the Autism Genetic Resource Exchange.

The CDC recently published its latest report on the prevalence of ASD in children aged 8 years, concluding again that continued efforts are needed for “early and equitable identification of ASD and timely enrollment in services.

The study was supported by grants from the National Institutes of Health and from the Intellectual and Developmental Disabilities Research Center at Washington University. Dr. Constantino is author of the Social Responsiveness Scale-2, from which he receives royalties. A coauthor helped author the Vineland-3 and receives royalties, and this coauthor and another associate also have ties to pharmaceutical companies or other organizations; the remaining authors of the study said they had no relevant financial disclosures. Dr. Broder-Fingert and associates said they have no relevant financial relationships; the editorial was funded by the National Institutes of Health. Dr. Dickerson said he had no relevant financial disclosures.

SOURCE: Constantino JN et al. Pediatrics. 2020. doi: 10.1542/peds.2019-3629.

An analysis of a large cohort of African American children with autism spectrum disorder (ASD) reveals a more than 3-year time lag between parental recognition of a development delay and an ASD diagnosis, reported John N. Constantino, MD, of the department of psychiatry at Washington University, St. Louis, and coauthors.

FreshSplash/E+

The analysis also highlights the need to further understand – and act on – the disproportionate burden of intellectual disability comorbidity among these children, the investigators say.

Their analysis, published in Pediatrics, builds on national community surveillance data from the Centers for Disease Control and Prevention published in 2018 showing near-equal rates of identification of ASD among African American (and other minorities) and non-Hispanic white children, but greater delays in diagnosis for African American children as well as twice the rate of comorbid intellectual disability, compared with non-Hispanic white children (44% vs. 22%).

To explore potential drivers of both diagnostic delays and the intellectual disability disparity, the investigators tapped into a repository of data on 584 African American children with ASD and their first-degree relatives who were consecutively enrolled in the National Institutes of Health–funded Autism Genetic Resource Exchange across four academic sites. The program aims to improve the representation of families of self-reported African ancestry in ASD genetics research.

The mean age of diagnosis was 65 months, which came at an average of more than 3 years after parents reported having concerns about their child’s language, behavior or development – and “the period when early developmental therapies (typically delivered through part C interventions in the United States) are initiated to ameliorate the disability associated with ASD,” Dr. Constantino and associates said.

Approximately 42% reported seeing multiple professionals before receiving an ASD diagnosis (14% saw six or more), and 31% said that a lack of available professionals had contributed to the delay. Almost all families – 98% – reported having some type of health insurance at the time of their first concerns (49% private, 46% public, and 5% others).

The data also show that excess intellectual disability comorbidity seen in African American children cannot be explained by familial or sociodemographic factors that have traditionally been associated with variation in IQ in the general population. Nor can it be explained by overclassification of intellectual disability, the authors said.

“The persistence of an unexplained excess of [intellectual disability] comorbidity of this magnitude in the [African American] population constitutes an urgent public health concern,” they wrote.

The NIH-funded program involved parental completion of “Diagnostic Odyssey” interviews (characterizing service-seeking experiences and obstacles to diagnosis, treatment, and care) and several in-person cognitive assessments and measurements of adaptive functioning. “These were in-depth [highly validated] intellectual assessments based on IQ measures that were tailored to the level of functioning of the children and backed by extensive assessments of adaptive functioning,” Dr. Constantino said in an interview.

Historically, autism has been underdiagnosed among minority children. Now that this is no longer the case, as demonstrated in the CDC’s 2018 report from its Autism and Developmental Disabilities Monitoring Network, the thought that higher rates of intellectual disability comorbidity among minority children are due to ascertainment bias – to “our only diagnosing the most serious cases” – “is no longer true,” he said.

And now, with use of data from the largest-available repository of diagnostic and phenotypic information on African American children with ASD, “we’ve dispelled other misperceptions, other factors that might be used to dismiss or explain away why Black children might have a high rate of intellectual disability,” Dr. Constantino said in the interview, referring to the absence of association between the IQ scores of children with ASD and those of their first-degree relatives as well as the lack of significant associations between the IQ of children with ASD and factors such as family income (above versus below the median income of the cohort), the mother having or not having a college degree, and the estimated gestational age at birth (before versus after 37 weeks).

“This kind of complication of autism lasts for the life of a child and profoundly impairs their functioning,” he said. “If anyone thinks there isn’t an opportunity to improve the timing of diagnosis and to improve access to services and appropriate developmental therapies, that’s wrong. There is opportunity – parents are raising the alarm, and we are not coming to these children’s rescue.”

In an accompanying editorial, Sarabeth Broder-Fingert, MD, MPH, of Boston University and Boston Medical Center, and associates wrote that the “confluence of findings [in this study] are suggestive of structural racism leading to inequity.”

For example, they said, “although the causes of delays from first parental concern to ASD diagnosis are complex, they can result from a number of issues, including racial bias and discrimination experienced by families, a lack of diversity in health professionals (impacting patient-provider relationships), and/or concentration of specialists in geographic areas with fewer minority residents.” Each of these issues, they wrote, can be linked to racism, both structural and individual.

Combined with previous research on inequity in ASD, the new data “necessitate an immediate evaluation of how issues of structural racism have impacted ASD diagnosis and, more importantly, an action plan to address inequity,” they said.

Issues of workforce capacity for ASD diagnosis need to be addressed by evaluating Medicaid reimbursement rates for ASD diagnosis, for instance, and removing restrictions on who is qualified to make a diagnosis, increasing adherence to evidence-based practices, “increasing workforce cultural humility, and recruiting a workforce that reflects the diverse communities they serve,” Dr. Broder-Fingert and associates said.

Jeremiah Dickerson, MD, a child and adolescent psychiatrist at the University of Vermont, Burlington, said he is hopeful that the inequities and structural obstacles that he sees in his patients are “being informed more and more by science” and that “we’re taking steps in exploring our own cultural humility and focusing on problems ... that have been under the surface for decades.”

Years of diagnostic delay and missed intervention for ASD can lead to increasing lifelong functional difficulties, which in turn can be compounded by enduring inequities and stigma, he said when asked to comment on the study.

“Diagnosing and teasing apart ID [intellectual disability] versus ASD, and ID co-occurring with ASD, can be very complicated, particularly in young children with significant language impairments,” he added. “If indeed there is a higher proportion of African American children with co-occurring ASD and ID ... we have to do a much better job with identifying those children earlier and providing longitudinal follow-up/assessment that can help provide diagnostic clarity and inform recommendations.”

Understanding better why this occurs “without repeating the history of assigning cause based upon racist thinking” is also important, said Dr. Dickerson, who directs the autism assessment clinic at the university’s Vermont Center for Children, Youth & Families.

Dr. Constantino, who has been involved in the CDC’s 11-site ASD surveillance network, said it is unclear to what extent broad implementation of early and high-quality interventions can reduce the proportion of African American children with autism and comorbid intellectual disability. “We may be only half-successful in closing the gap, or there may be other factors involved that we don’t understand yet,” he said. “But we haven’t even attempted to close the gap [through] reasonable application of an intervention strategy that is available and that we know can improve cognitive outcomes.”

“Some primary care doctors are reluctant to make the diagnosis in the first place because they have nothing to offer the families,” Dr. Constantino noted.

Continued research on the interactions between genetic background and specific biological susceptibilities to autism is an ongoing objective of the Autism Genetic Resource Exchange.

The CDC recently published its latest report on the prevalence of ASD in children aged 8 years, concluding again that continued efforts are needed for “early and equitable identification of ASD and timely enrollment in services.

The study was supported by grants from the National Institutes of Health and from the Intellectual and Developmental Disabilities Research Center at Washington University. Dr. Constantino is author of the Social Responsiveness Scale-2, from which he receives royalties. A coauthor helped author the Vineland-3 and receives royalties, and this coauthor and another associate also have ties to pharmaceutical companies or other organizations; the remaining authors of the study said they had no relevant financial disclosures. Dr. Broder-Fingert and associates said they have no relevant financial relationships; the editorial was funded by the National Institutes of Health. Dr. Dickerson said he had no relevant financial disclosures.

SOURCE: Constantino JN et al. Pediatrics. 2020. doi: 10.1542/peds.2019-3629.

An analysis of a large cohort of African American children with autism spectrum disorder (ASD) reveals a more than 3-year time lag between parental recognition of a development delay and an ASD diagnosis, reported John N. Constantino, MD, of the department of psychiatry at Washington University, St. Louis, and coauthors.

FreshSplash/E+

The analysis also highlights the need to further understand – and act on – the disproportionate burden of intellectual disability comorbidity among these children, the investigators say.

Their analysis, published in Pediatrics, builds on national community surveillance data from the Centers for Disease Control and Prevention published in 2018 showing near-equal rates of identification of ASD among African American (and other minorities) and non-Hispanic white children, but greater delays in diagnosis for African American children as well as twice the rate of comorbid intellectual disability, compared with non-Hispanic white children (44% vs. 22%).

To explore potential drivers of both diagnostic delays and the intellectual disability disparity, the investigators tapped into a repository of data on 584 African American children with ASD and their first-degree relatives who were consecutively enrolled in the National Institutes of Health–funded Autism Genetic Resource Exchange across four academic sites. The program aims to improve the representation of families of self-reported African ancestry in ASD genetics research.

The mean age of diagnosis was 65 months, which came at an average of more than 3 years after parents reported having concerns about their child’s language, behavior or development – and “the period when early developmental therapies (typically delivered through part C interventions in the United States) are initiated to ameliorate the disability associated with ASD,” Dr. Constantino and associates said.

Approximately 42% reported seeing multiple professionals before receiving an ASD diagnosis (14% saw six or more), and 31% said that a lack of available professionals had contributed to the delay. Almost all families – 98% – reported having some type of health insurance at the time of their first concerns (49% private, 46% public, and 5% others).

The data also show that excess intellectual disability comorbidity seen in African American children cannot be explained by familial or sociodemographic factors that have traditionally been associated with variation in IQ in the general population. Nor can it be explained by overclassification of intellectual disability, the authors said.

“The persistence of an unexplained excess of [intellectual disability] comorbidity of this magnitude in the [African American] population constitutes an urgent public health concern,” they wrote.

The NIH-funded program involved parental completion of “Diagnostic Odyssey” interviews (characterizing service-seeking experiences and obstacles to diagnosis, treatment, and care) and several in-person cognitive assessments and measurements of adaptive functioning. “These were in-depth [highly validated] intellectual assessments based on IQ measures that were tailored to the level of functioning of the children and backed by extensive assessments of adaptive functioning,” Dr. Constantino said in an interview.

Historically, autism has been underdiagnosed among minority children. Now that this is no longer the case, as demonstrated in the CDC’s 2018 report from its Autism and Developmental Disabilities Monitoring Network, the thought that higher rates of intellectual disability comorbidity among minority children are due to ascertainment bias – to “our only diagnosing the most serious cases” – “is no longer true,” he said.

And now, with use of data from the largest-available repository of diagnostic and phenotypic information on African American children with ASD, “we’ve dispelled other misperceptions, other factors that might be used to dismiss or explain away why Black children might have a high rate of intellectual disability,” Dr. Constantino said in the interview, referring to the absence of association between the IQ scores of children with ASD and those of their first-degree relatives as well as the lack of significant associations between the IQ of children with ASD and factors such as family income (above versus below the median income of the cohort), the mother having or not having a college degree, and the estimated gestational age at birth (before versus after 37 weeks).

“This kind of complication of autism lasts for the life of a child and profoundly impairs their functioning,” he said. “If anyone thinks there isn’t an opportunity to improve the timing of diagnosis and to improve access to services and appropriate developmental therapies, that’s wrong. There is opportunity – parents are raising the alarm, and we are not coming to these children’s rescue.”

In an accompanying editorial, Sarabeth Broder-Fingert, MD, MPH, of Boston University and Boston Medical Center, and associates wrote that the “confluence of findings [in this study] are suggestive of structural racism leading to inequity.”

For example, they said, “although the causes of delays from first parental concern to ASD diagnosis are complex, they can result from a number of issues, including racial bias and discrimination experienced by families, a lack of diversity in health professionals (impacting patient-provider relationships), and/or concentration of specialists in geographic areas with fewer minority residents.” Each of these issues, they wrote, can be linked to racism, both structural and individual.

Combined with previous research on inequity in ASD, the new data “necessitate an immediate evaluation of how issues of structural racism have impacted ASD diagnosis and, more importantly, an action plan to address inequity,” they said.

Issues of workforce capacity for ASD diagnosis need to be addressed by evaluating Medicaid reimbursement rates for ASD diagnosis, for instance, and removing restrictions on who is qualified to make a diagnosis, increasing adherence to evidence-based practices, “increasing workforce cultural humility, and recruiting a workforce that reflects the diverse communities they serve,” Dr. Broder-Fingert and associates said.

Jeremiah Dickerson, MD, a child and adolescent psychiatrist at the University of Vermont, Burlington, said he is hopeful that the inequities and structural obstacles that he sees in his patients are “being informed more and more by science” and that “we’re taking steps in exploring our own cultural humility and focusing on problems ... that have been under the surface for decades.”

Years of diagnostic delay and missed intervention for ASD can lead to increasing lifelong functional difficulties, which in turn can be compounded by enduring inequities and stigma, he said when asked to comment on the study.

“Diagnosing and teasing apart ID [intellectual disability] versus ASD, and ID co-occurring with ASD, can be very complicated, particularly in young children with significant language impairments,” he added. “If indeed there is a higher proportion of African American children with co-occurring ASD and ID ... we have to do a much better job with identifying those children earlier and providing longitudinal follow-up/assessment that can help provide diagnostic clarity and inform recommendations.”

Understanding better why this occurs “without repeating the history of assigning cause based upon racist thinking” is also important, said Dr. Dickerson, who directs the autism assessment clinic at the university’s Vermont Center for Children, Youth & Families.

Dr. Constantino, who has been involved in the CDC’s 11-site ASD surveillance network, said it is unclear to what extent broad implementation of early and high-quality interventions can reduce the proportion of African American children with autism and comorbid intellectual disability. “We may be only half-successful in closing the gap, or there may be other factors involved that we don’t understand yet,” he said. “But we haven’t even attempted to close the gap [through] reasonable application of an intervention strategy that is available and that we know can improve cognitive outcomes.”

“Some primary care doctors are reluctant to make the diagnosis in the first place because they have nothing to offer the families,” Dr. Constantino noted.

Continued research on the interactions between genetic background and specific biological susceptibilities to autism is an ongoing objective of the Autism Genetic Resource Exchange.

The CDC recently published its latest report on the prevalence of ASD in children aged 8 years, concluding again that continued efforts are needed for “early and equitable identification of ASD and timely enrollment in services.

The study was supported by grants from the National Institutes of Health and from the Intellectual and Developmental Disabilities Research Center at Washington University. Dr. Constantino is author of the Social Responsiveness Scale-2, from which he receives royalties. A coauthor helped author the Vineland-3 and receives royalties, and this coauthor and another associate also have ties to pharmaceutical companies or other organizations; the remaining authors of the study said they had no relevant financial disclosures. Dr. Broder-Fingert and associates said they have no relevant financial relationships; the editorial was funded by the National Institutes of Health. Dr. Dickerson said he had no relevant financial disclosures.

SOURCE: Constantino JN et al. Pediatrics. 2020. doi: 10.1542/peds.2019-3629.

The number of genes in humans seems inadequate to account for the diversity seen in people. While maternal and paternal factors do play a role in the development of offspring, increased attention is being paid to the forces that express these genes and the impact they have on the health of a person, including development of psychiatric conditions, according to Dolores Malaspina, MD.

Epigenetics, or changes that occur in a fetal phenotype that do not involve changes to the genotype, involve factors such as DNA methylation to control gene expression, histone modification or the wrapping of genes, or the silencing and activation of certain genes with noncoding RNA-associated factors, said Dr. Malaspina of the Icahn School of Medicine at Mount Sinai, New York.

When this occurs during pregnancy, “the fetus does not simply develop from a genetic blueprint of the genes from its father and mother. Instead, signals are received throughout the pregnancy as to the health of the mother and signals about the environment,” she said in a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

There is an evolutionary advantage to this so-called survival phenotype. “If, during the pregnancy, there’s a deficit of available nutrition, that may be a signal to the fetus that food will be scarce. In the setting of food scarcity, certain physiological adaptations during development can make the fetus more likely to survive to adulthood,” Dr. Malaspina said at the meeting, presented by Global Academy for Medical Education. But a fetus programmed to adapt to scarcity of food may also develop cardiovascular disease, metabolic disease, or mortality later in life if the prediction of scarce nutrition proved incorrect.

This approach to thinking about the developmental origins of health and disease, which examines how prenatal and perinatal exposure to environmental factors affect disease in adulthood, has also found a link between some exposures and psychiatric disorders. The most famous example, the Dutch Hunger Winter Families Study, found an increased risk of schizophrenia among children born during the height of the famine (Int J Epidemiol. 2007 Dec;36[6]:1196-204). During the Arab-Israeli war of 1967 (the Six-Day War), which took place in June, the fetuses of mothers who were pregnant during that month had a higher risk of schizophrenia if the fetus was in the second month (relative risk, 2.3; 95% confidence interval, 1.1-4.7) or third month (RR, 2.5; 95% CI, 1.2-5.2) of fetal life during June 1967, Dr. Malaspina and associates wrote (BMC Psychiatry. 2008 Aug 21;8:71).

“The key aspect is the ascertainment of individuals during a circumscribed period, the assessment and then the longitudinal follow-up,” she said. “Obviously, these are not easy studies to do, but enough of them have been done such that for the last decade at least, the general population should be aware of the developmental origins of health and disease.”

Maternal depression is another psychiatric condition that can serve as a prenatal exposure to adversity. A recent review found that children of women with untreated depression were 56% more likely to be born preterm and 96% more likely to have a low birth weight (Pediatr Res. 2019 Jan;85[2]:134-45). “Preterm birth and early birth along with low birth weight, these have ramifying effects throughout life, not only on neonatal and infant mortality, but on developmental disorders and lifetime morbidity,” she said. “These effects of maternal depression withstand all sorts of accounting for other correlated exposures, including maternal age and her medical complications or substance use.”

Maternal stress and depression can also harm neurocognitive development and effective functioning of the children, Dr. Malaspina noted. “The modulation of mood and affect can affect temperament and affect mental health. Studies exist linking maternal depression to autism, attention-deficit disorder, developmental delay, behavioral problems, sleep problems, externalizing behavior and depression, showing a very large effect of maternal depression on offspring well-being.”

To complicate matters, at least 15% of women will experience major depression during pregnancy, but of these, major depression is not being addressed in about half. Nonpharmacologic interventions can include cognitive-behavioral therapy and relaxation practices, but medication should be considered as well. “There’s an ongoing debate about whether antidepressant medications are harmful for the offspring,” she said. However, reviews conducted by Dr. Malaspina’s group have found low evidence of serious harm.

“My summary would be the depression itself holds much more evidence for disrupting offspring health and development than medications,” Dr. Malaspina said. “Most studies find no adverse birth effects when they properly controlled accounting for maternal age and the other conditions and other medications.”

Global Academy and this news organization are owned by the same parent company. Dr. Malaspina reported no relevant conflicts of interest.

The number of genes in humans seems inadequate to account for the diversity seen in people. While maternal and paternal factors do play a role in the development of offspring, increased attention is being paid to the forces that express these genes and the impact they have on the health of a person, including development of psychiatric conditions, according to Dolores Malaspina, MD.

Epigenetics, or changes that occur in a fetal phenotype that do not involve changes to the genotype, involve factors such as DNA methylation to control gene expression, histone modification or the wrapping of genes, or the silencing and activation of certain genes with noncoding RNA-associated factors, said Dr. Malaspina of the Icahn School of Medicine at Mount Sinai, New York.

When this occurs during pregnancy, “the fetus does not simply develop from a genetic blueprint of the genes from its father and mother. Instead, signals are received throughout the pregnancy as to the health of the mother and signals about the environment,” she said in a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

There is an evolutionary advantage to this so-called survival phenotype. “If, during the pregnancy, there’s a deficit of available nutrition, that may be a signal to the fetus that food will be scarce. In the setting of food scarcity, certain physiological adaptations during development can make the fetus more likely to survive to adulthood,” Dr. Malaspina said at the meeting, presented by Global Academy for Medical Education. But a fetus programmed to adapt to scarcity of food may also develop cardiovascular disease, metabolic disease, or mortality later in life if the prediction of scarce nutrition proved incorrect.

This approach to thinking about the developmental origins of health and disease, which examines how prenatal and perinatal exposure to environmental factors affect disease in adulthood, has also found a link between some exposures and psychiatric disorders. The most famous example, the Dutch Hunger Winter Families Study, found an increased risk of schizophrenia among children born during the height of the famine (Int J Epidemiol. 2007 Dec;36[6]:1196-204). During the Arab-Israeli war of 1967 (the Six-Day War), which took place in June, the fetuses of mothers who were pregnant during that month had a higher risk of schizophrenia if the fetus was in the second month (relative risk, 2.3; 95% confidence interval, 1.1-4.7) or third month (RR, 2.5; 95% CI, 1.2-5.2) of fetal life during June 1967, Dr. Malaspina and associates wrote (BMC Psychiatry. 2008 Aug 21;8:71).

“The key aspect is the ascertainment of individuals during a circumscribed period, the assessment and then the longitudinal follow-up,” she said. “Obviously, these are not easy studies to do, but enough of them have been done such that for the last decade at least, the general population should be aware of the developmental origins of health and disease.”

Maternal depression is another psychiatric condition that can serve as a prenatal exposure to adversity. A recent review found that children of women with untreated depression were 56% more likely to be born preterm and 96% more likely to have a low birth weight (Pediatr Res. 2019 Jan;85[2]:134-45). “Preterm birth and early birth along with low birth weight, these have ramifying effects throughout life, not only on neonatal and infant mortality, but on developmental disorders and lifetime morbidity,” she said. “These effects of maternal depression withstand all sorts of accounting for other correlated exposures, including maternal age and her medical complications or substance use.”

Maternal stress and depression can also harm neurocognitive development and effective functioning of the children, Dr. Malaspina noted. “The modulation of mood and affect can affect temperament and affect mental health. Studies exist linking maternal depression to autism, attention-deficit disorder, developmental delay, behavioral problems, sleep problems, externalizing behavior and depression, showing a very large effect of maternal depression on offspring well-being.”

To complicate matters, at least 15% of women will experience major depression during pregnancy, but of these, major depression is not being addressed in about half. Nonpharmacologic interventions can include cognitive-behavioral therapy and relaxation practices, but medication should be considered as well. “There’s an ongoing debate about whether antidepressant medications are harmful for the offspring,” she said. However, reviews conducted by Dr. Malaspina’s group have found low evidence of serious harm.

“My summary would be the depression itself holds much more evidence for disrupting offspring health and development than medications,” Dr. Malaspina said. “Most studies find no adverse birth effects when they properly controlled accounting for maternal age and the other conditions and other medications.”

Global Academy and this news organization are owned by the same parent company. Dr. Malaspina reported no relevant conflicts of interest.

The number of genes in humans seems inadequate to account for the diversity seen in people. While maternal and paternal factors do play a role in the development of offspring, increased attention is being paid to the forces that express these genes and the impact they have on the health of a person, including development of psychiatric conditions, according to Dolores Malaspina, MD.

Epigenetics, or changes that occur in a fetal phenotype that do not involve changes to the genotype, involve factors such as DNA methylation to control gene expression, histone modification or the wrapping of genes, or the silencing and activation of certain genes with noncoding RNA-associated factors, said Dr. Malaspina of the Icahn School of Medicine at Mount Sinai, New York.

When this occurs during pregnancy, “the fetus does not simply develop from a genetic blueprint of the genes from its father and mother. Instead, signals are received throughout the pregnancy as to the health of the mother and signals about the environment,” she said in a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

There is an evolutionary advantage to this so-called survival phenotype. “If, during the pregnancy, there’s a deficit of available nutrition, that may be a signal to the fetus that food will be scarce. In the setting of food scarcity, certain physiological adaptations during development can make the fetus more likely to survive to adulthood,” Dr. Malaspina said at the meeting, presented by Global Academy for Medical Education. But a fetus programmed to adapt to scarcity of food may also develop cardiovascular disease, metabolic disease, or mortality later in life if the prediction of scarce nutrition proved incorrect.

This approach to thinking about the developmental origins of health and disease, which examines how prenatal and perinatal exposure to environmental factors affect disease in adulthood, has also found a link between some exposures and psychiatric disorders. The most famous example, the Dutch Hunger Winter Families Study, found an increased risk of schizophrenia among children born during the height of the famine (Int J Epidemiol. 2007 Dec;36[6]:1196-204). During the Arab-Israeli war of 1967 (the Six-Day War), which took place in June, the fetuses of mothers who were pregnant during that month had a higher risk of schizophrenia if the fetus was in the second month (relative risk, 2.3; 95% confidence interval, 1.1-4.7) or third month (RR, 2.5; 95% CI, 1.2-5.2) of fetal life during June 1967, Dr. Malaspina and associates wrote (BMC Psychiatry. 2008 Aug 21;8:71).

“The key aspect is the ascertainment of individuals during a circumscribed period, the assessment and then the longitudinal follow-up,” she said. “Obviously, these are not easy studies to do, but enough of them have been done such that for the last decade at least, the general population should be aware of the developmental origins of health and disease.”

Maternal depression is another psychiatric condition that can serve as a prenatal exposure to adversity. A recent review found that children of women with untreated depression were 56% more likely to be born preterm and 96% more likely to have a low birth weight (Pediatr Res. 2019 Jan;85[2]:134-45). “Preterm birth and early birth along with low birth weight, these have ramifying effects throughout life, not only on neonatal and infant mortality, but on developmental disorders and lifetime morbidity,” she said. “These effects of maternal depression withstand all sorts of accounting for other correlated exposures, including maternal age and her medical complications or substance use.”

Maternal stress and depression can also harm neurocognitive development and effective functioning of the children, Dr. Malaspina noted. “The modulation of mood and affect can affect temperament and affect mental health. Studies exist linking maternal depression to autism, attention-deficit disorder, developmental delay, behavioral problems, sleep problems, externalizing behavior and depression, showing a very large effect of maternal depression on offspring well-being.”

To complicate matters, at least 15% of women will experience major depression during pregnancy, but of these, major depression is not being addressed in about half. Nonpharmacologic interventions can include cognitive-behavioral therapy and relaxation practices, but medication should be considered as well. “There’s an ongoing debate about whether antidepressant medications are harmful for the offspring,” she said. However, reviews conducted by Dr. Malaspina’s group have found low evidence of serious harm.

“My summary would be the depression itself holds much more evidence for disrupting offspring health and development than medications,” Dr. Malaspina said. “Most studies find no adverse birth effects when they properly controlled accounting for maternal age and the other conditions and other medications.”

Global Academy and this news organization are owned by the same parent company. Dr. Malaspina reported no relevant conflicts of interest.

The use of electronic cigarettes (e-cigarettes) in teenagers has been increasing rapidly in the United States, leading Surgeon General Jerome Adams, MD, MPH, to label it a public health concern.¹ Easy accessibility and extensive marketing for e-cigarettes counteract public education campaigns and policies aimed at decreasing e-cigarette use in teenagers.

E-cigarettes are marketed to teenagers as small, easy-to-use pens or USB flash drive–like devices that can be hidden easily. Some devices can be used to smoke nicotine, delta-9-tetrahydrocannabinol (THC), cannabidiol, and butane hash oil. Some are sold with different nicotine flavors to increase their appeal. E-cigarette ads appear in retail stores, movies, magazines, newspapers, and on the internet. 

According to the CDC, the number of middle and high school students using e-cigarettes increased from 3.6 million in 2018 to 5.4 million in 2019.² Nicotine dependence from e-cigarette use can increase the risk of starting to smoke cigarettes. A 2015-2016 National Institute on Drug Abuse survey found a higher prevalence of e-cigarette use among 9th-, 10th-, and 12th-grade students compared with cigarette smoking (9.5%, 14%, 16.2% vs 3.6%, 6.2%, 11.4%, respectively).³ Due to the growing popularity of vaping among adolescents in the United States, Congress recently raised the legal age to purchase tobacco and vaping products to 21 years.

Evidence of adverse health effects associated with e-cigarette use continues to grow. In 2020, the Department of Health and Services in Wisconsin and the Department of Public Health in Illinois looked at e-cigarette use and pulmonary disease.⁴ Of 98 participants who reported e-cigarette use, 97% presented with respiratory symptoms, 77% had gastrointestinal symptoms, and 100% had constitutional symptoms. Chest imaging showed bilateral infiltrates in all patients. In addition, 95% were hospitalized, 26% underwent intubation and mechanical ventilation, and 1 patient died. Most participants (89%) reported using THC in their e-cigarette devices.⁴ Blount et al⁵ recently found a link between e-cigarette- or vaping-associated lung injury and vitamin E acetate, a toxicant found in bronchoalveolar lavage fluid of some patients who reported using e-cigarettes. Also, nicotine dependency from e-cigarettes may adversely affect brain development in children and adolescents.²

The first step in fighting this crisis is to educate children, parents, teachers, and health care professionals about e-cigarette use, including its prevalence, use compared with cigarette smoking, trends among teenagers, marketing techniques, and adverse effects. Fortunately, the US government and medical professionals and organizations have made ongoing efforts to discourage e-cigarette use. For example, the American Academy of Child and Adolescent Psychiatry supports the FDA’s regulation of e-cigarette use; encourages using evidence-based treatments for tobacco cessation; advocates for vigorous education regarding adolescent e-cigarette use; and endorses restrictions on e-cigarette advertisement.⁶ We strongly urge clinicians to be vigilant about e-cigarette use in their adolescent patients and to intervene in this public health crisis.

Immad A. Kiani, MD
PGY-3 Psychiatry Resident
Christiana Care Health Services
Department of Psychiatry
Wilmington, Delaware

Narpinder K. Malhi, MD
Child and Adolescent Psychiatrist
Christiana Care Health Services
Wilmington, Delaware

Disclosures: The authors report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

The use of electronic cigarettes (e-cigarettes) in teenagers has been increasing rapidly in the United States, leading Surgeon General Jerome Adams, MD, MPH, to label it a public health concern.¹ Easy accessibility and extensive marketing for e-cigarettes counteract public education campaigns and policies aimed at decreasing e-cigarette use in teenagers.

E-cigarettes are marketed to teenagers as small, easy-to-use pens or USB flash drive–like devices that can be hidden easily. Some devices can be used to smoke nicotine, delta-9-tetrahydrocannabinol (THC), cannabidiol, and butane hash oil. Some are sold with different nicotine flavors to increase their appeal. E-cigarette ads appear in retail stores, movies, magazines, newspapers, and on the internet. 

According to the CDC, the number of middle and high school students using e-cigarettes increased from 3.6 million in 2018 to 5.4 million in 2019.² Nicotine dependence from e-cigarette use can increase the risk of starting to smoke cigarettes. A 2015-2016 National Institute on Drug Abuse survey found a higher prevalence of e-cigarette use among 9th-, 10th-, and 12th-grade students compared with cigarette smoking (9.5%, 14%, 16.2% vs 3.6%, 6.2%, 11.4%, respectively).³ Due to the growing popularity of vaping among adolescents in the United States, Congress recently raised the legal age to purchase tobacco and vaping products to 21 years.

Evidence of adverse health effects associated with e-cigarette use continues to grow. In 2020, the Department of Health and Services in Wisconsin and the Department of Public Health in Illinois looked at e-cigarette use and pulmonary disease.⁴ Of 98 participants who reported e-cigarette use, 97% presented with respiratory symptoms, 77% had gastrointestinal symptoms, and 100% had constitutional symptoms. Chest imaging showed bilateral infiltrates in all patients. In addition, 95% were hospitalized, 26% underwent intubation and mechanical ventilation, and 1 patient died. Most participants (89%) reported using THC in their e-cigarette devices.⁴ Blount et al⁵ recently found a link between e-cigarette- or vaping-associated lung injury and vitamin E acetate, a toxicant found in bronchoalveolar lavage fluid of some patients who reported using e-cigarettes. Also, nicotine dependency from e-cigarettes may adversely affect brain development in children and adolescents.²

The first step in fighting this crisis is to educate children, parents, teachers, and health care professionals about e-cigarette use, including its prevalence, use compared with cigarette smoking, trends among teenagers, marketing techniques, and adverse effects. Fortunately, the US government and medical professionals and organizations have made ongoing efforts to discourage e-cigarette use. For example, the American Academy of Child and Adolescent Psychiatry supports the FDA’s regulation of e-cigarette use; encourages using evidence-based treatments for tobacco cessation; advocates for vigorous education regarding adolescent e-cigarette use; and endorses restrictions on e-cigarette advertisement.⁶ We strongly urge clinicians to be vigilant about e-cigarette use in their adolescent patients and to intervene in this public health crisis.

Immad A. Kiani, MD
PGY-3 Psychiatry Resident
Christiana Care Health Services
Department of Psychiatry
Wilmington, Delaware

Narpinder K. Malhi, MD
Child and Adolescent Psychiatrist
Christiana Care Health Services
Wilmington, Delaware

Disclosures: The authors report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

The use of electronic cigarettes (e-cigarettes) in teenagers has been increasing rapidly in the United States, leading Surgeon General Jerome Adams, MD, MPH, to label it a public health concern.¹ Easy accessibility and extensive marketing for e-cigarettes counteract public education campaigns and policies aimed at decreasing e-cigarette use in teenagers.

E-cigarettes are marketed to teenagers as small, easy-to-use pens or USB flash drive–like devices that can be hidden easily. Some devices can be used to smoke nicotine, delta-9-tetrahydrocannabinol (THC), cannabidiol, and butane hash oil. Some are sold with different nicotine flavors to increase their appeal. E-cigarette ads appear in retail stores, movies, magazines, newspapers, and on the internet. 

According to the CDC, the number of middle and high school students using e-cigarettes increased from 3.6 million in 2018 to 5.4 million in 2019.² Nicotine dependence from e-cigarette use can increase the risk of starting to smoke cigarettes. A 2015-2016 National Institute on Drug Abuse survey found a higher prevalence of e-cigarette use among 9th-, 10th-, and 12th-grade students compared with cigarette smoking (9.5%, 14%, 16.2% vs 3.6%, 6.2%, 11.4%, respectively).³ Due to the growing popularity of vaping among adolescents in the United States, Congress recently raised the legal age to purchase tobacco and vaping products to 21 years.

Evidence of adverse health effects associated with e-cigarette use continues to grow. In 2020, the Department of Health and Services in Wisconsin and the Department of Public Health in Illinois looked at e-cigarette use and pulmonary disease.⁴ Of 98 participants who reported e-cigarette use, 97% presented with respiratory symptoms, 77% had gastrointestinal symptoms, and 100% had constitutional symptoms. Chest imaging showed bilateral infiltrates in all patients. In addition, 95% were hospitalized, 26% underwent intubation and mechanical ventilation, and 1 patient died. Most participants (89%) reported using THC in their e-cigarette devices.⁴ Blount et al⁵ recently found a link between e-cigarette- or vaping-associated lung injury and vitamin E acetate, a toxicant found in bronchoalveolar lavage fluid of some patients who reported using e-cigarettes. Also, nicotine dependency from e-cigarettes may adversely affect brain development in children and adolescents.²

The first step in fighting this crisis is to educate children, parents, teachers, and health care professionals about e-cigarette use, including its prevalence, use compared with cigarette smoking, trends among teenagers, marketing techniques, and adverse effects. Fortunately, the US government and medical professionals and organizations have made ongoing efforts to discourage e-cigarette use. For example, the American Academy of Child and Adolescent Psychiatry supports the FDA’s regulation of e-cigarette use; encourages using evidence-based treatments for tobacco cessation; advocates for vigorous education regarding adolescent e-cigarette use; and endorses restrictions on e-cigarette advertisement.⁶ We strongly urge clinicians to be vigilant about e-cigarette use in their adolescent patients and to intervene in this public health crisis.

Immad A. Kiani, MD
PGY-3 Psychiatry Resident
Christiana Care Health Services
Department of Psychiatry
Wilmington, Delaware

Narpinder K. Malhi, MD
Child and Adolescent Psychiatrist
Christiana Care Health Services
Wilmington, Delaware

Disclosures: The authors report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

In 2020, “the virus” has come to mean one thing: SARS-CoV-2. But just a few years ago, Zika had the world's attention, as one news report after another described children with microcephaly born to women who'd been infected while pregnant.

©Aunt_Spray/Thinkstock

It can be difficult for physicians to determine whether a birth defect is the result of Zika. Most infections have few or no symptoms, and mothers may not know if they’ve been exposed. Karin Nielsen, MD, remembers one child in particular, a 9-month-old boy born with microcephaly whose parents brought the infant to her in 2018 because he had started having seizures.

The child was born in Mexico in 2017, when the Zika virus was still known to be circulating in the Americas, said Dr. Nielsen, a pediatric infectious disease specialist at the University of California, Los Angeles. Brain imaging revealed calcifications and other signs in the boy’s brain that were consistent with exposure. But his mother said she was never sick during pregnancy.

Because Zika is transmitted not just via mosquito and from mother to fetus but also sexually, Dr. Nielsen thinks the mother probably contracted an asymptomatic infection from her husband, who recalled having a rash when she was 4 months pregnant. When they participated in a research study, both parents tested positive for Zika antibodies.

“The child had the classic symptoms of congenital Zika syndrome,” Dr. Nielsen said. “He was 9 months old, he had microcephaly, and he was having mal seizures.”

Researchers have since learned that children with such classic symptoms represent only a small proportion of those affected by prenatal Zika exposure – about 3%-5%. The virus was at its height during the 2016-2016 epidemic and is not currently causing outbreaks. But as researchers have followed cohorts of children exposed to Zika in utero, they have found many subtler effects physicians will need to monitor as the children grow up.

“When we’re seeing hundreds of kids with microcephaly, we had a lot of people infected,” Dr. Nielsen said. “Microcephaly is only the tip of the iceberg.”

Early evidence

Microcephaly may be the most identifiable symptom of fetal Zika infection, but researchers tracking cohorts of exposed children have begun to build a more complete picture of what long-term effects might look like. “Congenital Zika syndrome” refers specifically to the most severe effects from prenatal exposure: microcephaly, seizures, cerebral palsy, hearing and vision problems, feeding difficulties, and other disabilities. But hundreds, if not thousands, of children have been exposed to Zika in the womb – it’s not clear how many, Dr. Nielsen said – and many show a range of effects that don’t officially qualify as congenital Zika syndrome.

Current estimates suggest about one third of exposed children have some type of neurologic or neurodevelopmental problem, even though prevalence of visible effects is much lower. Over time, the incidence of these effects has fluctuated; some developmental delays and sensory deficits began manifesting later in childhood whereas others, at least in a few children, have resolved.

“We’re just beginning to have some of the data that we need to think about the full spectrum of outcomes,” said Cindy Moore, MD, chief medical officer in the Division of Congenital and Developmental Disorders in the Centers for Disease Control and Prevention’s National Center on Birth Defects and Developmental Disabilities.

“As we’re learning more and more, we’re learning the spectrum is expanding to less severe forms,” Dr. Moore said. “We do know that with some infections, there are later onset of problems.”

Studies published in 2018 described cohorts of children whose mothers had confirmed or suspected Zika infections during pregnancy in the French Territories of America (Guadalupe, Martinique, and French Guiana) and in Salvador, Brazil. The research provided valuable early data on the incidence of microcephaly and other severe effects in newborns, but noted the need for long-term follow up.

The U.S. Zika Pregnancy and Infant Registry is one of the largest such cohorts. In August 2018, researchers made their first report on data from the registry They looked at 1450 children age 1 or older who had undergone neuroimaging or screenings (developmental, vision, hearing) or both. In 6%, at least one birth defect was linked to Zika, and 9% had at least one neurodevelopmental abnormality.

As these children age past developmental milestones, more effects will likely manifest – even in those children whose appearance and imaging presented as healthy at birth.

Longer-term follow up

Nielsen at UCLA and M. Elisabeth Lopes Moreira, MD, of the Oswaldo Cruz Foundation in Rio de Janeiro, are following a cohort of more than 100 children born in Rio de Janeiro during Brazil’s 2015-2016 epidemic to mothers with symptomatic, PCR-confirmed Zika infections during pregnancy. In December 2018, their team reported that rates of severe neurodevelopmental delay and sensory dysfunction – 14% of 131 children aged 12-18 months – were higher than those found in earlier studies.

In August 2019, the team described neurodevelopmental, vision, and hearing outcomes in 216 Zika-exposed children 2 years after birth. They used the Bayley-III Scales of Infant and Toddler Development to assess cognitive, language and motor skills in 146 of the children. Forty percent of them were below or very below average in development, more than one third (35%) had language delays, 12% percent had hearing loss, and 7% had abnormal eye anatomy, such as underdeveloped retinas.

In two of the eight children in the cohort with microcephaly, the abnormality unexpectedly resolved. Although that finding received a lot of press, Dr. Nielsen pointed out that “not all microcephalies are created equal.”

In one case, a child born small for gestational age had proportional microcephaly: the baby›s head circumference met the criteria for microcephaly, but the infant›s head was proportional to the body so, as the child grew, the apparent microcephaly disappeared.

In the other case, the child was born with craniosynostosis, in which the skull sutures fuse too early – another effect seen with prenatal Zika exposure, Dr. Nielsen said. After corrective surgery, the child’s head circumference no longer met the definition of microcephaly, but the child still had symptoms related to congenital Zika: a developmental delay and calcifications in the brain. Meanwhile, two other children in the Rio cohort developed secondary microcephaly.

In another follow-up study of children up to age 4, Dr. Nielsen and colleagues found that both clinicians and family may think that Zika-exposed infants without microcephaly are developing normally, but that may not be true. Nearly 70% of children without microcephaly had neurologic abnormalities on physical examination, and more than half had failure to thrive because of poor feeding related to neurologic abnormalities.

Initially, some children may be able to mask subtle problems. A study published in January from Sarah B. Mulkey, MD, PhD, of Children’s National Hospital in Washington, DC, and colleagues described neurodevelopmental outcomes in 70 Colombian children up to 18 months old who had been exposed to Zika in utero. The children had a normal head circumference at birth and a normal fetal MRI, but – compared with typically developing peers – their communication, social cognition, and mobility scores on standardized assessments tended to decline as they got older.

“Especially in a very young child, there’s always going to be a possibility that you can compensate for a deficit, and it appears that at least some of these children are doing so,” said William J. Muller, MD, PhD, associate professor of pediatrics at Northwestern University, Chicago. When the children are older, certain behavioral effects will become easier to assess.

“With these children now approaching school age, understanding the full spectrum of neurodevelopmental abnormalities has important public health and educational system implications,” Dr. Muller and Dr. Mulkey wrote in a commentary about one of Dr. Nielsen’s studies.

Researchers face multiple barriers to understanding the long-term effects of fetal Zika infection. Many infants known to have been exposed in utero never received the recommended early assessments and haven’t been followed long-term. Particularly in Brazil, poverty, poor access to healthcare, and overcrowding all complicate surveillance efforts, Dr. Muller said. Stigma related to children’s neurodevelopmental problems also can potentially reduce a mother’s willingness to attend all follow-ups and assessments.

Some children may have been exposed but were never recognized as such, making it difficult for researchers to track their development and assemble a complete picture of prenatal Zika infection outcomes. Asymptomatic infection occurs in about 80% of Zika infections, though it’s not clear if that number holds for infections during pregnancy as well, according to Dr. Muller and Dr. Mulkey. Because nearly all the current research involves children whose mothers had symptomatic infections, the studies’ generalizability may be limited.

Those likely asymptomatic infections are also a major reason none of the cohorts have comparison groups.

“There are literally hundreds of things that can contribute to or cause developmental problems,” said Dr. Moore of the CDC, who noted that it would be nice to have a comparison group so as to know what Zika may not be responsible for. That said, it would be difficult-to-impossible to create a control group with similar geographic and demographic characteristics as the exposed children, a group who researchers can be certain weren’t exposed.

Neurodevelopmental disabilities occur in about 15% of the general population, making it difficult to determine whether Zika causes any or all long-term, less severe developmental findings in exposed children. The difficulty only compounds with time: the older a child is when a developmental problem is recognized, the harder it is to go back and say the problem is a result of something that occurred before birth, Dr. Moore said. “It’s a challenging field to say, this is what caused that outcome.” 

Exposed children need continued evaluation

Interpreting the clinical implications of available studies is also challenging. It can be difficult to distinguish between central nervous system damage and peripheral damage, leaving the true etiology of poor vision or hearing elusive. The Zika virus can attack both the optic nerve and the part of the brain that interprets what a person sees: “Are you not seeing well because that part of your brain is not developed, or is it just a problem with the eye?” Dr. Nielsen said. 

When problems can’t be precisely identified, successful interventions are harder. If the cochlea is normal, for instance, but the part of the brain that interprets sound or language has deficits, a hearing aid won’t help.

The services and interventions that children need depend on their specific developmental or cognitive deficits, regardless of the cause. But if clinicians know the cause is likely Zika exposure, they also know to look for other deficits.

Children showing likely effects of congenital Zika infection should be further evaluated for other possible birth defects and referred to a developmental specialist, early intervention services, and family support services. Depending on the child, primary care providers might consider referrals to an infectious disease specialist, clinical geneticist, neurologist, or other specialists.

Even with no confirmed infection or visible signs at birth, clinicians should remain vigilant with children who had possible exposure. A recently published study of 120 children conceived during the Zika outbreak in Paraíba, Brazil, assessed as infants and then again at 2 years old, exemplifies why. Researchers identified adverse neurologic outcomes and developmental delays in several children who had no physical evidence of birth defects as newborns, but whose antibody tests showed possible infection.

“In this post-epidemic period, with decreased Zika transmission and less public awareness,” wrote Dr. Mulkey and a colleague, “follow-up of these children is now more important than ever”.
 

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

In 2020, “the virus” has come to mean one thing: SARS-CoV-2. But just a few years ago, Zika had the world's attention, as one news report after another described children with microcephaly born to women who'd been infected while pregnant.

©Aunt_Spray/Thinkstock

It can be difficult for physicians to determine whether a birth defect is the result of Zika. Most infections have few or no symptoms, and mothers may not know if they’ve been exposed. Karin Nielsen, MD, remembers one child in particular, a 9-month-old boy born with microcephaly whose parents brought the infant to her in 2018 because he had started having seizures.

The child was born in Mexico in 2017, when the Zika virus was still known to be circulating in the Americas, said Dr. Nielsen, a pediatric infectious disease specialist at the University of California, Los Angeles. Brain imaging revealed calcifications and other signs in the boy’s brain that were consistent with exposure. But his mother said she was never sick during pregnancy.

Because Zika is transmitted not just via mosquito and from mother to fetus but also sexually, Dr. Nielsen thinks the mother probably contracted an asymptomatic infection from her husband, who recalled having a rash when she was 4 months pregnant. When they participated in a research study, both parents tested positive for Zika antibodies.

“The child had the classic symptoms of congenital Zika syndrome,” Dr. Nielsen said. “He was 9 months old, he had microcephaly, and he was having mal seizures.”

Researchers have since learned that children with such classic symptoms represent only a small proportion of those affected by prenatal Zika exposure – about 3%-5%. The virus was at its height during the 2016-2016 epidemic and is not currently causing outbreaks. But as researchers have followed cohorts of children exposed to Zika in utero, they have found many subtler effects physicians will need to monitor as the children grow up.

“When we’re seeing hundreds of kids with microcephaly, we had a lot of people infected,” Dr. Nielsen said. “Microcephaly is only the tip of the iceberg.”

Early evidence

Microcephaly may be the most identifiable symptom of fetal Zika infection, but researchers tracking cohorts of exposed children have begun to build a more complete picture of what long-term effects might look like. “Congenital Zika syndrome” refers specifically to the most severe effects from prenatal exposure: microcephaly, seizures, cerebral palsy, hearing and vision problems, feeding difficulties, and other disabilities. But hundreds, if not thousands, of children have been exposed to Zika in the womb – it’s not clear how many, Dr. Nielsen said – and many show a range of effects that don’t officially qualify as congenital Zika syndrome.

Current estimates suggest about one third of exposed children have some type of neurologic or neurodevelopmental problem, even though prevalence of visible effects is much lower. Over time, the incidence of these effects has fluctuated; some developmental delays and sensory deficits began manifesting later in childhood whereas others, at least in a few children, have resolved.

“We’re just beginning to have some of the data that we need to think about the full spectrum of outcomes,” said Cindy Moore, MD, chief medical officer in the Division of Congenital and Developmental Disorders in the Centers for Disease Control and Prevention’s National Center on Birth Defects and Developmental Disabilities.

“As we’re learning more and more, we’re learning the spectrum is expanding to less severe forms,” Dr. Moore said. “We do know that with some infections, there are later onset of problems.”

Studies published in 2018 described cohorts of children whose mothers had confirmed or suspected Zika infections during pregnancy in the French Territories of America (Guadalupe, Martinique, and French Guiana) and in Salvador, Brazil. The research provided valuable early data on the incidence of microcephaly and other severe effects in newborns, but noted the need for long-term follow up.

The U.S. Zika Pregnancy and Infant Registry is one of the largest such cohorts. In August 2018, researchers made their first report on data from the registry They looked at 1450 children age 1 or older who had undergone neuroimaging or screenings (developmental, vision, hearing) or both. In 6%, at least one birth defect was linked to Zika, and 9% had at least one neurodevelopmental abnormality.

As these children age past developmental milestones, more effects will likely manifest – even in those children whose appearance and imaging presented as healthy at birth.

Longer-term follow up

Nielsen at UCLA and M. Elisabeth Lopes Moreira, MD, of the Oswaldo Cruz Foundation in Rio de Janeiro, are following a cohort of more than 100 children born in Rio de Janeiro during Brazil’s 2015-2016 epidemic to mothers with symptomatic, PCR-confirmed Zika infections during pregnancy. In December 2018, their team reported that rates of severe neurodevelopmental delay and sensory dysfunction – 14% of 131 children aged 12-18 months – were higher than those found in earlier studies.

In August 2019, the team described neurodevelopmental, vision, and hearing outcomes in 216 Zika-exposed children 2 years after birth. They used the Bayley-III Scales of Infant and Toddler Development to assess cognitive, language and motor skills in 146 of the children. Forty percent of them were below or very below average in development, more than one third (35%) had language delays, 12% percent had hearing loss, and 7% had abnormal eye anatomy, such as underdeveloped retinas.

In two of the eight children in the cohort with microcephaly, the abnormality unexpectedly resolved. Although that finding received a lot of press, Dr. Nielsen pointed out that “not all microcephalies are created equal.”

In one case, a child born small for gestational age had proportional microcephaly: the baby›s head circumference met the criteria for microcephaly, but the infant›s head was proportional to the body so, as the child grew, the apparent microcephaly disappeared.

In the other case, the child was born with craniosynostosis, in which the skull sutures fuse too early – another effect seen with prenatal Zika exposure, Dr. Nielsen said. After corrective surgery, the child’s head circumference no longer met the definition of microcephaly, but the child still had symptoms related to congenital Zika: a developmental delay and calcifications in the brain. Meanwhile, two other children in the Rio cohort developed secondary microcephaly.

In another follow-up study of children up to age 4, Dr. Nielsen and colleagues found that both clinicians and family may think that Zika-exposed infants without microcephaly are developing normally, but that may not be true. Nearly 70% of children without microcephaly had neurologic abnormalities on physical examination, and more than half had failure to thrive because of poor feeding related to neurologic abnormalities.

Initially, some children may be able to mask subtle problems. A study published in January from Sarah B. Mulkey, MD, PhD, of Children’s National Hospital in Washington, DC, and colleagues described neurodevelopmental outcomes in 70 Colombian children up to 18 months old who had been exposed to Zika in utero. The children had a normal head circumference at birth and a normal fetal MRI, but – compared with typically developing peers – their communication, social cognition, and mobility scores on standardized assessments tended to decline as they got older.

“Especially in a very young child, there’s always going to be a possibility that you can compensate for a deficit, and it appears that at least some of these children are doing so,” said William J. Muller, MD, PhD, associate professor of pediatrics at Northwestern University, Chicago. When the children are older, certain behavioral effects will become easier to assess.

“With these children now approaching school age, understanding the full spectrum of neurodevelopmental abnormalities has important public health and educational system implications,” Dr. Muller and Dr. Mulkey wrote in a commentary about one of Dr. Nielsen’s studies.

Researchers face multiple barriers to understanding the long-term effects of fetal Zika infection. Many infants known to have been exposed in utero never received the recommended early assessments and haven’t been followed long-term. Particularly in Brazil, poverty, poor access to healthcare, and overcrowding all complicate surveillance efforts, Dr. Muller said. Stigma related to children’s neurodevelopmental problems also can potentially reduce a mother’s willingness to attend all follow-ups and assessments.

Some children may have been exposed but were never recognized as such, making it difficult for researchers to track their development and assemble a complete picture of prenatal Zika infection outcomes. Asymptomatic infection occurs in about 80% of Zika infections, though it’s not clear if that number holds for infections during pregnancy as well, according to Dr. Muller and Dr. Mulkey. Because nearly all the current research involves children whose mothers had symptomatic infections, the studies’ generalizability may be limited.

Those likely asymptomatic infections are also a major reason none of the cohorts have comparison groups.

“There are literally hundreds of things that can contribute to or cause developmental problems,” said Dr. Moore of the CDC, who noted that it would be nice to have a comparison group so as to know what Zika may not be responsible for. That said, it would be difficult-to-impossible to create a control group with similar geographic and demographic characteristics as the exposed children, a group who researchers can be certain weren’t exposed.

Neurodevelopmental disabilities occur in about 15% of the general population, making it difficult to determine whether Zika causes any or all long-term, less severe developmental findings in exposed children. The difficulty only compounds with time: the older a child is when a developmental problem is recognized, the harder it is to go back and say the problem is a result of something that occurred before birth, Dr. Moore said. “It’s a challenging field to say, this is what caused that outcome.” 

Exposed children need continued evaluation

Interpreting the clinical implications of available studies is also challenging. It can be difficult to distinguish between central nervous system damage and peripheral damage, leaving the true etiology of poor vision or hearing elusive. The Zika virus can attack both the optic nerve and the part of the brain that interprets what a person sees: “Are you not seeing well because that part of your brain is not developed, or is it just a problem with the eye?” Dr. Nielsen said. 

When problems can’t be precisely identified, successful interventions are harder. If the cochlea is normal, for instance, but the part of the brain that interprets sound or language has deficits, a hearing aid won’t help.

The services and interventions that children need depend on their specific developmental or cognitive deficits, regardless of the cause. But if clinicians know the cause is likely Zika exposure, they also know to look for other deficits.

Children showing likely effects of congenital Zika infection should be further evaluated for other possible birth defects and referred to a developmental specialist, early intervention services, and family support services. Depending on the child, primary care providers might consider referrals to an infectious disease specialist, clinical geneticist, neurologist, or other specialists.

Even with no confirmed infection or visible signs at birth, clinicians should remain vigilant with children who had possible exposure. A recently published study of 120 children conceived during the Zika outbreak in Paraíba, Brazil, assessed as infants and then again at 2 years old, exemplifies why. Researchers identified adverse neurologic outcomes and developmental delays in several children who had no physical evidence of birth defects as newborns, but whose antibody tests showed possible infection.

“In this post-epidemic period, with decreased Zika transmission and less public awareness,” wrote Dr. Mulkey and a colleague, “follow-up of these children is now more important than ever”.
 

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

In 2020, “the virus” has come to mean one thing: SARS-CoV-2. But just a few years ago, Zika had the world's attention, as one news report after another described children with microcephaly born to women who'd been infected while pregnant.

©Aunt_Spray/Thinkstock

It can be difficult for physicians to determine whether a birth defect is the result of Zika. Most infections have few or no symptoms, and mothers may not know if they’ve been exposed. Karin Nielsen, MD, remembers one child in particular, a 9-month-old boy born with microcephaly whose parents brought the infant to her in 2018 because he had started having seizures.

The child was born in Mexico in 2017, when the Zika virus was still known to be circulating in the Americas, said Dr. Nielsen, a pediatric infectious disease specialist at the University of California, Los Angeles. Brain imaging revealed calcifications and other signs in the boy’s brain that were consistent with exposure. But his mother said she was never sick during pregnancy.

Because Zika is transmitted not just via mosquito and from mother to fetus but also sexually, Dr. Nielsen thinks the mother probably contracted an asymptomatic infection from her husband, who recalled having a rash when she was 4 months pregnant. When they participated in a research study, both parents tested positive for Zika antibodies.

“The child had the classic symptoms of congenital Zika syndrome,” Dr. Nielsen said. “He was 9 months old, he had microcephaly, and he was having mal seizures.”

Researchers have since learned that children with such classic symptoms represent only a small proportion of those affected by prenatal Zika exposure – about 3%-5%. The virus was at its height during the 2016-2016 epidemic and is not currently causing outbreaks. But as researchers have followed cohorts of children exposed to Zika in utero, they have found many subtler effects physicians will need to monitor as the children grow up.

“When we’re seeing hundreds of kids with microcephaly, we had a lot of people infected,” Dr. Nielsen said. “Microcephaly is only the tip of the iceberg.”

Early evidence

Microcephaly may be the most identifiable symptom of fetal Zika infection, but researchers tracking cohorts of exposed children have begun to build a more complete picture of what long-term effects might look like. “Congenital Zika syndrome” refers specifically to the most severe effects from prenatal exposure: microcephaly, seizures, cerebral palsy, hearing and vision problems, feeding difficulties, and other disabilities. But hundreds, if not thousands, of children have been exposed to Zika in the womb – it’s not clear how many, Dr. Nielsen said – and many show a range of effects that don’t officially qualify as congenital Zika syndrome.

Current estimates suggest about one third of exposed children have some type of neurologic or neurodevelopmental problem, even though prevalence of visible effects is much lower. Over time, the incidence of these effects has fluctuated; some developmental delays and sensory deficits began manifesting later in childhood whereas others, at least in a few children, have resolved.

“We’re just beginning to have some of the data that we need to think about the full spectrum of outcomes,” said Cindy Moore, MD, chief medical officer in the Division of Congenital and Developmental Disorders in the Centers for Disease Control and Prevention’s National Center on Birth Defects and Developmental Disabilities.

“As we’re learning more and more, we’re learning the spectrum is expanding to less severe forms,” Dr. Moore said. “We do know that with some infections, there are later onset of problems.”

Studies published in 2018 described cohorts of children whose mothers had confirmed or suspected Zika infections during pregnancy in the French Territories of America (Guadalupe, Martinique, and French Guiana) and in Salvador, Brazil. The research provided valuable early data on the incidence of microcephaly and other severe effects in newborns, but noted the need for long-term follow up.

The U.S. Zika Pregnancy and Infant Registry is one of the largest such cohorts. In August 2018, researchers made their first report on data from the registry They looked at 1450 children age 1 or older who had undergone neuroimaging or screenings (developmental, vision, hearing) or both. In 6%, at least one birth defect was linked to Zika, and 9% had at least one neurodevelopmental abnormality.

As these children age past developmental milestones, more effects will likely manifest – even in those children whose appearance and imaging presented as healthy at birth.

Longer-term follow up

Nielsen at UCLA and M. Elisabeth Lopes Moreira, MD, of the Oswaldo Cruz Foundation in Rio de Janeiro, are following a cohort of more than 100 children born in Rio de Janeiro during Brazil’s 2015-2016 epidemic to mothers with symptomatic, PCR-confirmed Zika infections during pregnancy. In December 2018, their team reported that rates of severe neurodevelopmental delay and sensory dysfunction – 14% of 131 children aged 12-18 months – were higher than those found in earlier studies.

In August 2019, the team described neurodevelopmental, vision, and hearing outcomes in 216 Zika-exposed children 2 years after birth. They used the Bayley-III Scales of Infant and Toddler Development to assess cognitive, language and motor skills in 146 of the children. Forty percent of them were below or very below average in development, more than one third (35%) had language delays, 12% percent had hearing loss, and 7% had abnormal eye anatomy, such as underdeveloped retinas.

In two of the eight children in the cohort with microcephaly, the abnormality unexpectedly resolved. Although that finding received a lot of press, Dr. Nielsen pointed out that “not all microcephalies are created equal.”

In one case, a child born small for gestational age had proportional microcephaly: the baby›s head circumference met the criteria for microcephaly, but the infant›s head was proportional to the body so, as the child grew, the apparent microcephaly disappeared.

In the other case, the child was born with craniosynostosis, in which the skull sutures fuse too early – another effect seen with prenatal Zika exposure, Dr. Nielsen said. After corrective surgery, the child’s head circumference no longer met the definition of microcephaly, but the child still had symptoms related to congenital Zika: a developmental delay and calcifications in the brain. Meanwhile, two other children in the Rio cohort developed secondary microcephaly.

In another follow-up study of children up to age 4, Dr. Nielsen and colleagues found that both clinicians and family may think that Zika-exposed infants without microcephaly are developing normally, but that may not be true. Nearly 70% of children without microcephaly had neurologic abnormalities on physical examination, and more than half had failure to thrive because of poor feeding related to neurologic abnormalities.

Initially, some children may be able to mask subtle problems. A study published in January from Sarah B. Mulkey, MD, PhD, of Children’s National Hospital in Washington, DC, and colleagues described neurodevelopmental outcomes in 70 Colombian children up to 18 months old who had been exposed to Zika in utero. The children had a normal head circumference at birth and a normal fetal MRI, but – compared with typically developing peers – their communication, social cognition, and mobility scores on standardized assessments tended to decline as they got older.

“Especially in a very young child, there’s always going to be a possibility that you can compensate for a deficit, and it appears that at least some of these children are doing so,” said William J. Muller, MD, PhD, associate professor of pediatrics at Northwestern University, Chicago. When the children are older, certain behavioral effects will become easier to assess.

“With these children now approaching school age, understanding the full spectrum of neurodevelopmental abnormalities has important public health and educational system implications,” Dr. Muller and Dr. Mulkey wrote in a commentary about one of Dr. Nielsen’s studies.

Researchers face multiple barriers to understanding the long-term effects of fetal Zika infection. Many infants known to have been exposed in utero never received the recommended early assessments and haven’t been followed long-term. Particularly in Brazil, poverty, poor access to healthcare, and overcrowding all complicate surveillance efforts, Dr. Muller said. Stigma related to children’s neurodevelopmental problems also can potentially reduce a mother’s willingness to attend all follow-ups and assessments.

Some children may have been exposed but were never recognized as such, making it difficult for researchers to track their development and assemble a complete picture of prenatal Zika infection outcomes. Asymptomatic infection occurs in about 80% of Zika infections, though it’s not clear if that number holds for infections during pregnancy as well, according to Dr. Muller and Dr. Mulkey. Because nearly all the current research involves children whose mothers had symptomatic infections, the studies’ generalizability may be limited.

Those likely asymptomatic infections are also a major reason none of the cohorts have comparison groups.

“There are literally hundreds of things that can contribute to or cause developmental problems,” said Dr. Moore of the CDC, who noted that it would be nice to have a comparison group so as to know what Zika may not be responsible for. That said, it would be difficult-to-impossible to create a control group with similar geographic and demographic characteristics as the exposed children, a group who researchers can be certain weren’t exposed.

Neurodevelopmental disabilities occur in about 15% of the general population, making it difficult to determine whether Zika causes any or all long-term, less severe developmental findings in exposed children. The difficulty only compounds with time: the older a child is when a developmental problem is recognized, the harder it is to go back and say the problem is a result of something that occurred before birth, Dr. Moore said. “It’s a challenging field to say, this is what caused that outcome.” 

Exposed children need continued evaluation

Interpreting the clinical implications of available studies is also challenging. It can be difficult to distinguish between central nervous system damage and peripheral damage, leaving the true etiology of poor vision or hearing elusive. The Zika virus can attack both the optic nerve and the part of the brain that interprets what a person sees: “Are you not seeing well because that part of your brain is not developed, or is it just a problem with the eye?” Dr. Nielsen said. 

When problems can’t be precisely identified, successful interventions are harder. If the cochlea is normal, for instance, but the part of the brain that interprets sound or language has deficits, a hearing aid won’t help.

The services and interventions that children need depend on their specific developmental or cognitive deficits, regardless of the cause. But if clinicians know the cause is likely Zika exposure, they also know to look for other deficits.

Children showing likely effects of congenital Zika infection should be further evaluated for other possible birth defects and referred to a developmental specialist, early intervention services, and family support services. Depending on the child, primary care providers might consider referrals to an infectious disease specialist, clinical geneticist, neurologist, or other specialists.

Even with no confirmed infection or visible signs at birth, clinicians should remain vigilant with children who had possible exposure. A recently published study of 120 children conceived during the Zika outbreak in Paraíba, Brazil, assessed as infants and then again at 2 years old, exemplifies why. Researchers identified adverse neurologic outcomes and developmental delays in several children who had no physical evidence of birth defects as newborns, but whose antibody tests showed possible infection.

“In this post-epidemic period, with decreased Zika transmission and less public awareness,” wrote Dr. Mulkey and a colleague, “follow-up of these children is now more important than ever”.
 

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

Case: A 56-year-old man with a history of type 2 diabetes, hypertension, hyperlipidemia, and obesity calls clinic to discuss concerns about COVID-19, stating: “I want to do everything I can to reduce my risk of infection.” In addition to physical distancing, mask wearing, hand hygiene, and control of chronic conditions, which of the following supplements would you recommend for this patient?

1. Coenzyme Q10 160 mg twice a day

2. Vitamin D 2,000 IU daily

3. Vitamin E 400 IU daily

4. Vitamin B₁₂ 1,000 mcg daily

Of these choices, vitamin D supplementation is likely the best option, based on the limited data that is available.

Vitamin D has been implicated in the prevention of many disease processes, including acute respiratory infections. Risk factors for worse COVID-19 outcome, such as older age, obesity, and more pigmented skin are also risk factors for vitamin D deficiency. This makes the study of vitamin D and COVID-19 both challenging and relevant.

In a recent study of 7,807 people living in Israel, Merzon and colleagues found that low plasma vitamin D level was an independent risk factor for COVID-19 infection. Mean plasma vitamin D level was significantly lower among those who tested positive for COVID-19 (19.00 ng/mL) than negative (20.55 ng/ mL). After controlling for demographic variables and several medical conditions, the adjusted odds ratio of COVID-19 infection in those with lower vitamin D was 1.45 (95% confidence interval, 1.08-1.95; P < .001). However, the odds of hospitalization for COVID-19 was not significantly associated with vitamin D level.¹

yulka3ice/Getty Images

Prior studies have also looked at vitamin D and respiratory infection. Martineau and colleagues analyzed 25 randomized, controlled trials with a pooled number of 11,321 individuals, including healthy ones and those with comorbidities, and found that oral vitamin D supplementation in daily or weekly doses had a protective effect against acute respiratory infection (adjusted odds ratio, 0.88; 95% CI, 0.81-0.96; P < .001). Patients with vitamin D deficiency (less than 25 nmol/L) experienced the most protective benefit. Vitamin D did not influence respiratory infection outcome.²

These studies suggest an adequate vitamin D level may be protective against infection with COVID-19, but who will benefit from vitamin D supplementation, and in what dose? Per U.S. Preventive Services Task Force guidelines, there is insufficient evidence to recommend screening for vitamin D deficiency in asymptomatic adults. Regarding daily dietary intake, the Institute of Medicine recommends 600 IU for persons aged 1-70, and 800 IU for those aged over 70 years. Salmon (447 IU per 3 oz serving), tuna (154 IU), and fortified milk (116 IU) are among the most vitamin D–rich foods.³ The recommended upper level of intake is 4,000 IU/day.
 

Too much of a good thing?

Extra vitamin D is stored in adipose tissue. If it builds up over time, storage sites may be overwhelmed, causing a rise in serum D level. While one might expect a subsequent rise in calcium levels, studies have shown this happens inconsistently, and at very high vitamin D levels, over 120 ng/mL.⁴ Most people would have to take at least 50,000 IU daily for several months to see an effect. The main adverse outcome of vitamin D toxicity is kidney stones, mediated by increased calcium in the blood and urine.

Several animal models have demonstrated hypervitaminosis D–induced aortic and coronary artery calcification. Like with kidney stones, the mechanism appears to be through increased calcium and phosphate levels. Shroff and colleagues studied serum vitamin D levels and vascular disease in children with renal disease on dialysis and found a U-shaped distribution: Children with both low and high vitamin D levels had significantly increased carotid artery intima-media thickness and calcification.⁵ Given the specialized nature of this population, it’s unclear whether these results can be generalized to most people. More studies are warranted on this topic.
 

Other benefits

Vitamin D is perhaps most famous for helping to build strong bones. Avenell and colleagues performed a Cochrane meta-analysis of vitamin D supplementation in older adults and found that vitamin D alone did not significantly reduce the risk of hip or other new fracture. Vitamin D plus calcium supplementation did reduce the risk of hip fracture (nine trials, pooled number of individuals was 49,853; relative risk, 0.84; P = .01).⁶

A lesser-known benefit of vitamin D is muscle protection. A prospective study out of the Jewish Hospital of Cincinnati followed 146 adults who were intolerant to two or more statins because of muscle side effects and found to have a vitamin D level below 32 ng per mL. Subjects were given vitamin D replacement (50,000 units weekly) and followed for 2 years. On statin rechallenge, 88-95% tolerated a statin with vitamin D levels 53-55 ng/mL.⁷

Pearl

Vitamin D supplementation may protect against COVID-19 infection and has very low chance of harm at daily doses at or below 4,000 IU. Other benefits of taking vitamin D include bone protection and reduction in statin-induced myopathy. The main adverse effect is kidney stones.

Ms. Sharninghausen is a medical student at the University of Washington, Seattle. Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.

References

1. Merzon E et al. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: An Israeli population‐based study. FEBS J. 2020. doi: 10.1111/febs.15495.

2. Martineau AR et al. Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. doi:10.1136/bmj.i6583

3. “How to Get More Vitamin D From Your Food,” Cleveland Clinic. 2019 Oct 23. https://health.clevelandclinic.org/how-to-get-more-vitamin-d-from-your-food/.

4. Galior K et al. Development of vitamin d toxicity from overcorrection of vitamin D Deficiency: A review of case reports. Nutrients. 2018;10(8):953. doi: 10.3390/nu10080953

5. Shroff R et al. A bimodal association of vitamin D levels and vascular disease in children on dialysis. J Am Soc Nephrol. 2008;19(6):1239-46. doi: 10.1681/ASN.2007090993.

6. Avenell A et al. Vitamin D and vitamin D analogues for preventing fractures in post‐menopausal women and older men. Cochrane Database Syst Rev. 2014 Apr 14;2014(4):CD000227. doi: 10.1002/14651858.CD000227.pub4.

7. Khayznikov M et al. Statin intolerance because of myalgia, myositis, myopathy, or myonecrosis can in most cases be safely resolved by vitamin D supplementation. N Am J Med Sci. 2015;7(3):86-93. doi:10.4103/1947-2714.153919
 

Case: A 56-year-old man with a history of type 2 diabetes, hypertension, hyperlipidemia, and obesity calls clinic to discuss concerns about COVID-19, stating: “I want to do everything I can to reduce my risk of infection.” In addition to physical distancing, mask wearing, hand hygiene, and control of chronic conditions, which of the following supplements would you recommend for this patient?

1. Coenzyme Q10 160 mg twice a day

2. Vitamin D 2,000 IU daily

3. Vitamin E 400 IU daily

4. Vitamin B₁₂ 1,000 mcg daily

Of these choices, vitamin D supplementation is likely the best option, based on the limited data that is available.

Vitamin D has been implicated in the prevention of many disease processes, including acute respiratory infections. Risk factors for worse COVID-19 outcome, such as older age, obesity, and more pigmented skin are also risk factors for vitamin D deficiency. This makes the study of vitamin D and COVID-19 both challenging and relevant.

In a recent study of 7,807 people living in Israel, Merzon and colleagues found that low plasma vitamin D level was an independent risk factor for COVID-19 infection. Mean plasma vitamin D level was significantly lower among those who tested positive for COVID-19 (19.00 ng/mL) than negative (20.55 ng/ mL). After controlling for demographic variables and several medical conditions, the adjusted odds ratio of COVID-19 infection in those with lower vitamin D was 1.45 (95% confidence interval, 1.08-1.95; P < .001). However, the odds of hospitalization for COVID-19 was not significantly associated with vitamin D level.¹

yulka3ice/Getty Images

Prior studies have also looked at vitamin D and respiratory infection. Martineau and colleagues analyzed 25 randomized, controlled trials with a pooled number of 11,321 individuals, including healthy ones and those with comorbidities, and found that oral vitamin D supplementation in daily or weekly doses had a protective effect against acute respiratory infection (adjusted odds ratio, 0.88; 95% CI, 0.81-0.96; P < .001). Patients with vitamin D deficiency (less than 25 nmol/L) experienced the most protective benefit. Vitamin D did not influence respiratory infection outcome.²

These studies suggest an adequate vitamin D level may be protective against infection with COVID-19, but who will benefit from vitamin D supplementation, and in what dose? Per U.S. Preventive Services Task Force guidelines, there is insufficient evidence to recommend screening for vitamin D deficiency in asymptomatic adults. Regarding daily dietary intake, the Institute of Medicine recommends 600 IU for persons aged 1-70, and 800 IU for those aged over 70 years. Salmon (447 IU per 3 oz serving), tuna (154 IU), and fortified milk (116 IU) are among the most vitamin D–rich foods.³ The recommended upper level of intake is 4,000 IU/day.
 

Too much of a good thing?

Extra vitamin D is stored in adipose tissue. If it builds up over time, storage sites may be overwhelmed, causing a rise in serum D level. While one might expect a subsequent rise in calcium levels, studies have shown this happens inconsistently, and at very high vitamin D levels, over 120 ng/mL.⁴ Most people would have to take at least 50,000 IU daily for several months to see an effect. The main adverse outcome of vitamin D toxicity is kidney stones, mediated by increased calcium in the blood and urine.

Several animal models have demonstrated hypervitaminosis D–induced aortic and coronary artery calcification. Like with kidney stones, the mechanism appears to be through increased calcium and phosphate levels. Shroff and colleagues studied serum vitamin D levels and vascular disease in children with renal disease on dialysis and found a U-shaped distribution: Children with both low and high vitamin D levels had significantly increased carotid artery intima-media thickness and calcification.⁵ Given the specialized nature of this population, it’s unclear whether these results can be generalized to most people. More studies are warranted on this topic.
 

Other benefits

Vitamin D is perhaps most famous for helping to build strong bones. Avenell and colleagues performed a Cochrane meta-analysis of vitamin D supplementation in older adults and found that vitamin D alone did not significantly reduce the risk of hip or other new fracture. Vitamin D plus calcium supplementation did reduce the risk of hip fracture (nine trials, pooled number of individuals was 49,853; relative risk, 0.84; P = .01).⁶

A lesser-known benefit of vitamin D is muscle protection. A prospective study out of the Jewish Hospital of Cincinnati followed 146 adults who were intolerant to two or more statins because of muscle side effects and found to have a vitamin D level below 32 ng per mL. Subjects were given vitamin D replacement (50,000 units weekly) and followed for 2 years. On statin rechallenge, 88-95% tolerated a statin with vitamin D levels 53-55 ng/mL.⁷

Pearl

Vitamin D supplementation may protect against COVID-19 infection and has very low chance of harm at daily doses at or below 4,000 IU. Other benefits of taking vitamin D include bone protection and reduction in statin-induced myopathy. The main adverse effect is kidney stones.

Ms. Sharninghausen is a medical student at the University of Washington, Seattle. Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.

References

1. Merzon E et al. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: An Israeli population‐based study. FEBS J. 2020. doi: 10.1111/febs.15495.

2. Martineau AR et al. Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. doi:10.1136/bmj.i6583

3. “How to Get More Vitamin D From Your Food,” Cleveland Clinic. 2019 Oct 23. https://health.clevelandclinic.org/how-to-get-more-vitamin-d-from-your-food/.

4. Galior K et al. Development of vitamin d toxicity from overcorrection of vitamin D Deficiency: A review of case reports. Nutrients. 2018;10(8):953. doi: 10.3390/nu10080953

5. Shroff R et al. A bimodal association of vitamin D levels and vascular disease in children on dialysis. J Am Soc Nephrol. 2008;19(6):1239-46. doi: 10.1681/ASN.2007090993.

6. Avenell A et al. Vitamin D and vitamin D analogues for preventing fractures in post‐menopausal women and older men. Cochrane Database Syst Rev. 2014 Apr 14;2014(4):CD000227. doi: 10.1002/14651858.CD000227.pub4.

7. Khayznikov M et al. Statin intolerance because of myalgia, myositis, myopathy, or myonecrosis can in most cases be safely resolved by vitamin D supplementation. N Am J Med Sci. 2015;7(3):86-93. doi:10.4103/1947-2714.153919
 

Case: A 56-year-old man with a history of type 2 diabetes, hypertension, hyperlipidemia, and obesity calls clinic to discuss concerns about COVID-19, stating: “I want to do everything I can to reduce my risk of infection.” In addition to physical distancing, mask wearing, hand hygiene, and control of chronic conditions, which of the following supplements would you recommend for this patient?

1. Coenzyme Q10 160 mg twice a day

2. Vitamin D 2,000 IU daily

3. Vitamin E 400 IU daily

4. Vitamin B₁₂ 1,000 mcg daily

Of these choices, vitamin D supplementation is likely the best option, based on the limited data that is available.

Vitamin D has been implicated in the prevention of many disease processes, including acute respiratory infections. Risk factors for worse COVID-19 outcome, such as older age, obesity, and more pigmented skin are also risk factors for vitamin D deficiency. This makes the study of vitamin D and COVID-19 both challenging and relevant.

In a recent study of 7,807 people living in Israel, Merzon and colleagues found that low plasma vitamin D level was an independent risk factor for COVID-19 infection. Mean plasma vitamin D level was significantly lower among those who tested positive for COVID-19 (19.00 ng/mL) than negative (20.55 ng/ mL). After controlling for demographic variables and several medical conditions, the adjusted odds ratio of COVID-19 infection in those with lower vitamin D was 1.45 (95% confidence interval, 1.08-1.95; P < .001). However, the odds of hospitalization for COVID-19 was not significantly associated with vitamin D level.¹

yulka3ice/Getty Images

Prior studies have also looked at vitamin D and respiratory infection. Martineau and colleagues analyzed 25 randomized, controlled trials with a pooled number of 11,321 individuals, including healthy ones and those with comorbidities, and found that oral vitamin D supplementation in daily or weekly doses had a protective effect against acute respiratory infection (adjusted odds ratio, 0.88; 95% CI, 0.81-0.96; P < .001). Patients with vitamin D deficiency (less than 25 nmol/L) experienced the most protective benefit. Vitamin D did not influence respiratory infection outcome.²

These studies suggest an adequate vitamin D level may be protective against infection with COVID-19, but who will benefit from vitamin D supplementation, and in what dose? Per U.S. Preventive Services Task Force guidelines, there is insufficient evidence to recommend screening for vitamin D deficiency in asymptomatic adults. Regarding daily dietary intake, the Institute of Medicine recommends 600 IU for persons aged 1-70, and 800 IU for those aged over 70 years. Salmon (447 IU per 3 oz serving), tuna (154 IU), and fortified milk (116 IU) are among the most vitamin D–rich foods.³ The recommended upper level of intake is 4,000 IU/day.
 

Too much of a good thing?

Extra vitamin D is stored in adipose tissue. If it builds up over time, storage sites may be overwhelmed, causing a rise in serum D level. While one might expect a subsequent rise in calcium levels, studies have shown this happens inconsistently, and at very high vitamin D levels, over 120 ng/mL.⁴ Most people would have to take at least 50,000 IU daily for several months to see an effect. The main adverse outcome of vitamin D toxicity is kidney stones, mediated by increased calcium in the blood and urine.

Several animal models have demonstrated hypervitaminosis D–induced aortic and coronary artery calcification. Like with kidney stones, the mechanism appears to be through increased calcium and phosphate levels. Shroff and colleagues studied serum vitamin D levels and vascular disease in children with renal disease on dialysis and found a U-shaped distribution: Children with both low and high vitamin D levels had significantly increased carotid artery intima-media thickness and calcification.⁵ Given the specialized nature of this population, it’s unclear whether these results can be generalized to most people. More studies are warranted on this topic.
 

Other benefits

Vitamin D is perhaps most famous for helping to build strong bones. Avenell and colleagues performed a Cochrane meta-analysis of vitamin D supplementation in older adults and found that vitamin D alone did not significantly reduce the risk of hip or other new fracture. Vitamin D plus calcium supplementation did reduce the risk of hip fracture (nine trials, pooled number of individuals was 49,853; relative risk, 0.84; P = .01).⁶

A lesser-known benefit of vitamin D is muscle protection. A prospective study out of the Jewish Hospital of Cincinnati followed 146 adults who were intolerant to two or more statins because of muscle side effects and found to have a vitamin D level below 32 ng per mL. Subjects were given vitamin D replacement (50,000 units weekly) and followed for 2 years. On statin rechallenge, 88-95% tolerated a statin with vitamin D levels 53-55 ng/mL.⁷

Pearl

Vitamin D supplementation may protect against COVID-19 infection and has very low chance of harm at daily doses at or below 4,000 IU. Other benefits of taking vitamin D include bone protection and reduction in statin-induced myopathy. The main adverse effect is kidney stones.

Ms. Sharninghausen is a medical student at the University of Washington, Seattle. Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.

References

1. Merzon E et al. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: An Israeli population‐based study. FEBS J. 2020. doi: 10.1111/febs.15495.

2. Martineau AR et al. Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. doi:10.1136/bmj.i6583

3. “How to Get More Vitamin D From Your Food,” Cleveland Clinic. 2019 Oct 23. https://health.clevelandclinic.org/how-to-get-more-vitamin-d-from-your-food/.

4. Galior K et al. Development of vitamin d toxicity from overcorrection of vitamin D Deficiency: A review of case reports. Nutrients. 2018;10(8):953. doi: 10.3390/nu10080953

5. Shroff R et al. A bimodal association of vitamin D levels and vascular disease in children on dialysis. J Am Soc Nephrol. 2008;19(6):1239-46. doi: 10.1681/ASN.2007090993.

6. Avenell A et al. Vitamin D and vitamin D analogues for preventing fractures in post‐menopausal women and older men. Cochrane Database Syst Rev. 2014 Apr 14;2014(4):CD000227. doi: 10.1002/14651858.CD000227.pub4.

7. Khayznikov M et al. Statin intolerance because of myalgia, myositis, myopathy, or myonecrosis can in most cases be safely resolved by vitamin D supplementation. N Am J Med Sci. 2015;7(3):86-93. doi:10.4103/1947-2714.153919
 

American Indian/Alaska Native high school students are almost three times more likely to attempt suicide than high schoolers as a whole, according to newly released data from the 2019 Youth Risk Behavior Survey.

The prevalence of attempted suicide during the previous 12 months was 8.9% among the 13,677 students in grades 9-12 who took the survey last year, but the rate was 25.5% for American Indian/Alaska Native (AI/AN) respondents, almost 2.9 times higher, the YRBS data show.

Respondents with multiple races in their backgrounds, at 12.9%, and African Americans, with a prevalence of 11.8%, also were above the high school average for suicide attempts, while Whites (7.9%) and Asians (7.7%) were under it and Hispanics equaled it, the Centers for Disease Control and Prevention reported.

The number of AI/AN students was insufficient to examine differences by sex, but females in all of the other racial/ethnic groups were more likely than males to have attempted suicide: multiple race (17.8% vs. 7.3%), African American (15.2% vs. 8.5%), Hispanic (11.9% vs. 5.5%), White (9.4% vs. 6.4%), and Asian (8.4% vs. 7.1%), the CDC’s Division of Adolescent and School Health said.

Among all respondents, 11.0% of females had attempted suicide in the 12 months before the survey, a figure that is significantly higher than the 6.6% prevalence in males. Females also were significantly more likely than males to make a plan about how they would attempt suicide (19.9% vs. 11.3%) and to seriously consider an attempt (24.1% vs. 13.3%), CDC investigators said in a separate report.

Significant differences also were seen when looking at sexual identity. Suicide attempts were reported by 6.4% of heterosexuals, 16.1% of those who weren’t sure, and 23.4% of lesbians/gays/bisexuals (LGBs). For serious consideration of suicide, the respective numbers were 14.5%, 30.4%, and 46.8%, they reported (MMWR Supp. 2020 Aug 21;69[1]:47-55).

For nonheterosexuals, however, males were slightly more likely (23.8%) than females (23.6%) to have attempted suicide, but females were more likely to seriously consider it (49.0% vs. 40.4%) and to make a plan (42.4% vs. 33.0%), according to the YRBS data.

“Adolescence … represents a time for expanded identity development, with sexual identity development representing a complex, multidimensional, and often stressful process for youths,” the CDC investigators said in the MMWR. “To address the health differences in suicidal ideation and behaviors observed by student demographics and to decrease these outcomes overall, a comprehensive approach to suicide prevention, including programs, practices, and policies based on the best available evidence, is needed.”

rfranki@mdedge.com

American Indian/Alaska Native high school students are almost three times more likely to attempt suicide than high schoolers as a whole, according to newly released data from the 2019 Youth Risk Behavior Survey.

The prevalence of attempted suicide during the previous 12 months was 8.9% among the 13,677 students in grades 9-12 who took the survey last year, but the rate was 25.5% for American Indian/Alaska Native (AI/AN) respondents, almost 2.9 times higher, the YRBS data show.

Respondents with multiple races in their backgrounds, at 12.9%, and African Americans, with a prevalence of 11.8%, also were above the high school average for suicide attempts, while Whites (7.9%) and Asians (7.7%) were under it and Hispanics equaled it, the Centers for Disease Control and Prevention reported.

The number of AI/AN students was insufficient to examine differences by sex, but females in all of the other racial/ethnic groups were more likely than males to have attempted suicide: multiple race (17.8% vs. 7.3%), African American (15.2% vs. 8.5%), Hispanic (11.9% vs. 5.5%), White (9.4% vs. 6.4%), and Asian (8.4% vs. 7.1%), the CDC’s Division of Adolescent and School Health said.

Among all respondents, 11.0% of females had attempted suicide in the 12 months before the survey, a figure that is significantly higher than the 6.6% prevalence in males. Females also were significantly more likely than males to make a plan about how they would attempt suicide (19.9% vs. 11.3%) and to seriously consider an attempt (24.1% vs. 13.3%), CDC investigators said in a separate report.

Significant differences also were seen when looking at sexual identity. Suicide attempts were reported by 6.4% of heterosexuals, 16.1% of those who weren’t sure, and 23.4% of lesbians/gays/bisexuals (LGBs). For serious consideration of suicide, the respective numbers were 14.5%, 30.4%, and 46.8%, they reported (MMWR Supp. 2020 Aug 21;69[1]:47-55).

For nonheterosexuals, however, males were slightly more likely (23.8%) than females (23.6%) to have attempted suicide, but females were more likely to seriously consider it (49.0% vs. 40.4%) and to make a plan (42.4% vs. 33.0%), according to the YRBS data.

“Adolescence … represents a time for expanded identity development, with sexual identity development representing a complex, multidimensional, and often stressful process for youths,” the CDC investigators said in the MMWR. “To address the health differences in suicidal ideation and behaviors observed by student demographics and to decrease these outcomes overall, a comprehensive approach to suicide prevention, including programs, practices, and policies based on the best available evidence, is needed.”

rfranki@mdedge.com

American Indian/Alaska Native high school students are almost three times more likely to attempt suicide than high schoolers as a whole, according to newly released data from the 2019 Youth Risk Behavior Survey.

The prevalence of attempted suicide during the previous 12 months was 8.9% among the 13,677 students in grades 9-12 who took the survey last year, but the rate was 25.5% for American Indian/Alaska Native (AI/AN) respondents, almost 2.9 times higher, the YRBS data show.

Respondents with multiple races in their backgrounds, at 12.9%, and African Americans, with a prevalence of 11.8%, also were above the high school average for suicide attempts, while Whites (7.9%) and Asians (7.7%) were under it and Hispanics equaled it, the Centers for Disease Control and Prevention reported.

The number of AI/AN students was insufficient to examine differences by sex, but females in all of the other racial/ethnic groups were more likely than males to have attempted suicide: multiple race (17.8% vs. 7.3%), African American (15.2% vs. 8.5%), Hispanic (11.9% vs. 5.5%), White (9.4% vs. 6.4%), and Asian (8.4% vs. 7.1%), the CDC’s Division of Adolescent and School Health said.

Among all respondents, 11.0% of females had attempted suicide in the 12 months before the survey, a figure that is significantly higher than the 6.6% prevalence in males. Females also were significantly more likely than males to make a plan about how they would attempt suicide (19.9% vs. 11.3%) and to seriously consider an attempt (24.1% vs. 13.3%), CDC investigators said in a separate report.

Significant differences also were seen when looking at sexual identity. Suicide attempts were reported by 6.4% of heterosexuals, 16.1% of those who weren’t sure, and 23.4% of lesbians/gays/bisexuals (LGBs). For serious consideration of suicide, the respective numbers were 14.5%, 30.4%, and 46.8%, they reported (MMWR Supp. 2020 Aug 21;69[1]:47-55).

For nonheterosexuals, however, males were slightly more likely (23.8%) than females (23.6%) to have attempted suicide, but females were more likely to seriously consider it (49.0% vs. 40.4%) and to make a plan (42.4% vs. 33.0%), according to the YRBS data.

“Adolescence … represents a time for expanded identity development, with sexual identity development representing a complex, multidimensional, and often stressful process for youths,” the CDC investigators said in the MMWR. “To address the health differences in suicidal ideation and behaviors observed by student demographics and to decrease these outcomes overall, a comprehensive approach to suicide prevention, including programs, practices, and policies based on the best available evidence, is needed.”

rfranki@mdedge.com

The Food and Drug Administration has approved clascoterone 1% cream for the topical therapy of acne, providing a treatment with a novel mechanism of action for acne.

Clascoterone is a topical androgen receptor inhibitor indicated for treatment of acne vulgaris in patients aged 12 years and older, according to the labeling from manufacturer Cassiopea. Clascoterone, which will be marketed as Winlevi, targets the androgen hormones that contribute to acne by inhibiting serum production and inflammation, according to a company press release.

“Although clascoterone’s exact mechanism of action is unknown, laboratory studies suggest clascoterone competes with androgens, specifically dihydrotestosterone, for binding to the androgen receptors within the sebaceous gland and hair follicles,” according to the release.

Approval was based in part on a pair of phase 3, double-blind, vehicle-controlled, 12-week, randomized trials including 1,440 patients aged 9 years and older with moderate to severe facial acne. The findings were published in April, in JAMA Dermatology .

Participants were randomized to twice-daily application of clascoterone or a control vehicle; treatment success was defined as having an Investigator’s Global Assessment score of 0 (clear) or 1 (almost clear), as well as at least a 2-grade improvement from baseline, and absolute change in noninflammatory and inflammatory lesion counts at week 12.

At 12 weeks, treatment success rates were 18.4% and 20.3% among those on clascoterone, compared with 9% and 6.5%, respectively, among controls. There were also significant reductions in noninflammatory and inflammatory lesions from baseline at 12 weeks, compared with controls.

In the studies, treatment was well tolerated, with a safety profile similar to safety in controls. Adverse events thought to be related to clascoterone in the studies (a total of 13) included application-site pain; erythema; oropharyngeal pain; hypersensitivity, dryness, or hypertrichosis at the application site; eye irritation; headache; and hair color changes. “Clascoterone targets androgen receptors at the site of application and is quickly metabolized to an inactive form, thus limiting systemic activity,” the authors of the study wrote.

Clascoterone is expected to be available in the United States in early 2021, according to the manufacturer.

The Food and Drug Administration has approved clascoterone 1% cream for the topical therapy of acne, providing a treatment with a novel mechanism of action for acne.

Clascoterone is a topical androgen receptor inhibitor indicated for treatment of acne vulgaris in patients aged 12 years and older, according to the labeling from manufacturer Cassiopea. Clascoterone, which will be marketed as Winlevi, targets the androgen hormones that contribute to acne by inhibiting serum production and inflammation, according to a company press release.

“Although clascoterone’s exact mechanism of action is unknown, laboratory studies suggest clascoterone competes with androgens, specifically dihydrotestosterone, for binding to the androgen receptors within the sebaceous gland and hair follicles,” according to the release.

Approval was based in part on a pair of phase 3, double-blind, vehicle-controlled, 12-week, randomized trials including 1,440 patients aged 9 years and older with moderate to severe facial acne. The findings were published in April, in JAMA Dermatology .

Participants were randomized to twice-daily application of clascoterone or a control vehicle; treatment success was defined as having an Investigator’s Global Assessment score of 0 (clear) or 1 (almost clear), as well as at least a 2-grade improvement from baseline, and absolute change in noninflammatory and inflammatory lesion counts at week 12.

At 12 weeks, treatment success rates were 18.4% and 20.3% among those on clascoterone, compared with 9% and 6.5%, respectively, among controls. There were also significant reductions in noninflammatory and inflammatory lesions from baseline at 12 weeks, compared with controls.

In the studies, treatment was well tolerated, with a safety profile similar to safety in controls. Adverse events thought to be related to clascoterone in the studies (a total of 13) included application-site pain; erythema; oropharyngeal pain; hypersensitivity, dryness, or hypertrichosis at the application site; eye irritation; headache; and hair color changes. “Clascoterone targets androgen receptors at the site of application and is quickly metabolized to an inactive form, thus limiting systemic activity,” the authors of the study wrote.

Clascoterone is expected to be available in the United States in early 2021, according to the manufacturer.

The Food and Drug Administration has approved clascoterone 1% cream for the topical therapy of acne, providing a treatment with a novel mechanism of action for acne.

Clascoterone is a topical androgen receptor inhibitor indicated for treatment of acne vulgaris in patients aged 12 years and older, according to the labeling from manufacturer Cassiopea. Clascoterone, which will be marketed as Winlevi, targets the androgen hormones that contribute to acne by inhibiting serum production and inflammation, according to a company press release.

“Although clascoterone’s exact mechanism of action is unknown, laboratory studies suggest clascoterone competes with androgens, specifically dihydrotestosterone, for binding to the androgen receptors within the sebaceous gland and hair follicles,” according to the release.

Approval was based in part on a pair of phase 3, double-blind, vehicle-controlled, 12-week, randomized trials including 1,440 patients aged 9 years and older with moderate to severe facial acne. The findings were published in April, in JAMA Dermatology .

Participants were randomized to twice-daily application of clascoterone or a control vehicle; treatment success was defined as having an Investigator’s Global Assessment score of 0 (clear) or 1 (almost clear), as well as at least a 2-grade improvement from baseline, and absolute change in noninflammatory and inflammatory lesion counts at week 12.

At 12 weeks, treatment success rates were 18.4% and 20.3% among those on clascoterone, compared with 9% and 6.5%, respectively, among controls. There were also significant reductions in noninflammatory and inflammatory lesions from baseline at 12 weeks, compared with controls.

In the studies, treatment was well tolerated, with a safety profile similar to safety in controls. Adverse events thought to be related to clascoterone in the studies (a total of 13) included application-site pain; erythema; oropharyngeal pain; hypersensitivity, dryness, or hypertrichosis at the application site; eye irritation; headache; and hair color changes. “Clascoterone targets androgen receptors at the site of application and is quickly metabolized to an inactive form, thus limiting systemic activity,” the authors of the study wrote.

Clascoterone is expected to be available in the United States in early 2021, according to the manufacturer.

The photograph submitted for the telemedicine visit showed 2 classic umbilicated lesions and 1 dome-shaped papule consistent with molluscum contagiosum. Not all skin conditions can be diagnosed or treated via telehealth, but with a careful history, cooperative patients (and parents in this case), and photos taken on newer cell phones or digital cameras, many conditions can be diagnosed and managed appropriately.

Molluscum contagiosum is caused by the Molluscipox genus poxvirus and Is commonly seen in preschool and school-aged children. It can be passed through direct contact with infected individuals or spread by fomites. (In this case, the child may have picked up the virus by sharing a towel with an infected individual.)

The flesh-colored lesions are umbilicated or popular, and occur in clusters on the trunk, face, and extremities. Typically, the lesions will resolve spontaneously, but it may take several weeks to many months for resolution.

Given this lengthy time for spontaneous resolution, the risk of spreading to family members or other contacts, and the skin’s appearance, many patients choose to treat the lesions. Treatment options include curettage, cryosurgery, and laser. Available topical destructive agents include podophyllotoxin, trichloroacetic acid, benzoyl peroxide, potassium hydroxide, and cantharidin (which is from the blister beetle and often difficult to obtain). There also are naturopathic topical products and immune system modulators, including topical imiquimod. These treatments are commonly used, but are off-label for the treatment of molluscum contagiosum.

The family was counseled that there is debate about the effectiveness of imiquimod for molluscum contagiosum, but that some studies find it to be useful. In this case, the mother chose a prescription for imiquimod cream 5%, to be applied 3 times weekly at bedtime until the lesions resolved. (The cream can be used for up to 16 weeks.) The family was advised that erythema and irritation are expected adverse effects at the application site.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

The photograph submitted for the telemedicine visit showed 2 classic umbilicated lesions and 1 dome-shaped papule consistent with molluscum contagiosum. Not all skin conditions can be diagnosed or treated via telehealth, but with a careful history, cooperative patients (and parents in this case), and photos taken on newer cell phones or digital cameras, many conditions can be diagnosed and managed appropriately.

Molluscum contagiosum is caused by the Molluscipox genus poxvirus and Is commonly seen in preschool and school-aged children. It can be passed through direct contact with infected individuals or spread by fomites. (In this case, the child may have picked up the virus by sharing a towel with an infected individual.)

The flesh-colored lesions are umbilicated or popular, and occur in clusters on the trunk, face, and extremities. Typically, the lesions will resolve spontaneously, but it may take several weeks to many months for resolution.

Given this lengthy time for spontaneous resolution, the risk of spreading to family members or other contacts, and the skin’s appearance, many patients choose to treat the lesions. Treatment options include curettage, cryosurgery, and laser. Available topical destructive agents include podophyllotoxin, trichloroacetic acid, benzoyl peroxide, potassium hydroxide, and cantharidin (which is from the blister beetle and often difficult to obtain). There also are naturopathic topical products and immune system modulators, including topical imiquimod. These treatments are commonly used, but are off-label for the treatment of molluscum contagiosum.

The family was counseled that there is debate about the effectiveness of imiquimod for molluscum contagiosum, but that some studies find it to be useful. In this case, the mother chose a prescription for imiquimod cream 5%, to be applied 3 times weekly at bedtime until the lesions resolved. (The cream can be used for up to 16 weeks.) The family was advised that erythema and irritation are expected adverse effects at the application site.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

The photograph submitted for the telemedicine visit showed 2 classic umbilicated lesions and 1 dome-shaped papule consistent with molluscum contagiosum. Not all skin conditions can be diagnosed or treated via telehealth, but with a careful history, cooperative patients (and parents in this case), and photos taken on newer cell phones or digital cameras, many conditions can be diagnosed and managed appropriately.

Molluscum contagiosum is caused by the Molluscipox genus poxvirus and Is commonly seen in preschool and school-aged children. It can be passed through direct contact with infected individuals or spread by fomites. (In this case, the child may have picked up the virus by sharing a towel with an infected individual.)

The flesh-colored lesions are umbilicated or popular, and occur in clusters on the trunk, face, and extremities. Typically, the lesions will resolve spontaneously, but it may take several weeks to many months for resolution.

Given this lengthy time for spontaneous resolution, the risk of spreading to family members or other contacts, and the skin’s appearance, many patients choose to treat the lesions. Treatment options include curettage, cryosurgery, and laser. Available topical destructive agents include podophyllotoxin, trichloroacetic acid, benzoyl peroxide, potassium hydroxide, and cantharidin (which is from the blister beetle and often difficult to obtain). There also are naturopathic topical products and immune system modulators, including topical imiquimod. These treatments are commonly used, but are off-label for the treatment of molluscum contagiosum.

The family was counseled that there is debate about the effectiveness of imiquimod for molluscum contagiosum, but that some studies find it to be useful. In this case, the mother chose a prescription for imiquimod cream 5%, to be applied 3 times weekly at bedtime until the lesions resolved. (The cream can be used for up to 16 weeks.) The family was advised that erythema and irritation are expected adverse effects at the application site.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

As communities wrestle with the decision to send children back to school or opt for distance learning, a key question is how many children are likely to have asymptomatic SARS-CoV-2 infections. Researchers have now found that the prevalence of asymptomatic infections in children correlates with the overall incidence of COVID-19 in the local population, according to an analysis of data from 28 U.S. children’s hospitals.

Courtesy NIAID

“The strong association between prevalence of SARS-CoV-2 in children who are asymptomatic and contemporaneous weekly incidence of COVID-19 in the general population ... provides a simple means for institutions to estimate local pediatric asymptomatic prevalence from the publicly available Johns Hopkins University database,” researchers say in an article published online August 25 in JAMA Pediatrics.

Ana Marija Sola, BS, a researcher at the University of California, San Francisco, and colleagues examined the prevalence of SARS-CoV-2 infection among 33,041 children who underwent routine testing in April and May when hospitals resumed elective medical and surgical care. The hospitals performed reverse transcription–polymerase chain reaction tests for SARS-CoV-2 RNA before surgery, clinic visits, or hospital admissions. Pediatric otolaryngologists reported the prevalence data through May 29 as part of a quality improvement project.

In all, 250 patients tested positive for the virus, for an overall prevalence of 0.65%. Across 25 geographic areas, the prevalence ranged from 0% to 2.2%. By region, prevalence was highest in the Northeast, at 0.90%, and the Midwest, at 0.87%; prevalence was lower in the West, at 0.59%, and the South, at 0.52%.

To get a sense of how those rates compared with overall rates in the same geographic areas, the researchers used the Johns Hopkins University confirmed cases database to calculate the average weekly incidence of COVID-19 for the entire population for each geographic area.

“Asymptomatic pediatric prevalence was significantly associated with weekly incidence of COVID-19 in the general population during the 6-week period over which most testing of individuals without symptoms occurred,” Ms. Sola and colleagues reported. An analysis using additional data from 11 geographic areas demonstrated that this association persisted at a later time point.

The study provides “another window on the question of how likely is it that an asymptomatic child will be carrying coronavirus,” said Susan E. Coffin, MD, MPH, an attending physician for the division of infectious diseases at Children’s Hospital of Philadelphia. However, important related questions remain, said Dr. Coffin, who was not involved with the study.

For one, it is unclear how many children remain asymptomatic in comparison with those who were in a presymptomatic phase at the time of testing. And importantly, “what proportion of these children are infectious?” said Dr. Coffin. “There is some data to suggest that children with asymptomatic infection may be less infectious than children with symptomatic infection.”

It also could be that patients seen at children’s hospitals differ from the general pediatric population. “What does this look like if you do the exact same study in a group of randomly selected children, not children who are queueing up to have a procedure? ... And what do these numbers look like now that stay-at-home orders have been lifted?” Dr. Coffin asked.

Further studies are needed to establish that detection of COVID-19 in the general population is predictive of the prevalence of SARS-CoV-2 infection in asymptomatic children, Dr. Coffin said.

The authors have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

As communities wrestle with the decision to send children back to school or opt for distance learning, a key question is how many children are likely to have asymptomatic SARS-CoV-2 infections. Researchers have now found that the prevalence of asymptomatic infections in children correlates with the overall incidence of COVID-19 in the local population, according to an analysis of data from 28 U.S. children’s hospitals.

Courtesy NIAID

“The strong association between prevalence of SARS-CoV-2 in children who are asymptomatic and contemporaneous weekly incidence of COVID-19 in the general population ... provides a simple means for institutions to estimate local pediatric asymptomatic prevalence from the publicly available Johns Hopkins University database,” researchers say in an article published online August 25 in JAMA Pediatrics.

Ana Marija Sola, BS, a researcher at the University of California, San Francisco, and colleagues examined the prevalence of SARS-CoV-2 infection among 33,041 children who underwent routine testing in April and May when hospitals resumed elective medical and surgical care. The hospitals performed reverse transcription–polymerase chain reaction tests for SARS-CoV-2 RNA before surgery, clinic visits, or hospital admissions. Pediatric otolaryngologists reported the prevalence data through May 29 as part of a quality improvement project.

In all, 250 patients tested positive for the virus, for an overall prevalence of 0.65%. Across 25 geographic areas, the prevalence ranged from 0% to 2.2%. By region, prevalence was highest in the Northeast, at 0.90%, and the Midwest, at 0.87%; prevalence was lower in the West, at 0.59%, and the South, at 0.52%.

To get a sense of how those rates compared with overall rates in the same geographic areas, the researchers used the Johns Hopkins University confirmed cases database to calculate the average weekly incidence of COVID-19 for the entire population for each geographic area.

“Asymptomatic pediatric prevalence was significantly associated with weekly incidence of COVID-19 in the general population during the 6-week period over which most testing of individuals without symptoms occurred,” Ms. Sola and colleagues reported. An analysis using additional data from 11 geographic areas demonstrated that this association persisted at a later time point.

The study provides “another window on the question of how likely is it that an asymptomatic child will be carrying coronavirus,” said Susan E. Coffin, MD, MPH, an attending physician for the division of infectious diseases at Children’s Hospital of Philadelphia. However, important related questions remain, said Dr. Coffin, who was not involved with the study.

For one, it is unclear how many children remain asymptomatic in comparison with those who were in a presymptomatic phase at the time of testing. And importantly, “what proportion of these children are infectious?” said Dr. Coffin. “There is some data to suggest that children with asymptomatic infection may be less infectious than children with symptomatic infection.”

It also could be that patients seen at children’s hospitals differ from the general pediatric population. “What does this look like if you do the exact same study in a group of randomly selected children, not children who are queueing up to have a procedure? ... And what do these numbers look like now that stay-at-home orders have been lifted?” Dr. Coffin asked.

Further studies are needed to establish that detection of COVID-19 in the general population is predictive of the prevalence of SARS-CoV-2 infection in asymptomatic children, Dr. Coffin said.

The authors have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

As communities wrestle with the decision to send children back to school or opt for distance learning, a key question is how many children are likely to have asymptomatic SARS-CoV-2 infections. Researchers have now found that the prevalence of asymptomatic infections in children correlates with the overall incidence of COVID-19 in the local population, according to an analysis of data from 28 U.S. children’s hospitals.

Courtesy NIAID

“The strong association between prevalence of SARS-CoV-2 in children who are asymptomatic and contemporaneous weekly incidence of COVID-19 in the general population ... provides a simple means for institutions to estimate local pediatric asymptomatic prevalence from the publicly available Johns Hopkins University database,” researchers say in an article published online August 25 in JAMA Pediatrics.

Ana Marija Sola, BS, a researcher at the University of California, San Francisco, and colleagues examined the prevalence of SARS-CoV-2 infection among 33,041 children who underwent routine testing in April and May when hospitals resumed elective medical and surgical care. The hospitals performed reverse transcription–polymerase chain reaction tests for SARS-CoV-2 RNA before surgery, clinic visits, or hospital admissions. Pediatric otolaryngologists reported the prevalence data through May 29 as part of a quality improvement project.

In all, 250 patients tested positive for the virus, for an overall prevalence of 0.65%. Across 25 geographic areas, the prevalence ranged from 0% to 2.2%. By region, prevalence was highest in the Northeast, at 0.90%, and the Midwest, at 0.87%; prevalence was lower in the West, at 0.59%, and the South, at 0.52%.

To get a sense of how those rates compared with overall rates in the same geographic areas, the researchers used the Johns Hopkins University confirmed cases database to calculate the average weekly incidence of COVID-19 for the entire population for each geographic area.

“Asymptomatic pediatric prevalence was significantly associated with weekly incidence of COVID-19 in the general population during the 6-week period over which most testing of individuals without symptoms occurred,” Ms. Sola and colleagues reported. An analysis using additional data from 11 geographic areas demonstrated that this association persisted at a later time point.

The study provides “another window on the question of how likely is it that an asymptomatic child will be carrying coronavirus,” said Susan E. Coffin, MD, MPH, an attending physician for the division of infectious diseases at Children’s Hospital of Philadelphia. However, important related questions remain, said Dr. Coffin, who was not involved with the study.

For one, it is unclear how many children remain asymptomatic in comparison with those who were in a presymptomatic phase at the time of testing. And importantly, “what proportion of these children are infectious?” said Dr. Coffin. “There is some data to suggest that children with asymptomatic infection may be less infectious than children with symptomatic infection.”

It also could be that patients seen at children’s hospitals differ from the general pediatric population. “What does this look like if you do the exact same study in a group of randomly selected children, not children who are queueing up to have a procedure? ... And what do these numbers look like now that stay-at-home orders have been lifted?” Dr. Coffin asked.

Further studies are needed to establish that detection of COVID-19 in the general population is predictive of the prevalence of SARS-CoV-2 infection in asymptomatic children, Dr. Coffin said.

The authors have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

A large postmarketing surveillance study of topical calcineurin inhibitor exposure in adults with atopic dermatitis has found no increased risk of developing keratinocyte carcinomas overall or with basal cell or squamous cell carcinomas associated with treatment.

The results also suggest dose, frequency, and exposure duration to the topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus are not associated with an increased risk of keratinocyte carcinomas (KCs), basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs) in patients with atopic dermatitis (AD), according to Maryam M. Asgari, MD, MPH, professor of dermatology, Harvard Medical School, Boston, and colleagues. In 2006, the Food and Drug Administration announced the addition of the boxed warning to the labeling of TCIs regarding a possible risk of cancer associated with use of pimecrolimus (Elidel) and with tacrolimus (Protopic), because of an increased risk of KCs associated with oral calcineurin inhibitors and reports of skin cancer in patients on TCIs.

“Controversy has surrounded the association between TCI exposure and KC risk since the black-box warning was issued by the FDA. A hypothesized mechanism of action for TCIs increasing KC risk includes a direct effect of calcineurin inhibition on DNA repair and apoptosis, which could influence keratinocyte carcinogenesis,” the authors of the study wrote in JAMA Dermatology. But, they added, there have been “conflicting results” in research exploring this association.

In the retrospective cohort study, Dr. Asgari and coauthors evaluated 93,746 adult patients with AD at Kaiser Permanente Northern California, diagnosed between January 2002 and December 2013, comparing skin cancer risk among 7,033 patients exposed to TCIs, 73,674 patients taking topical corticosteroids, and 46,141 patients who had not been exposed to TCIs or topical corticosteroids. Results were adjusted in a multivariate Cox regression analysis for age, gender, race/ethnicity, calendar year, number of dermatology visits per year, history of KCs, immunosuppression, prior systemic AD treatment, autoimmune disease, treatment with ultraviolet therapy, chemotherapy, and radiotherapy.

The researchers also examined how TCI dose, frequency and exposure duration impacted skin cancer risk. Patients were grouped by high-dose (0.1%) and low-dose (0.03%) formulations of tacrolimus; and the 1% formulation of pimecrolimus. Frequency of use was defined as low (once daily or less) or high (twice daily or more), and exposure duration was based on short- (less than 2 years), moderate- (2-4 years), and long-term (4 years or more) use. Patients were at least 40 years old (mean age, 58.5 years), 58.7% were women, 50.5% were White, 20.6% were Asian, 12.2% were Hispanic, and 7.9% were Black. They were followed for a mean of 7.70 years.

Compared with patients who were exposed to topical corticosteroids, there was no association between risk of KCs and exposure to TCIs in patients with AD (adjusted hazard ratio, 1.02; 95% confidence interval, 0.93-1.13). There were also no significant differences in risk of BCCs and TCI exposure (aHR, 1.01; 95% CI, 0.90-1.14) and risk of SCCs and TCI exposure (aHR, 0.94; 95% CI, 0.82-1.08), compared with patients exposed to topical corticosteroids.

Results were similar for risk of KCs (aHR, 1.03; 95% CI, 0.92-1.14), BCCs (aHR, 1.04; 95% CI, 0.91-1.19), and SCCs (aHR, 0.91; 95% CI, 0.78-1.06) when patients exposed to TCIs were compared with those with AD who were unexposed to any medication. In secondary analyses, Dr. Asgari and coauthors found no association with overall risk of KCs, or risk of BCCs or SCCs, and the dose, frequency, or exposure duration to TCIs.

“Our findings appear to support those of smaller postmarketing surveillance studies of TCI and KC risk and may provide some reassurance about the safety profile of this class of topical agents in the treatment of AD,” they concluded.

In an interview, Jonathan Silverberg, MD, PhD, MPH, associate professor of dermatology, George Washington University, Washington, said initial concerns surrounding TCIs were based on high doses potentially increasing the risk of malignancy, and off-label use of TCIs for inflammatory skin diseases other than AD.

“However, the FDA’s concerns may not have been justified,” he said. The manufacturers of pimecrolimus and tacrolimus have published results of 10-year observational registries that assess cancer risk, which “found no evidence of any associations between TCIs and malignancy,” noted Dr. Silverberg, who is also director of clinical research and contact dermatitis at George Washington University.

Elizabeth Hughes, MD, a dermatologist in private practice in San Antonio, said in an interview that initial enthusiasm was “huge” for use of TCIs like tacrolimus in patients with AD when they first became available, especially in the pediatric population, for whom clinicians are hesitant to use long-term strong topical steroids. However, parents of children taking the medication soon became concerned about potential side effects.

“The TCIs can be absorbed to a small extent through body surface area, so it was not a big leap to become concerned that infants and small children could absorb enough ... into the bloodstream to give a similar side effect profile as oral tacrolimus,” she said.

The addition of the boxed warning in 2006 was frustrating for dermatologists “because a medication we needed very much for a young population now was ‘labeled’ and parents were scared to use it,” Dr. Hughes explained.

Dr. Silverberg noted that, while the results of the new study are unlikely to change clinical practice, they are reassuring, and provide real-world data and “further confirmation of previous studies showing no associations between AD and malignancy.”

“Since AD and skin cancer are both commonly managed by dermatologists, there is potential for increased surveillance and detection of skin cancers in AD patients. So, the greatest chance of seeing a false-positive signal for malignancy would likely occur with skin cancers,” he pointed out. “Yet, even in the case of skin cancers, there were no demonstrable signals.”

Based on the results, “I think it is definitely reasonable to reconsider” the TCI boxed warning, but there isn’t much precedent for boxed warnings to be removed from labeling, Dr. Silverberg commented. “Unfortunately, the black-box warning may persist despite a lot of reassuring data.”

In a related editorial, Aaron M. Drucker, MD, ScM, and Mina Tadrous, PharmD, PhD, of the University of Toronto, said the boxed warning “had the intent of helping patients and clinicians understand possible risks,” but also carried the “potential for harm” if patients discontinued or did not adhere to treatment. “Safety warnings on topical medications could lead to undertreatment of atopic dermatitis, reduced quality of life and, potentially, increased use of more toxic systemic medications.”

Long-term studies of medications and cancer risk are challenging to perform, having to account for dose-response relationships, confounding by indication, and time bias, among other factors, and this study “recognizes and attempts to address many of these challenges,” Dr. Drucker and Dr. Tadrous wrote.

These results are similar to previous studies that have “consistently reported no or minimal association between TCI use and skin cancer,” they noted, adding that, “if an association exists, it is likely very small, meaning that skin cancer attributable to TCI use is rare. Clinicians can use this evidence to counsel and reassure patients for whom the benefits of ongoing treatment with TCIs may outweigh the harms.”

This study was funded by a grant from Valeant Pharmaceuticals. Dr. Asgari reported receiving grants from Valeant during the study, and from Pfizer not related to the study. The other authors reported no relevant conflicts of interest. Dr. Drucker reported relationships with the Canadian Agency for Drugs and Technology in Health, CME Outfitters, Eczema Society of Canada, Sanofi, Regeneron, and RTI Health Solutions in the form of paid fees, consultancies, honoraria, educational grants, and other compensation paid to him and/or his institution. Dr. Tadrous reported no relevant disclosures. Dr. Silverberg reported receiving honoraria for advisory board, speaker, and consultant services from numerous pharmaceutical manufacturers, and research grants for investigator services from GlaxoSmithKline and Galderma. Dr. Hughes Tichy reported no relevant financial disclosures. Dr. Silverberg is a member of the Dermatology News editorial advisory board.

SOURCE: Asgari MM et al. JAMA Dermatol. 2020 Aug 12. doi: 10.1001/jamadermatol.2020.2240.

A large postmarketing surveillance study of topical calcineurin inhibitor exposure in adults with atopic dermatitis has found no increased risk of developing keratinocyte carcinomas overall or with basal cell or squamous cell carcinomas associated with treatment.

The results also suggest dose, frequency, and exposure duration to the topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus are not associated with an increased risk of keratinocyte carcinomas (KCs), basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs) in patients with atopic dermatitis (AD), according to Maryam M. Asgari, MD, MPH, professor of dermatology, Harvard Medical School, Boston, and colleagues. In 2006, the Food and Drug Administration announced the addition of the boxed warning to the labeling of TCIs regarding a possible risk of cancer associated with use of pimecrolimus (Elidel) and with tacrolimus (Protopic), because of an increased risk of KCs associated with oral calcineurin inhibitors and reports of skin cancer in patients on TCIs.

“Controversy has surrounded the association between TCI exposure and KC risk since the black-box warning was issued by the FDA. A hypothesized mechanism of action for TCIs increasing KC risk includes a direct effect of calcineurin inhibition on DNA repair and apoptosis, which could influence keratinocyte carcinogenesis,” the authors of the study wrote in JAMA Dermatology. But, they added, there have been “conflicting results” in research exploring this association.

In the retrospective cohort study, Dr. Asgari and coauthors evaluated 93,746 adult patients with AD at Kaiser Permanente Northern California, diagnosed between January 2002 and December 2013, comparing skin cancer risk among 7,033 patients exposed to TCIs, 73,674 patients taking topical corticosteroids, and 46,141 patients who had not been exposed to TCIs or topical corticosteroids. Results were adjusted in a multivariate Cox regression analysis for age, gender, race/ethnicity, calendar year, number of dermatology visits per year, history of KCs, immunosuppression, prior systemic AD treatment, autoimmune disease, treatment with ultraviolet therapy, chemotherapy, and radiotherapy.

The researchers also examined how TCI dose, frequency and exposure duration impacted skin cancer risk. Patients were grouped by high-dose (0.1%) and low-dose (0.03%) formulations of tacrolimus; and the 1% formulation of pimecrolimus. Frequency of use was defined as low (once daily or less) or high (twice daily or more), and exposure duration was based on short- (less than 2 years), moderate- (2-4 years), and long-term (4 years or more) use. Patients were at least 40 years old (mean age, 58.5 years), 58.7% were women, 50.5% were White, 20.6% were Asian, 12.2% were Hispanic, and 7.9% were Black. They were followed for a mean of 7.70 years.

Compared with patients who were exposed to topical corticosteroids, there was no association between risk of KCs and exposure to TCIs in patients with AD (adjusted hazard ratio, 1.02; 95% confidence interval, 0.93-1.13). There were also no significant differences in risk of BCCs and TCI exposure (aHR, 1.01; 95% CI, 0.90-1.14) and risk of SCCs and TCI exposure (aHR, 0.94; 95% CI, 0.82-1.08), compared with patients exposed to topical corticosteroids.

Results were similar for risk of KCs (aHR, 1.03; 95% CI, 0.92-1.14), BCCs (aHR, 1.04; 95% CI, 0.91-1.19), and SCCs (aHR, 0.91; 95% CI, 0.78-1.06) when patients exposed to TCIs were compared with those with AD who were unexposed to any medication. In secondary analyses, Dr. Asgari and coauthors found no association with overall risk of KCs, or risk of BCCs or SCCs, and the dose, frequency, or exposure duration to TCIs.

“Our findings appear to support those of smaller postmarketing surveillance studies of TCI and KC risk and may provide some reassurance about the safety profile of this class of topical agents in the treatment of AD,” they concluded.

In an interview, Jonathan Silverberg, MD, PhD, MPH, associate professor of dermatology, George Washington University, Washington, said initial concerns surrounding TCIs were based on high doses potentially increasing the risk of malignancy, and off-label use of TCIs for inflammatory skin diseases other than AD.

“However, the FDA’s concerns may not have been justified,” he said. The manufacturers of pimecrolimus and tacrolimus have published results of 10-year observational registries that assess cancer risk, which “found no evidence of any associations between TCIs and malignancy,” noted Dr. Silverberg, who is also director of clinical research and contact dermatitis at George Washington University.

Elizabeth Hughes, MD, a dermatologist in private practice in San Antonio, said in an interview that initial enthusiasm was “huge” for use of TCIs like tacrolimus in patients with AD when they first became available, especially in the pediatric population, for whom clinicians are hesitant to use long-term strong topical steroids. However, parents of children taking the medication soon became concerned about potential side effects.

“The TCIs can be absorbed to a small extent through body surface area, so it was not a big leap to become concerned that infants and small children could absorb enough ... into the bloodstream to give a similar side effect profile as oral tacrolimus,” she said.

The addition of the boxed warning in 2006 was frustrating for dermatologists “because a medication we needed very much for a young population now was ‘labeled’ and parents were scared to use it,” Dr. Hughes explained.

Dr. Silverberg noted that, while the results of the new study are unlikely to change clinical practice, they are reassuring, and provide real-world data and “further confirmation of previous studies showing no associations between AD and malignancy.”

“Since AD and skin cancer are both commonly managed by dermatologists, there is potential for increased surveillance and detection of skin cancers in AD patients. So, the greatest chance of seeing a false-positive signal for malignancy would likely occur with skin cancers,” he pointed out. “Yet, even in the case of skin cancers, there were no demonstrable signals.”

Based on the results, “I think it is definitely reasonable to reconsider” the TCI boxed warning, but there isn’t much precedent for boxed warnings to be removed from labeling, Dr. Silverberg commented. “Unfortunately, the black-box warning may persist despite a lot of reassuring data.”

In a related editorial, Aaron M. Drucker, MD, ScM, and Mina Tadrous, PharmD, PhD, of the University of Toronto, said the boxed warning “had the intent of helping patients and clinicians understand possible risks,” but also carried the “potential for harm” if patients discontinued or did not adhere to treatment. “Safety warnings on topical medications could lead to undertreatment of atopic dermatitis, reduced quality of life and, potentially, increased use of more toxic systemic medications.”

Long-term studies of medications and cancer risk are challenging to perform, having to account for dose-response relationships, confounding by indication, and time bias, among other factors, and this study “recognizes and attempts to address many of these challenges,” Dr. Drucker and Dr. Tadrous wrote.

These results are similar to previous studies that have “consistently reported no or minimal association between TCI use and skin cancer,” they noted, adding that, “if an association exists, it is likely very small, meaning that skin cancer attributable to TCI use is rare. Clinicians can use this evidence to counsel and reassure patients for whom the benefits of ongoing treatment with TCIs may outweigh the harms.”

This study was funded by a grant from Valeant Pharmaceuticals. Dr. Asgari reported receiving grants from Valeant during the study, and from Pfizer not related to the study. The other authors reported no relevant conflicts of interest. Dr. Drucker reported relationships with the Canadian Agency for Drugs and Technology in Health, CME Outfitters, Eczema Society of Canada, Sanofi, Regeneron, and RTI Health Solutions in the form of paid fees, consultancies, honoraria, educational grants, and other compensation paid to him and/or his institution. Dr. Tadrous reported no relevant disclosures. Dr. Silverberg reported receiving honoraria for advisory board, speaker, and consultant services from numerous pharmaceutical manufacturers, and research grants for investigator services from GlaxoSmithKline and Galderma. Dr. Hughes Tichy reported no relevant financial disclosures. Dr. Silverberg is a member of the Dermatology News editorial advisory board.

SOURCE: Asgari MM et al. JAMA Dermatol. 2020 Aug 12. doi: 10.1001/jamadermatol.2020.2240.

A large postmarketing surveillance study of topical calcineurin inhibitor exposure in adults with atopic dermatitis has found no increased risk of developing keratinocyte carcinomas overall or with basal cell or squamous cell carcinomas associated with treatment.

The results also suggest dose, frequency, and exposure duration to the topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus are not associated with an increased risk of keratinocyte carcinomas (KCs), basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs) in patients with atopic dermatitis (AD), according to Maryam M. Asgari, MD, MPH, professor of dermatology, Harvard Medical School, Boston, and colleagues. In 2006, the Food and Drug Administration announced the addition of the boxed warning to the labeling of TCIs regarding a possible risk of cancer associated with use of pimecrolimus (Elidel) and with tacrolimus (Protopic), because of an increased risk of KCs associated with oral calcineurin inhibitors and reports of skin cancer in patients on TCIs.

“Controversy has surrounded the association between TCI exposure and KC risk since the black-box warning was issued by the FDA. A hypothesized mechanism of action for TCIs increasing KC risk includes a direct effect of calcineurin inhibition on DNA repair and apoptosis, which could influence keratinocyte carcinogenesis,” the authors of the study wrote in JAMA Dermatology. But, they added, there have been “conflicting results” in research exploring this association.

In the retrospective cohort study, Dr. Asgari and coauthors evaluated 93,746 adult patients with AD at Kaiser Permanente Northern California, diagnosed between January 2002 and December 2013, comparing skin cancer risk among 7,033 patients exposed to TCIs, 73,674 patients taking topical corticosteroids, and 46,141 patients who had not been exposed to TCIs or topical corticosteroids. Results were adjusted in a multivariate Cox regression analysis for age, gender, race/ethnicity, calendar year, number of dermatology visits per year, history of KCs, immunosuppression, prior systemic AD treatment, autoimmune disease, treatment with ultraviolet therapy, chemotherapy, and radiotherapy.

The researchers also examined how TCI dose, frequency and exposure duration impacted skin cancer risk. Patients were grouped by high-dose (0.1%) and low-dose (0.03%) formulations of tacrolimus; and the 1% formulation of pimecrolimus. Frequency of use was defined as low (once daily or less) or high (twice daily or more), and exposure duration was based on short- (less than 2 years), moderate- (2-4 years), and long-term (4 years or more) use. Patients were at least 40 years old (mean age, 58.5 years), 58.7% were women, 50.5% were White, 20.6% were Asian, 12.2% were Hispanic, and 7.9% were Black. They were followed for a mean of 7.70 years.

Compared with patients who were exposed to topical corticosteroids, there was no association between risk of KCs and exposure to TCIs in patients with AD (adjusted hazard ratio, 1.02; 95% confidence interval, 0.93-1.13). There were also no significant differences in risk of BCCs and TCI exposure (aHR, 1.01; 95% CI, 0.90-1.14) and risk of SCCs and TCI exposure (aHR, 0.94; 95% CI, 0.82-1.08), compared with patients exposed to topical corticosteroids.

Results were similar for risk of KCs (aHR, 1.03; 95% CI, 0.92-1.14), BCCs (aHR, 1.04; 95% CI, 0.91-1.19), and SCCs (aHR, 0.91; 95% CI, 0.78-1.06) when patients exposed to TCIs were compared with those with AD who were unexposed to any medication. In secondary analyses, Dr. Asgari and coauthors found no association with overall risk of KCs, or risk of BCCs or SCCs, and the dose, frequency, or exposure duration to TCIs.

“Our findings appear to support those of smaller postmarketing surveillance studies of TCI and KC risk and may provide some reassurance about the safety profile of this class of topical agents in the treatment of AD,” they concluded.

In an interview, Jonathan Silverberg, MD, PhD, MPH, associate professor of dermatology, George Washington University, Washington, said initial concerns surrounding TCIs were based on high doses potentially increasing the risk of malignancy, and off-label use of TCIs for inflammatory skin diseases other than AD.

“However, the FDA’s concerns may not have been justified,” he said. The manufacturers of pimecrolimus and tacrolimus have published results of 10-year observational registries that assess cancer risk, which “found no evidence of any associations between TCIs and malignancy,” noted Dr. Silverberg, who is also director of clinical research and contact dermatitis at George Washington University.

Elizabeth Hughes, MD, a dermatologist in private practice in San Antonio, said in an interview that initial enthusiasm was “huge” for use of TCIs like tacrolimus in patients with AD when they first became available, especially in the pediatric population, for whom clinicians are hesitant to use long-term strong topical steroids. However, parents of children taking the medication soon became concerned about potential side effects.

“The TCIs can be absorbed to a small extent through body surface area, so it was not a big leap to become concerned that infants and small children could absorb enough ... into the bloodstream to give a similar side effect profile as oral tacrolimus,” she said.

The addition of the boxed warning in 2006 was frustrating for dermatologists “because a medication we needed very much for a young population now was ‘labeled’ and parents were scared to use it,” Dr. Hughes explained.

Dr. Silverberg noted that, while the results of the new study are unlikely to change clinical practice, they are reassuring, and provide real-world data and “further confirmation of previous studies showing no associations between AD and malignancy.”

“Since AD and skin cancer are both commonly managed by dermatologists, there is potential for increased surveillance and detection of skin cancers in AD patients. So, the greatest chance of seeing a false-positive signal for malignancy would likely occur with skin cancers,” he pointed out. “Yet, even in the case of skin cancers, there were no demonstrable signals.”

Based on the results, “I think it is definitely reasonable to reconsider” the TCI boxed warning, but there isn’t much precedent for boxed warnings to be removed from labeling, Dr. Silverberg commented. “Unfortunately, the black-box warning may persist despite a lot of reassuring data.”

In a related editorial, Aaron M. Drucker, MD, ScM, and Mina Tadrous, PharmD, PhD, of the University of Toronto, said the boxed warning “had the intent of helping patients and clinicians understand possible risks,” but also carried the “potential for harm” if patients discontinued or did not adhere to treatment. “Safety warnings on topical medications could lead to undertreatment of atopic dermatitis, reduced quality of life and, potentially, increased use of more toxic systemic medications.”

Long-term studies of medications and cancer risk are challenging to perform, having to account for dose-response relationships, confounding by indication, and time bias, among other factors, and this study “recognizes and attempts to address many of these challenges,” Dr. Drucker and Dr. Tadrous wrote.

These results are similar to previous studies that have “consistently reported no or minimal association between TCI use and skin cancer,” they noted, adding that, “if an association exists, it is likely very small, meaning that skin cancer attributable to TCI use is rare. Clinicians can use this evidence to counsel and reassure patients for whom the benefits of ongoing treatment with TCIs may outweigh the harms.”

This study was funded by a grant from Valeant Pharmaceuticals. Dr. Asgari reported receiving grants from Valeant during the study, and from Pfizer not related to the study. The other authors reported no relevant conflicts of interest. Dr. Drucker reported relationships with the Canadian Agency for Drugs and Technology in Health, CME Outfitters, Eczema Society of Canada, Sanofi, Regeneron, and RTI Health Solutions in the form of paid fees, consultancies, honoraria, educational grants, and other compensation paid to him and/or his institution. Dr. Tadrous reported no relevant disclosures. Dr. Silverberg reported receiving honoraria for advisory board, speaker, and consultant services from numerous pharmaceutical manufacturers, and research grants for investigator services from GlaxoSmithKline and Galderma. Dr. Hughes Tichy reported no relevant financial disclosures. Dr. Silverberg is a member of the Dermatology News editorial advisory board.

SOURCE: Asgari MM et al. JAMA Dermatol. 2020 Aug 12. doi: 10.1001/jamadermatol.2020.2240.