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Prevalence of dementia before age 65 much higher than expected
Results of a large meta-analysis show that currently 3.9 million individuals are living with young-onset dementia. Among these patients, symptoms of the disease start before age 65.
Recent global young-onset dementia estimates have ranged from 42.3 to 54.0 per 100,000 population, the researchers noted. However, the new study, which included 74 global studies with 2.7 million participants, shows that the global age-standardized prevalence of young-onset dementia is 119.00 per 100,000 among individuals aged 30-64 years; there was little difference in prevalence between men and women. On the basis of the latest population estimates, these new prevalence data imply that there are approximately 175,000 persons with young-onset dementia in the United States.
Although the new global estimate of young-onset dementia is higher than previously thought, “it is still probably an underestimation owing to lack of high-quality data. This should raise awareness for policy makers and health care professionals to organize more and better care for this subgroup of individuals with dementia,” wrote the investigators, with first author Stevie Hendriks, MSc, Maastricht (the Netherlands) University, and the Young-Onset Dementia Epidemiology Study Group.
The study was published online July 19, 2021, in JAMA Neurology.
‘Essential’ data
Young-onset dementia is exceedingly rare in those aged 30-63 years (1.1 per 100,000) but is more prevalent at age 60-64 years (77.4 per 100,000). “Our findings fit the general observation that prevalence of dementia increases exponentially from 60 years of age onward,” they wrote.
The prevalence of young-onset dementia was similar in men and women, lower in the United States than in Europe, highest in upper- to middle-income countries, and highest for Alzheimer’s disease, followed by vascular dementia and frontotemporal dementia.
Monitoring the prevalence of young-onset dementia is “essential” to adequately plan and organize health services, the investigators noted.
To ensure more accurate prevalence estimates in the future, “efforts should be made to conduct more cohort studies and to standardize procedures and reporting of prevalence studies. In addition, more data are needed from low-income countries as well as studies that include younger age ranges,” they said.
New insights
In an accompanying editorial, David S. Knopman, MD, department of neurology, Mayo Clinic, Rochester, Minn., noted that the study provides new insights into an “underappreciated problem.”.
Young-onset dementia is a “particularly disheartening diagnosis because it affects individuals in their prime years, in the midst of their careers, and while raising families,” Dr. Knopman wrote.
“Most dementia care is geared for older patients, and as a consequence, services are rarely available to address the needs of someone diagnosed with dementia in their 50s who has dependent children at home and a spouse who must continue working. Understanding the prevalence and incidence of young-onset dementia is a first step in addressing this challenge,” Dr. Knopman wrote.
He noted that the authors of this analysis have “done a service to the dementia community by collecting and analyzing the dozens of individual studies of young-onset dementia.
“The product, a rationally derived estimate of dementia prevalence across the population aged 30-64 years, provides a basis for initiating more efforts to improve methods for timely diagnosis and to address the unique needs of patients with young-onset dementia,” Dr. Knopman concluded.
A version of this article first appeared on Medscape.com.
Results of a large meta-analysis show that currently 3.9 million individuals are living with young-onset dementia. Among these patients, symptoms of the disease start before age 65.
Recent global young-onset dementia estimates have ranged from 42.3 to 54.0 per 100,000 population, the researchers noted. However, the new study, which included 74 global studies with 2.7 million participants, shows that the global age-standardized prevalence of young-onset dementia is 119.00 per 100,000 among individuals aged 30-64 years; there was little difference in prevalence between men and women. On the basis of the latest population estimates, these new prevalence data imply that there are approximately 175,000 persons with young-onset dementia in the United States.
Although the new global estimate of young-onset dementia is higher than previously thought, “it is still probably an underestimation owing to lack of high-quality data. This should raise awareness for policy makers and health care professionals to organize more and better care for this subgroup of individuals with dementia,” wrote the investigators, with first author Stevie Hendriks, MSc, Maastricht (the Netherlands) University, and the Young-Onset Dementia Epidemiology Study Group.
The study was published online July 19, 2021, in JAMA Neurology.
‘Essential’ data
Young-onset dementia is exceedingly rare in those aged 30-63 years (1.1 per 100,000) but is more prevalent at age 60-64 years (77.4 per 100,000). “Our findings fit the general observation that prevalence of dementia increases exponentially from 60 years of age onward,” they wrote.
The prevalence of young-onset dementia was similar in men and women, lower in the United States than in Europe, highest in upper- to middle-income countries, and highest for Alzheimer’s disease, followed by vascular dementia and frontotemporal dementia.
Monitoring the prevalence of young-onset dementia is “essential” to adequately plan and organize health services, the investigators noted.
To ensure more accurate prevalence estimates in the future, “efforts should be made to conduct more cohort studies and to standardize procedures and reporting of prevalence studies. In addition, more data are needed from low-income countries as well as studies that include younger age ranges,” they said.
New insights
In an accompanying editorial, David S. Knopman, MD, department of neurology, Mayo Clinic, Rochester, Minn., noted that the study provides new insights into an “underappreciated problem.”.
Young-onset dementia is a “particularly disheartening diagnosis because it affects individuals in their prime years, in the midst of their careers, and while raising families,” Dr. Knopman wrote.
“Most dementia care is geared for older patients, and as a consequence, services are rarely available to address the needs of someone diagnosed with dementia in their 50s who has dependent children at home and a spouse who must continue working. Understanding the prevalence and incidence of young-onset dementia is a first step in addressing this challenge,” Dr. Knopman wrote.
He noted that the authors of this analysis have “done a service to the dementia community by collecting and analyzing the dozens of individual studies of young-onset dementia.
“The product, a rationally derived estimate of dementia prevalence across the population aged 30-64 years, provides a basis for initiating more efforts to improve methods for timely diagnosis and to address the unique needs of patients with young-onset dementia,” Dr. Knopman concluded.
A version of this article first appeared on Medscape.com.
Results of a large meta-analysis show that currently 3.9 million individuals are living with young-onset dementia. Among these patients, symptoms of the disease start before age 65.
Recent global young-onset dementia estimates have ranged from 42.3 to 54.0 per 100,000 population, the researchers noted. However, the new study, which included 74 global studies with 2.7 million participants, shows that the global age-standardized prevalence of young-onset dementia is 119.00 per 100,000 among individuals aged 30-64 years; there was little difference in prevalence between men and women. On the basis of the latest population estimates, these new prevalence data imply that there are approximately 175,000 persons with young-onset dementia in the United States.
Although the new global estimate of young-onset dementia is higher than previously thought, “it is still probably an underestimation owing to lack of high-quality data. This should raise awareness for policy makers and health care professionals to organize more and better care for this subgroup of individuals with dementia,” wrote the investigators, with first author Stevie Hendriks, MSc, Maastricht (the Netherlands) University, and the Young-Onset Dementia Epidemiology Study Group.
The study was published online July 19, 2021, in JAMA Neurology.
‘Essential’ data
Young-onset dementia is exceedingly rare in those aged 30-63 years (1.1 per 100,000) but is more prevalent at age 60-64 years (77.4 per 100,000). “Our findings fit the general observation that prevalence of dementia increases exponentially from 60 years of age onward,” they wrote.
The prevalence of young-onset dementia was similar in men and women, lower in the United States than in Europe, highest in upper- to middle-income countries, and highest for Alzheimer’s disease, followed by vascular dementia and frontotemporal dementia.
Monitoring the prevalence of young-onset dementia is “essential” to adequately plan and organize health services, the investigators noted.
To ensure more accurate prevalence estimates in the future, “efforts should be made to conduct more cohort studies and to standardize procedures and reporting of prevalence studies. In addition, more data are needed from low-income countries as well as studies that include younger age ranges,” they said.
New insights
In an accompanying editorial, David S. Knopman, MD, department of neurology, Mayo Clinic, Rochester, Minn., noted that the study provides new insights into an “underappreciated problem.”.
Young-onset dementia is a “particularly disheartening diagnosis because it affects individuals in their prime years, in the midst of their careers, and while raising families,” Dr. Knopman wrote.
“Most dementia care is geared for older patients, and as a consequence, services are rarely available to address the needs of someone diagnosed with dementia in their 50s who has dependent children at home and a spouse who must continue working. Understanding the prevalence and incidence of young-onset dementia is a first step in addressing this challenge,” Dr. Knopman wrote.
He noted that the authors of this analysis have “done a service to the dementia community by collecting and analyzing the dozens of individual studies of young-onset dementia.
“The product, a rationally derived estimate of dementia prevalence across the population aged 30-64 years, provides a basis for initiating more efforts to improve methods for timely diagnosis and to address the unique needs of patients with young-onset dementia,” Dr. Knopman concluded.
A version of this article first appeared on Medscape.com.
FROM JAMA NEUROLOGY
‘Shocking’ early complications from teen-onset type 2 diabetes
Newly published data show alarmingly high rates and severity of early diabetes-specific complications in individuals who develop type 2 diabetes at a young age. This suggests intervention should be early and aggressive among these youngsters, said the researchers.
The results for the 500 young adult participants in the Treatment Options for Type 2 Diabetes in Adolescents and Youth 2 (TODAY 2) study were published online July 29 in the New England Journal of Medicine by the TODAY study group.
At follow-up – after originally participating in the TODAY trial when they were young teenagers – they had a mean age of 26.4 years.
At this time, more than two thirds had hypertension and half had dyslipidemia.
Overall, 60% had at least one diabetic microvascular complication (retinal disease, neuropathy, or diabetic kidney disease), and more than a quarter had two or more such complications.
“These data illustrate the serious personal and public health consequences of youth-onset type 2 diabetes in the transition to adulthood,” the researchers noted.
Don’t tread lightly just because they are young
“The fact that these youth are accumulating complications at a rapid rate and are broadly affected early in adulthood certainly suggests that aggressive therapy is needed, both for glycemic control and treatment of risk factors like hypertension and dyslipidemia,” study coauthor Philip S. Zeitler, MD, PhD, said in an interview.
“In the absence of studies specifically addressing this, we need to take a more aggressive approach than people might be inclined to, given that the age at diagnosis is young, around 14 years,” he added.
“Contrary to the inclination to be ‘gentle’ in treating them because they are kids, these data suggest that we can’t let these initial years go by without strong intervention, and we need to be prepared for polypharmacy.”
Unfortunately, as Dr. Zeitler and coauthors explained, youth-onset type 2 diabetes is characterized by a suboptimal response to currently approved diabetes medications.
New pediatric indications in the United States for drugs used to treat type 2 diabetes in adults, including the recent Food and Drug Administration approval of extended-release exenatide for children as young as 10 years of age, “helps, but only marginally,” said Dr. Zeitler, of the Clinical & Translational Research Center, Children’s Hospital Colorado, Aurora.
“In some cases, it will help get them covered by carriers, which is always good. But this is still a very limited set of medications. It doesn’t include more recently approved more potent glucagon-like peptide-1 (GLP-1) agonists, like semaglutide, and doesn’t include the sodium-glucose cotransporter 2 (SGLT2) inhibitors. Pediatricians are used to using medications off label and that is necessary here while we await further approvals,” he said.
And he noted that most individuals with youth-onset type 2 diabetes in the United States are covered by public insurance or are uninsured, depending on which state they live in. While the two major Medicaid programs in Colorado allow full access to adult formularies, that’s not the case everywhere. Moreover, patients often face further access barriers in states without expanded Medicaid.
Follow-up shows all metrics worsening over time
In TODAY 2, patients participated in an observational follow-up in their usual care settings in 2011-2020. At the start, they were receiving metformin with or without insulin for diabetes, but whether this continued and whether they were treated for other risk factors was down to individual circumstances.
Participants’ median A1c increased over time, and the percentage with A1c < 6% (< 48 mmol/mol) declined from 75% at the time of TODAY entry to just 19% at the 15-year end of follow-up.
The proportion with an A1c ≤ 10% (≤ 86 mmol/mol) rose from 0% at baseline to 34% at 15 years.
At that time, nearly 50% were taking both metformin and insulin, while more than a quarter were taking no medications.
The prevalence of hypertension increased from 19.2% at baseline to 67.5% at 15 years, while dyslipidemia rose from 20.8% to 51.6%.
Kidney disease prevalence increased from 8.0% at baseline to 54.8% at 15 years. Nerve disease rose from 1.0% to 32.4%. Retinal disease jumped from 13.7% with milder nonproliferative retinopathy in 2010-2011 to 51.0% with any eye disease in 2017-2018, including 8.8% with moderate to severe retinal changes and 3.5% with macular edema.
Overall, at the time of the last visit, 39.9% had no diabetes complications, 31.8% had one, 21.3% had two, and 7.1% had three complications.
Serious cardiovascular events in mid-20s
There were 17 adjudicated serious cardiovascular events, including four myocardial infarctions, six heart failure events, three diagnoses of coronary artery disease, and four strokes.
Six participants died, one each from myocardial infarction, kidney failure, and drug overdose, and three from sepsis.
Dr. Zeitler called the macrovascular events “shocking,” noting that although the numbers are small, for people in their mid-20s “they should be zero ... While we don’t yet know if the rates are the same or faster than in adults, even if they are the same, these kids are only in their late 20s, as opposed to adults experiencing these problems in their 50s, 60s, and 70s.
“The fact that these complications are occurring when these individuals should be in the prime of their life for both family and work has huge implications,” he stressed.
Findings have multiple causes
The reasons for the findings are both biologic and socioeconomic, Dr. Zeitler said.
“We know already that many kids with type 2 have rapid [deterioration of] beta-cell [function], which is probably very biologic. It stands to reason that an individual who can get diabetes as an adolescent probably has more fragile beta cells in some way,” he noted.
“But we also know that many other things contribute: stress, social determinants, access to quality care and medications, access to healthy foods and physical activity, availability of family supervision given the realities of families’ economic status and jobs, etc.”
It’s also known that youth with type 2 diabetes have much more severe insulin resistance than that of adults with the condition, and that “once the kids left ... the [TODAY] study, risk factor treatment in the community was less than ideal, and a lot of kids who met criteria for treatment of their blood pressure or lipids were not being treated. This is likely at least partly sociologic and partly the general pediatric hesitancy to use medications.”
He said the TODAY team will soon have some new data to show that “glycemia during the early years makes a difference, again supporting intensive intervention early on.”
The TODAY study was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Zeitler had no further disclosures.
A version of this article first appeared on Medscape.com.
Newly published data show alarmingly high rates and severity of early diabetes-specific complications in individuals who develop type 2 diabetes at a young age. This suggests intervention should be early and aggressive among these youngsters, said the researchers.
The results for the 500 young adult participants in the Treatment Options for Type 2 Diabetes in Adolescents and Youth 2 (TODAY 2) study were published online July 29 in the New England Journal of Medicine by the TODAY study group.
At follow-up – after originally participating in the TODAY trial when they were young teenagers – they had a mean age of 26.4 years.
At this time, more than two thirds had hypertension and half had dyslipidemia.
Overall, 60% had at least one diabetic microvascular complication (retinal disease, neuropathy, or diabetic kidney disease), and more than a quarter had two or more such complications.
“These data illustrate the serious personal and public health consequences of youth-onset type 2 diabetes in the transition to adulthood,” the researchers noted.
Don’t tread lightly just because they are young
“The fact that these youth are accumulating complications at a rapid rate and are broadly affected early in adulthood certainly suggests that aggressive therapy is needed, both for glycemic control and treatment of risk factors like hypertension and dyslipidemia,” study coauthor Philip S. Zeitler, MD, PhD, said in an interview.
“In the absence of studies specifically addressing this, we need to take a more aggressive approach than people might be inclined to, given that the age at diagnosis is young, around 14 years,” he added.
“Contrary to the inclination to be ‘gentle’ in treating them because they are kids, these data suggest that we can’t let these initial years go by without strong intervention, and we need to be prepared for polypharmacy.”
Unfortunately, as Dr. Zeitler and coauthors explained, youth-onset type 2 diabetes is characterized by a suboptimal response to currently approved diabetes medications.
New pediatric indications in the United States for drugs used to treat type 2 diabetes in adults, including the recent Food and Drug Administration approval of extended-release exenatide for children as young as 10 years of age, “helps, but only marginally,” said Dr. Zeitler, of the Clinical & Translational Research Center, Children’s Hospital Colorado, Aurora.
“In some cases, it will help get them covered by carriers, which is always good. But this is still a very limited set of medications. It doesn’t include more recently approved more potent glucagon-like peptide-1 (GLP-1) agonists, like semaglutide, and doesn’t include the sodium-glucose cotransporter 2 (SGLT2) inhibitors. Pediatricians are used to using medications off label and that is necessary here while we await further approvals,” he said.
And he noted that most individuals with youth-onset type 2 diabetes in the United States are covered by public insurance or are uninsured, depending on which state they live in. While the two major Medicaid programs in Colorado allow full access to adult formularies, that’s not the case everywhere. Moreover, patients often face further access barriers in states without expanded Medicaid.
Follow-up shows all metrics worsening over time
In TODAY 2, patients participated in an observational follow-up in their usual care settings in 2011-2020. At the start, they were receiving metformin with or without insulin for diabetes, but whether this continued and whether they were treated for other risk factors was down to individual circumstances.
Participants’ median A1c increased over time, and the percentage with A1c < 6% (< 48 mmol/mol) declined from 75% at the time of TODAY entry to just 19% at the 15-year end of follow-up.
The proportion with an A1c ≤ 10% (≤ 86 mmol/mol) rose from 0% at baseline to 34% at 15 years.
At that time, nearly 50% were taking both metformin and insulin, while more than a quarter were taking no medications.
The prevalence of hypertension increased from 19.2% at baseline to 67.5% at 15 years, while dyslipidemia rose from 20.8% to 51.6%.
Kidney disease prevalence increased from 8.0% at baseline to 54.8% at 15 years. Nerve disease rose from 1.0% to 32.4%. Retinal disease jumped from 13.7% with milder nonproliferative retinopathy in 2010-2011 to 51.0% with any eye disease in 2017-2018, including 8.8% with moderate to severe retinal changes and 3.5% with macular edema.
Overall, at the time of the last visit, 39.9% had no diabetes complications, 31.8% had one, 21.3% had two, and 7.1% had three complications.
Serious cardiovascular events in mid-20s
There were 17 adjudicated serious cardiovascular events, including four myocardial infarctions, six heart failure events, three diagnoses of coronary artery disease, and four strokes.
Six participants died, one each from myocardial infarction, kidney failure, and drug overdose, and three from sepsis.
Dr. Zeitler called the macrovascular events “shocking,” noting that although the numbers are small, for people in their mid-20s “they should be zero ... While we don’t yet know if the rates are the same or faster than in adults, even if they are the same, these kids are only in their late 20s, as opposed to adults experiencing these problems in their 50s, 60s, and 70s.
“The fact that these complications are occurring when these individuals should be in the prime of their life for both family and work has huge implications,” he stressed.
Findings have multiple causes
The reasons for the findings are both biologic and socioeconomic, Dr. Zeitler said.
“We know already that many kids with type 2 have rapid [deterioration of] beta-cell [function], which is probably very biologic. It stands to reason that an individual who can get diabetes as an adolescent probably has more fragile beta cells in some way,” he noted.
“But we also know that many other things contribute: stress, social determinants, access to quality care and medications, access to healthy foods and physical activity, availability of family supervision given the realities of families’ economic status and jobs, etc.”
It’s also known that youth with type 2 diabetes have much more severe insulin resistance than that of adults with the condition, and that “once the kids left ... the [TODAY] study, risk factor treatment in the community was less than ideal, and a lot of kids who met criteria for treatment of their blood pressure or lipids were not being treated. This is likely at least partly sociologic and partly the general pediatric hesitancy to use medications.”
He said the TODAY team will soon have some new data to show that “glycemia during the early years makes a difference, again supporting intensive intervention early on.”
The TODAY study was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Zeitler had no further disclosures.
A version of this article first appeared on Medscape.com.
Newly published data show alarmingly high rates and severity of early diabetes-specific complications in individuals who develop type 2 diabetes at a young age. This suggests intervention should be early and aggressive among these youngsters, said the researchers.
The results for the 500 young adult participants in the Treatment Options for Type 2 Diabetes in Adolescents and Youth 2 (TODAY 2) study were published online July 29 in the New England Journal of Medicine by the TODAY study group.
At follow-up – after originally participating in the TODAY trial when they were young teenagers – they had a mean age of 26.4 years.
At this time, more than two thirds had hypertension and half had dyslipidemia.
Overall, 60% had at least one diabetic microvascular complication (retinal disease, neuropathy, or diabetic kidney disease), and more than a quarter had two or more such complications.
“These data illustrate the serious personal and public health consequences of youth-onset type 2 diabetes in the transition to adulthood,” the researchers noted.
Don’t tread lightly just because they are young
“The fact that these youth are accumulating complications at a rapid rate and are broadly affected early in adulthood certainly suggests that aggressive therapy is needed, both for glycemic control and treatment of risk factors like hypertension and dyslipidemia,” study coauthor Philip S. Zeitler, MD, PhD, said in an interview.
“In the absence of studies specifically addressing this, we need to take a more aggressive approach than people might be inclined to, given that the age at diagnosis is young, around 14 years,” he added.
“Contrary to the inclination to be ‘gentle’ in treating them because they are kids, these data suggest that we can’t let these initial years go by without strong intervention, and we need to be prepared for polypharmacy.”
Unfortunately, as Dr. Zeitler and coauthors explained, youth-onset type 2 diabetes is characterized by a suboptimal response to currently approved diabetes medications.
New pediatric indications in the United States for drugs used to treat type 2 diabetes in adults, including the recent Food and Drug Administration approval of extended-release exenatide for children as young as 10 years of age, “helps, but only marginally,” said Dr. Zeitler, of the Clinical & Translational Research Center, Children’s Hospital Colorado, Aurora.
“In some cases, it will help get them covered by carriers, which is always good. But this is still a very limited set of medications. It doesn’t include more recently approved more potent glucagon-like peptide-1 (GLP-1) agonists, like semaglutide, and doesn’t include the sodium-glucose cotransporter 2 (SGLT2) inhibitors. Pediatricians are used to using medications off label and that is necessary here while we await further approvals,” he said.
And he noted that most individuals with youth-onset type 2 diabetes in the United States are covered by public insurance or are uninsured, depending on which state they live in. While the two major Medicaid programs in Colorado allow full access to adult formularies, that’s not the case everywhere. Moreover, patients often face further access barriers in states without expanded Medicaid.
Follow-up shows all metrics worsening over time
In TODAY 2, patients participated in an observational follow-up in their usual care settings in 2011-2020. At the start, they were receiving metformin with or without insulin for diabetes, but whether this continued and whether they were treated for other risk factors was down to individual circumstances.
Participants’ median A1c increased over time, and the percentage with A1c < 6% (< 48 mmol/mol) declined from 75% at the time of TODAY entry to just 19% at the 15-year end of follow-up.
The proportion with an A1c ≤ 10% (≤ 86 mmol/mol) rose from 0% at baseline to 34% at 15 years.
At that time, nearly 50% were taking both metformin and insulin, while more than a quarter were taking no medications.
The prevalence of hypertension increased from 19.2% at baseline to 67.5% at 15 years, while dyslipidemia rose from 20.8% to 51.6%.
Kidney disease prevalence increased from 8.0% at baseline to 54.8% at 15 years. Nerve disease rose from 1.0% to 32.4%. Retinal disease jumped from 13.7% with milder nonproliferative retinopathy in 2010-2011 to 51.0% with any eye disease in 2017-2018, including 8.8% with moderate to severe retinal changes and 3.5% with macular edema.
Overall, at the time of the last visit, 39.9% had no diabetes complications, 31.8% had one, 21.3% had two, and 7.1% had three complications.
Serious cardiovascular events in mid-20s
There were 17 adjudicated serious cardiovascular events, including four myocardial infarctions, six heart failure events, three diagnoses of coronary artery disease, and four strokes.
Six participants died, one each from myocardial infarction, kidney failure, and drug overdose, and three from sepsis.
Dr. Zeitler called the macrovascular events “shocking,” noting that although the numbers are small, for people in their mid-20s “they should be zero ... While we don’t yet know if the rates are the same or faster than in adults, even if they are the same, these kids are only in their late 20s, as opposed to adults experiencing these problems in their 50s, 60s, and 70s.
“The fact that these complications are occurring when these individuals should be in the prime of their life for both family and work has huge implications,” he stressed.
Findings have multiple causes
The reasons for the findings are both biologic and socioeconomic, Dr. Zeitler said.
“We know already that many kids with type 2 have rapid [deterioration of] beta-cell [function], which is probably very biologic. It stands to reason that an individual who can get diabetes as an adolescent probably has more fragile beta cells in some way,” he noted.
“But we also know that many other things contribute: stress, social determinants, access to quality care and medications, access to healthy foods and physical activity, availability of family supervision given the realities of families’ economic status and jobs, etc.”
It’s also known that youth with type 2 diabetes have much more severe insulin resistance than that of adults with the condition, and that “once the kids left ... the [TODAY] study, risk factor treatment in the community was less than ideal, and a lot of kids who met criteria for treatment of their blood pressure or lipids were not being treated. This is likely at least partly sociologic and partly the general pediatric hesitancy to use medications.”
He said the TODAY team will soon have some new data to show that “glycemia during the early years makes a difference, again supporting intensive intervention early on.”
The TODAY study was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Zeitler had no further disclosures.
A version of this article first appeared on Medscape.com.
COVID-19 leaves wake of medical debt among U.S. adults
Despite the passage of four major relief bills in 2020 and 2021 and federal efforts to offset pandemic- and job-related coverage loss, many people continued to face financial challenges, especially those with a low income and those who are Black or Latino.
The survey, which included responses from 5,450 adults, revealed that 10% of adults aged 19-64 were uninsured during the first half of 2021, a rate lower than what was recorded in 2020 and 2019 in both federal and private surveys. However, uninsured rates were highest among those with low income, those younger than 50 years old, and Black and Latino adults.
For most adults who lost employee health insurance, the coverage gap was relatively brief, with 54% saying their coverage gap lasted 3-4 months. Only 16% of adults said coverage gaps lasted a year or longer.
“The good news is that this survey is suggesting that the coverage losses during the pandemic may have been offset by federal efforts to help people get and maintain health insurance coverage,” lead author Sara Collins, PhD, Commonwealth Fund vice president for health care coverage, access, and tracking, said in an interview.
“The bad news is that a third of Americans continue to struggle with medical bills and medical debt, even among those who have health insurance coverage,” Dr. Collins added.
Indeed, the survey found that about one-third of insured adults reported a medical bill problem or that they were paying off medical debt, as did approximately half of those who were uninsured. Medical debt caused 35% of respondents to use up most or all of their savings to pay it off.
Meanwhile, 27% of adults said medical bills left them unable to pay for necessities such as food, heat, or rent. What surprised Dr. Collins was that 43% of adults said they received a lower credit rating as a result of their medical debt, and 35% said they had taken on more credit card debt to pay off these bills.
“The fact that it’s bleeding over into people’s financial security in terms of their credit scores, I think is something that really needs to be looked at by policymakers,” Dr. Collins said.
When analyzed by race/ethnicity, the researchers found that 55% of Black adults and 44% of Latino/Hispanic adults reported medical bills and debt problems, compared with 32% of White adults. In addition, 47% of those living below the poverty line also reported problems with medical bills.
According to the survey, 45% of respondents were directly affected by the pandemic in at least one of three ways – testing positive or getting sick from COVID-19, losing income, or losing employer coverage – with Black and Latinx adults and those with lower incomes at greater risk.
George Abraham, MD, president of the American College of Physicians, said the Commonwealth Fund’s findings were not surprising because it has always been known that underrepresented populations struggle for access to care because of socioeconomic factors. He said these populations were more vulnerable in terms of more severe infections and disease burden during the pandemic.
“[This study] validates what primary care physicians have been saying all along in regard to our patients’ access to care and their ability to cover health care costs,” said Dr. Abraham, who was not involved with the study. “This will hopefully be an eye-opener and wake-up call that reiterates that we still do not have equitable access to care and vulnerable populations are disproportionately affected.”
He believes that, although people are insured, many of them may contend with medical debt when they fall ill because they can’t afford the premiums.
“Even though they may have been registered for health coverage, they may not have active coverage at the time of illness simply because they weren’t able to make their last premium payments because they’ve been down, because they lost their job, or whatever else,” Dr. Abraham explained. “On paper, they appear to have health care coverage. But in reality, clearly, that coverage does not match their needs or it’s not affordable.”
For Dr. Abraham, the study emphasizes the need to continue support for health care reform, including pricing it so that insurance is available for those with fewer socioeconomic resources.
Yalda Jabbarpour, MD, medical director of the Robert Graham Center for Policy Studies, Washington, said high-deductible health plans need to be “reined in” because they can lead to greater debt, particularly among vulnerable populations.
“Hopefully this will encourage policymakers to look more closely at the problem of medical debt as a contributing factor to financial instability,” Dr. Jabbarpour said. “Federal relief is important, so is expanding access to comprehensive, affordable health care coverage.”
Dr. Collins said there should also be a way to raise awareness of the health care marketplace and coverage options so that people have an easier time getting insured.
A version of this article first appeared on Medscape.com.
Despite the passage of four major relief bills in 2020 and 2021 and federal efforts to offset pandemic- and job-related coverage loss, many people continued to face financial challenges, especially those with a low income and those who are Black or Latino.
The survey, which included responses from 5,450 adults, revealed that 10% of adults aged 19-64 were uninsured during the first half of 2021, a rate lower than what was recorded in 2020 and 2019 in both federal and private surveys. However, uninsured rates were highest among those with low income, those younger than 50 years old, and Black and Latino adults.
For most adults who lost employee health insurance, the coverage gap was relatively brief, with 54% saying their coverage gap lasted 3-4 months. Only 16% of adults said coverage gaps lasted a year or longer.
“The good news is that this survey is suggesting that the coverage losses during the pandemic may have been offset by federal efforts to help people get and maintain health insurance coverage,” lead author Sara Collins, PhD, Commonwealth Fund vice president for health care coverage, access, and tracking, said in an interview.
“The bad news is that a third of Americans continue to struggle with medical bills and medical debt, even among those who have health insurance coverage,” Dr. Collins added.
Indeed, the survey found that about one-third of insured adults reported a medical bill problem or that they were paying off medical debt, as did approximately half of those who were uninsured. Medical debt caused 35% of respondents to use up most or all of their savings to pay it off.
Meanwhile, 27% of adults said medical bills left them unable to pay for necessities such as food, heat, or rent. What surprised Dr. Collins was that 43% of adults said they received a lower credit rating as a result of their medical debt, and 35% said they had taken on more credit card debt to pay off these bills.
“The fact that it’s bleeding over into people’s financial security in terms of their credit scores, I think is something that really needs to be looked at by policymakers,” Dr. Collins said.
When analyzed by race/ethnicity, the researchers found that 55% of Black adults and 44% of Latino/Hispanic adults reported medical bills and debt problems, compared with 32% of White adults. In addition, 47% of those living below the poverty line also reported problems with medical bills.
According to the survey, 45% of respondents were directly affected by the pandemic in at least one of three ways – testing positive or getting sick from COVID-19, losing income, or losing employer coverage – with Black and Latinx adults and those with lower incomes at greater risk.
George Abraham, MD, president of the American College of Physicians, said the Commonwealth Fund’s findings were not surprising because it has always been known that underrepresented populations struggle for access to care because of socioeconomic factors. He said these populations were more vulnerable in terms of more severe infections and disease burden during the pandemic.
“[This study] validates what primary care physicians have been saying all along in regard to our patients’ access to care and their ability to cover health care costs,” said Dr. Abraham, who was not involved with the study. “This will hopefully be an eye-opener and wake-up call that reiterates that we still do not have equitable access to care and vulnerable populations are disproportionately affected.”
He believes that, although people are insured, many of them may contend with medical debt when they fall ill because they can’t afford the premiums.
“Even though they may have been registered for health coverage, they may not have active coverage at the time of illness simply because they weren’t able to make their last premium payments because they’ve been down, because they lost their job, or whatever else,” Dr. Abraham explained. “On paper, they appear to have health care coverage. But in reality, clearly, that coverage does not match their needs or it’s not affordable.”
For Dr. Abraham, the study emphasizes the need to continue support for health care reform, including pricing it so that insurance is available for those with fewer socioeconomic resources.
Yalda Jabbarpour, MD, medical director of the Robert Graham Center for Policy Studies, Washington, said high-deductible health plans need to be “reined in” because they can lead to greater debt, particularly among vulnerable populations.
“Hopefully this will encourage policymakers to look more closely at the problem of medical debt as a contributing factor to financial instability,” Dr. Jabbarpour said. “Federal relief is important, so is expanding access to comprehensive, affordable health care coverage.”
Dr. Collins said there should also be a way to raise awareness of the health care marketplace and coverage options so that people have an easier time getting insured.
A version of this article first appeared on Medscape.com.
Despite the passage of four major relief bills in 2020 and 2021 and federal efforts to offset pandemic- and job-related coverage loss, many people continued to face financial challenges, especially those with a low income and those who are Black or Latino.
The survey, which included responses from 5,450 adults, revealed that 10% of adults aged 19-64 were uninsured during the first half of 2021, a rate lower than what was recorded in 2020 and 2019 in both federal and private surveys. However, uninsured rates were highest among those with low income, those younger than 50 years old, and Black and Latino adults.
For most adults who lost employee health insurance, the coverage gap was relatively brief, with 54% saying their coverage gap lasted 3-4 months. Only 16% of adults said coverage gaps lasted a year or longer.
“The good news is that this survey is suggesting that the coverage losses during the pandemic may have been offset by federal efforts to help people get and maintain health insurance coverage,” lead author Sara Collins, PhD, Commonwealth Fund vice president for health care coverage, access, and tracking, said in an interview.
“The bad news is that a third of Americans continue to struggle with medical bills and medical debt, even among those who have health insurance coverage,” Dr. Collins added.
Indeed, the survey found that about one-third of insured adults reported a medical bill problem or that they were paying off medical debt, as did approximately half of those who were uninsured. Medical debt caused 35% of respondents to use up most or all of their savings to pay it off.
Meanwhile, 27% of adults said medical bills left them unable to pay for necessities such as food, heat, or rent. What surprised Dr. Collins was that 43% of adults said they received a lower credit rating as a result of their medical debt, and 35% said they had taken on more credit card debt to pay off these bills.
“The fact that it’s bleeding over into people’s financial security in terms of their credit scores, I think is something that really needs to be looked at by policymakers,” Dr. Collins said.
When analyzed by race/ethnicity, the researchers found that 55% of Black adults and 44% of Latino/Hispanic adults reported medical bills and debt problems, compared with 32% of White adults. In addition, 47% of those living below the poverty line also reported problems with medical bills.
According to the survey, 45% of respondents were directly affected by the pandemic in at least one of three ways – testing positive or getting sick from COVID-19, losing income, or losing employer coverage – with Black and Latinx adults and those with lower incomes at greater risk.
George Abraham, MD, president of the American College of Physicians, said the Commonwealth Fund’s findings were not surprising because it has always been known that underrepresented populations struggle for access to care because of socioeconomic factors. He said these populations were more vulnerable in terms of more severe infections and disease burden during the pandemic.
“[This study] validates what primary care physicians have been saying all along in regard to our patients’ access to care and their ability to cover health care costs,” said Dr. Abraham, who was not involved with the study. “This will hopefully be an eye-opener and wake-up call that reiterates that we still do not have equitable access to care and vulnerable populations are disproportionately affected.”
He believes that, although people are insured, many of them may contend with medical debt when they fall ill because they can’t afford the premiums.
“Even though they may have been registered for health coverage, they may not have active coverage at the time of illness simply because they weren’t able to make their last premium payments because they’ve been down, because they lost their job, or whatever else,” Dr. Abraham explained. “On paper, they appear to have health care coverage. But in reality, clearly, that coverage does not match their needs or it’s not affordable.”
For Dr. Abraham, the study emphasizes the need to continue support for health care reform, including pricing it so that insurance is available for those with fewer socioeconomic resources.
Yalda Jabbarpour, MD, medical director of the Robert Graham Center for Policy Studies, Washington, said high-deductible health plans need to be “reined in” because they can lead to greater debt, particularly among vulnerable populations.
“Hopefully this will encourage policymakers to look more closely at the problem of medical debt as a contributing factor to financial instability,” Dr. Jabbarpour said. “Federal relief is important, so is expanding access to comprehensive, affordable health care coverage.”
Dr. Collins said there should also be a way to raise awareness of the health care marketplace and coverage options so that people have an easier time getting insured.
A version of this article first appeared on Medscape.com.
Vaccinated people infected with Delta remain contagious
, The New York Times reported late on July 29.
The revelation is one reason the agency reversed course this week and said fully vaccinated people should go back to wearing masks in many cases.
The new findings also are a reversal from what scientists had believed to be true about other variants of the virus, the Times said. The bottom line is that the CDC data show people with so-called breakthrough cases of the Delta variant may be just as contagious as unvaccinated people, even if they do not show symptoms.
ABC News reported earlier on July 29 that the CDC’s updated mask guidance followed an outbreak in Cape Cod, where crowds gathered for the Fourth of July.
As of July 29, 882 people were tied to the outbreak centered in Provincetown, Mass. Of those who live in Massachusetts, 74% were unvaccinated. ABC said the majority were showing symptoms of COVID-19.
, The New York Times reported late on July 29.
The revelation is one reason the agency reversed course this week and said fully vaccinated people should go back to wearing masks in many cases.
The new findings also are a reversal from what scientists had believed to be true about other variants of the virus, the Times said. The bottom line is that the CDC data show people with so-called breakthrough cases of the Delta variant may be just as contagious as unvaccinated people, even if they do not show symptoms.
ABC News reported earlier on July 29 that the CDC’s updated mask guidance followed an outbreak in Cape Cod, where crowds gathered for the Fourth of July.
As of July 29, 882 people were tied to the outbreak centered in Provincetown, Mass. Of those who live in Massachusetts, 74% were unvaccinated. ABC said the majority were showing symptoms of COVID-19.
, The New York Times reported late on July 29.
The revelation is one reason the agency reversed course this week and said fully vaccinated people should go back to wearing masks in many cases.
The new findings also are a reversal from what scientists had believed to be true about other variants of the virus, the Times said. The bottom line is that the CDC data show people with so-called breakthrough cases of the Delta variant may be just as contagious as unvaccinated people, even if they do not show symptoms.
ABC News reported earlier on July 29 that the CDC’s updated mask guidance followed an outbreak in Cape Cod, where crowds gathered for the Fourth of July.
As of July 29, 882 people were tied to the outbreak centered in Provincetown, Mass. Of those who live in Massachusetts, 74% were unvaccinated. ABC said the majority were showing symptoms of COVID-19.
Study highlights impact of acne in adult women on quality of life, mental health
results from a qualitative study demonstrated.
“Nearly 50% of women experience acne in their 20s, and 35% experience acne in their 30s,” the study’s corresponding author, John S. Barbieri, MD, MBA, formerly of the department of dermatology at the University of Pennsylvania, Philadelphia, told this news organization. “While several qualitative studies have examined acne in adolescence, the lived experience of adult female acne has not been explored in detail and prior studies have included relatively few patients. As a result, we conducted a series of semistructured interviews among adult women with acne to examine the lived experience of adult acne and its treatment.”
For the study, published online July 28, 2021, in JAMA Dermatology, Dr. Barbieri and colleagues conducted voluntary, confidential phone interviews with 50 women aged between 18 and 40 years with moderate to severe acne who were recruited from the University of Pennsylvania Health System and from a private dermatology clinic in Cincinnati. They used free listing and open-ended, semistructured interviews to elicit opinions from the women on how acne affected their lives; their experience with acne treatments, dermatologists, and health care systems; as well as their views on treatment success.
The mean age of the participants was 28 years and 48% were white (10% were Black, 8% were Asian, 4% were more than one race, and the rest abstained from answering this question; 10% said they were Hispanic).
More than three-quarters (78%) reported prior treatment with topical retinoids, followed by spironolactone (70%), topical antibiotics (43%), combined oral contraceptives (43%), and isotretinoin (41%). During the free-listing part of interviews, where the women reported the first words that came to their mind when asked about success of treatment and adverse effects, the most important terms expressed related to treatment success were clear skin, no scarring, and no acne. The most important terms related to treatment adverse effects were dryness, redness, and burning.
In the semistructured interview portion of the study, the main themes expressed were acne-related concerns about appearance, including feeling less confident at work; mental and emotional health, including feelings of depression, anxiety, depression, and low self-worth during acne breakouts; and everyday life impact, including the notion that acne affected how other people perceived them. The other main themes included successful treatment, with clear skin and having a manageable number of lesions being desirable outcomes; and interactions with health care, including varied experiences with dermatologists. The researchers observed that most participants did not think oral antibiotics were appropriate treatments for their acne, specifically because of limited long-term effectiveness.
“Many patients described frustration with finding a dermatologist with whom they were comfortable and with identifying effective treatments for their acne,” the authors wrote. “In contrast, those who thought their dermatologist listened to their concerns and individualized their treatment plan reported higher levels of satisfaction.”
In an interview, Dr. Barbieri, who is now with the department of dermatology at Brigham and Women’s Hospital, Boston, said that he was surprised by how many patients expressed interest in nonantibiotic treatments for acne, “given that oral antibiotics are by far the most commonly prescribed systemic treatment for acne.”
Moreover, he added, “although I have experienced many patients being hesitant about isotretinoin, I was surprised by how strong patients’ concerns were about isotretinoin side effects. Unfortunately, there are many misconceptions about isotretinoin that limit use of this treatment that can be highly effective and safe for the appropriate patient.”
In an accompanying editorial, dermatologists Diane M. Thiboutot, MD and Andrea L. Zaenglein, MD, with Penn State University, Hershey, and Alison M. Layton, MB, ChB, with the Harrogate Foundation Trust, Harrogate, North Yorkshire, England, wrote that the findings from the study “resonate with those recently reported in several international studies that examine the impacts of acne, how patients assess treatment success, and what is important to measure from a patient and health care professional perspective in a clinical trial for acne.”
A large systematic review on the impact of acne on patients, conducted by the Acne Core Outcomes Research Network (ACORN), found that “appearance-related concerns and negative psychosocial effects were found to be a major impact of acne,” they noted. “Surprisingly, only 22 of the 473 studies identified in this review included qualitative data gathered from patient interviews. It is encouraging to see the concordance between the concerns voiced by the participants in the current study and those identified from the literature review, wherein a variety of methods were used to assess acne impacts.”
For his part, Dr. Barbieri said that the study findings “justify the importance of having a discussion with patients about their unique lived experience of acne and individualizing treatment to their specific needs. Patient reported outcome measures could be a useful adjunctive tool to capture these impacts on quality of life.”
This study was funded by grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Barbieri disclosed that he received partial salary support through a Pfizer Fellowship in Dermatology Patient Oriented Research grant to the Trustees of the University of Pennsylvania. Dr. Thiboutot reported receiving consultant fees from Galderma and Novartis outside the submitted work. Dr. Layton reported receiving unrestricted educational presentation, advisory board, and consultancy fees from Galderma Honoraria; unrestricted educational presentation and advisory board honoraria from Leo; advisory board honoraria from Novartis and Mylan; consultancy honoraria from Procter and Gamble and Meda; grants from Galderma; and consultancy and advisory board honoraria from Origimm outside the submitted work.
results from a qualitative study demonstrated.
“Nearly 50% of women experience acne in their 20s, and 35% experience acne in their 30s,” the study’s corresponding author, John S. Barbieri, MD, MBA, formerly of the department of dermatology at the University of Pennsylvania, Philadelphia, told this news organization. “While several qualitative studies have examined acne in adolescence, the lived experience of adult female acne has not been explored in detail and prior studies have included relatively few patients. As a result, we conducted a series of semistructured interviews among adult women with acne to examine the lived experience of adult acne and its treatment.”
For the study, published online July 28, 2021, in JAMA Dermatology, Dr. Barbieri and colleagues conducted voluntary, confidential phone interviews with 50 women aged between 18 and 40 years with moderate to severe acne who were recruited from the University of Pennsylvania Health System and from a private dermatology clinic in Cincinnati. They used free listing and open-ended, semistructured interviews to elicit opinions from the women on how acne affected their lives; their experience with acne treatments, dermatologists, and health care systems; as well as their views on treatment success.
The mean age of the participants was 28 years and 48% were white (10% were Black, 8% were Asian, 4% were more than one race, and the rest abstained from answering this question; 10% said they were Hispanic).
More than three-quarters (78%) reported prior treatment with topical retinoids, followed by spironolactone (70%), topical antibiotics (43%), combined oral contraceptives (43%), and isotretinoin (41%). During the free-listing part of interviews, where the women reported the first words that came to their mind when asked about success of treatment and adverse effects, the most important terms expressed related to treatment success were clear skin, no scarring, and no acne. The most important terms related to treatment adverse effects were dryness, redness, and burning.
In the semistructured interview portion of the study, the main themes expressed were acne-related concerns about appearance, including feeling less confident at work; mental and emotional health, including feelings of depression, anxiety, depression, and low self-worth during acne breakouts; and everyday life impact, including the notion that acne affected how other people perceived them. The other main themes included successful treatment, with clear skin and having a manageable number of lesions being desirable outcomes; and interactions with health care, including varied experiences with dermatologists. The researchers observed that most participants did not think oral antibiotics were appropriate treatments for their acne, specifically because of limited long-term effectiveness.
“Many patients described frustration with finding a dermatologist with whom they were comfortable and with identifying effective treatments for their acne,” the authors wrote. “In contrast, those who thought their dermatologist listened to their concerns and individualized their treatment plan reported higher levels of satisfaction.”
In an interview, Dr. Barbieri, who is now with the department of dermatology at Brigham and Women’s Hospital, Boston, said that he was surprised by how many patients expressed interest in nonantibiotic treatments for acne, “given that oral antibiotics are by far the most commonly prescribed systemic treatment for acne.”
Moreover, he added, “although I have experienced many patients being hesitant about isotretinoin, I was surprised by how strong patients’ concerns were about isotretinoin side effects. Unfortunately, there are many misconceptions about isotretinoin that limit use of this treatment that can be highly effective and safe for the appropriate patient.”
In an accompanying editorial, dermatologists Diane M. Thiboutot, MD and Andrea L. Zaenglein, MD, with Penn State University, Hershey, and Alison M. Layton, MB, ChB, with the Harrogate Foundation Trust, Harrogate, North Yorkshire, England, wrote that the findings from the study “resonate with those recently reported in several international studies that examine the impacts of acne, how patients assess treatment success, and what is important to measure from a patient and health care professional perspective in a clinical trial for acne.”
A large systematic review on the impact of acne on patients, conducted by the Acne Core Outcomes Research Network (ACORN), found that “appearance-related concerns and negative psychosocial effects were found to be a major impact of acne,” they noted. “Surprisingly, only 22 of the 473 studies identified in this review included qualitative data gathered from patient interviews. It is encouraging to see the concordance between the concerns voiced by the participants in the current study and those identified from the literature review, wherein a variety of methods were used to assess acne impacts.”
For his part, Dr. Barbieri said that the study findings “justify the importance of having a discussion with patients about their unique lived experience of acne and individualizing treatment to their specific needs. Patient reported outcome measures could be a useful adjunctive tool to capture these impacts on quality of life.”
This study was funded by grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Barbieri disclosed that he received partial salary support through a Pfizer Fellowship in Dermatology Patient Oriented Research grant to the Trustees of the University of Pennsylvania. Dr. Thiboutot reported receiving consultant fees from Galderma and Novartis outside the submitted work. Dr. Layton reported receiving unrestricted educational presentation, advisory board, and consultancy fees from Galderma Honoraria; unrestricted educational presentation and advisory board honoraria from Leo; advisory board honoraria from Novartis and Mylan; consultancy honoraria from Procter and Gamble and Meda; grants from Galderma; and consultancy and advisory board honoraria from Origimm outside the submitted work.
results from a qualitative study demonstrated.
“Nearly 50% of women experience acne in their 20s, and 35% experience acne in their 30s,” the study’s corresponding author, John S. Barbieri, MD, MBA, formerly of the department of dermatology at the University of Pennsylvania, Philadelphia, told this news organization. “While several qualitative studies have examined acne in adolescence, the lived experience of adult female acne has not been explored in detail and prior studies have included relatively few patients. As a result, we conducted a series of semistructured interviews among adult women with acne to examine the lived experience of adult acne and its treatment.”
For the study, published online July 28, 2021, in JAMA Dermatology, Dr. Barbieri and colleagues conducted voluntary, confidential phone interviews with 50 women aged between 18 and 40 years with moderate to severe acne who were recruited from the University of Pennsylvania Health System and from a private dermatology clinic in Cincinnati. They used free listing and open-ended, semistructured interviews to elicit opinions from the women on how acne affected their lives; their experience with acne treatments, dermatologists, and health care systems; as well as their views on treatment success.
The mean age of the participants was 28 years and 48% were white (10% were Black, 8% were Asian, 4% were more than one race, and the rest abstained from answering this question; 10% said they were Hispanic).
More than three-quarters (78%) reported prior treatment with topical retinoids, followed by spironolactone (70%), topical antibiotics (43%), combined oral contraceptives (43%), and isotretinoin (41%). During the free-listing part of interviews, where the women reported the first words that came to their mind when asked about success of treatment and adverse effects, the most important terms expressed related to treatment success were clear skin, no scarring, and no acne. The most important terms related to treatment adverse effects were dryness, redness, and burning.
In the semistructured interview portion of the study, the main themes expressed were acne-related concerns about appearance, including feeling less confident at work; mental and emotional health, including feelings of depression, anxiety, depression, and low self-worth during acne breakouts; and everyday life impact, including the notion that acne affected how other people perceived them. The other main themes included successful treatment, with clear skin and having a manageable number of lesions being desirable outcomes; and interactions with health care, including varied experiences with dermatologists. The researchers observed that most participants did not think oral antibiotics were appropriate treatments for their acne, specifically because of limited long-term effectiveness.
“Many patients described frustration with finding a dermatologist with whom they were comfortable and with identifying effective treatments for their acne,” the authors wrote. “In contrast, those who thought their dermatologist listened to their concerns and individualized their treatment plan reported higher levels of satisfaction.”
In an interview, Dr. Barbieri, who is now with the department of dermatology at Brigham and Women’s Hospital, Boston, said that he was surprised by how many patients expressed interest in nonantibiotic treatments for acne, “given that oral antibiotics are by far the most commonly prescribed systemic treatment for acne.”
Moreover, he added, “although I have experienced many patients being hesitant about isotretinoin, I was surprised by how strong patients’ concerns were about isotretinoin side effects. Unfortunately, there are many misconceptions about isotretinoin that limit use of this treatment that can be highly effective and safe for the appropriate patient.”
In an accompanying editorial, dermatologists Diane M. Thiboutot, MD and Andrea L. Zaenglein, MD, with Penn State University, Hershey, and Alison M. Layton, MB, ChB, with the Harrogate Foundation Trust, Harrogate, North Yorkshire, England, wrote that the findings from the study “resonate with those recently reported in several international studies that examine the impacts of acne, how patients assess treatment success, and what is important to measure from a patient and health care professional perspective in a clinical trial for acne.”
A large systematic review on the impact of acne on patients, conducted by the Acne Core Outcomes Research Network (ACORN), found that “appearance-related concerns and negative psychosocial effects were found to be a major impact of acne,” they noted. “Surprisingly, only 22 of the 473 studies identified in this review included qualitative data gathered from patient interviews. It is encouraging to see the concordance between the concerns voiced by the participants in the current study and those identified from the literature review, wherein a variety of methods were used to assess acne impacts.”
For his part, Dr. Barbieri said that the study findings “justify the importance of having a discussion with patients about their unique lived experience of acne and individualizing treatment to their specific needs. Patient reported outcome measures could be a useful adjunctive tool to capture these impacts on quality of life.”
This study was funded by grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Barbieri disclosed that he received partial salary support through a Pfizer Fellowship in Dermatology Patient Oriented Research grant to the Trustees of the University of Pennsylvania. Dr. Thiboutot reported receiving consultant fees from Galderma and Novartis outside the submitted work. Dr. Layton reported receiving unrestricted educational presentation, advisory board, and consultancy fees from Galderma Honoraria; unrestricted educational presentation and advisory board honoraria from Leo; advisory board honoraria from Novartis and Mylan; consultancy honoraria from Procter and Gamble and Meda; grants from Galderma; and consultancy and advisory board honoraria from Origimm outside the submitted work.
FROM JAMA DERMATOLOGY
Hyperimmune globulin fails to prevent congenital CMV infection
Administering hyperimmune globulin to pregnant women who tested positive for cytomegalovirus did not reduce CMV infections or deaths among their fetuses or newborns, according to a randomized controlled trial published online July 28 in the New England Journal of Medicine.
Up to 40,000 infants a year have congenital CMV infections, which can lead to stillbirth, neonatal death, deafness, and cognitive and motor delay. An estimated 35%-40% of fetuses of women with a primary CMV infection will develop an infection, write Brenna Hughes, MD, an associate professor of ob/gyn and chief of the division of maternal fetal medicine at Duke University, Durham, N.C., and colleagues.
Previous trials and observational studies have shown mixed results with hyperimmune globulin for the prevention of congenital CMV infection.
“It was surprising to us that none of the outcomes in this trial were in the direction of potential benefit,” Dr. Hughes told this news organization. “However, this is why it is important to do large trials in a diverse population.”
The study cohort comprised 206,082 pregnant women who were screened for CMV infection before 23 weeks’ gestation. Of those women, 712 (0.35%) tested positive for CMV. The researchers enrolled 399 women who had tested positive and randomly assigned them to receive either a monthly infusion of CMV hyperimmune globulin (100 mg/kg) or placebo until delivery. The researchers used a composite of CMV infection or, if no testing occurred, fetal/neonatal death as the primary endpoint.
The trial was stopped early for futility when data from 394 participants revealed that 22.7% of offspring in the hyperimmune globulin group and 19.4% of those in the placebo group had had a CMV infection or had died (relative risk = 1.17; P = .42).
When individual endpoints were examined, trends were detected in favor of the placebo, but they did not reach statistical significance. The incidence of death was higher in the hyperimmune globulin group (4.9%) than in the placebo group (2.6%). The rate of preterm birth was also higher in the intervention group (12.2%) than in the group that received placebo (8.3%). The incidence of birth weight below the fifth percentile was 10.3% in the intervention group and 5.4% in the placebo group.
One woman who received hyperimmune globulin experienced a severe allergic reaction to the first infusion. Additionally, more women in the hyperimmune globulin group experienced headaches and shaking chills during infusions than did those who received placebo. There were no differences in maternal outcomes between the groups. There were no thromboembolic or ischemic events in either group.
“These findings suggest CMV hyperimmune globulin should not be used for the prevention of congenital CMV in pregnant patients with primary CMV during pregnancy,” Dr. Hughes said in an interview.
“A CMV vaccine is likely to be the most effective public health measure that we can offer, and that should be at the forefront of research investments,” she said. “But some of the other medications that work against CMV should be tested on a large scale as well,” she said. For example, a small trial in Israel showed that high-dose valacyclovir in early pregnancy decreased congenital CMV, and thus the drug merits study in a larger trial, she said.
Other experts agree that developing a vaccine should be the priority.
“The ultimate goal for preventing the brain damage and birth defects caused by congenital CMV infection is a vaccine that is as effective as the rubella vaccine has been for eliminating congenital rubella syndrome and that can be given well before pregnancy,” said Sallie Permar, MD, PhD, chair of pediatrics at Weill Cornell Medicine and pediatrician-in-chief at New York–Presbyterian/Weill Cornell Medical Center and the New York–Presbyterian Komansky Children’s Hospital in New York.
“While trials of vaccines are ongoing, there is a need to have a therapeutic option, especially for the high-risk setting of a mother acquiring the virus for the first time during pregnancy,” Dr. Permar said in an interview.
Dr. Permar was not involved in this study but is involved in follow-up studies of this cohort and is conducting research on CMV maternal vaccines. She noted the need for safe, effective antiviral treatments and for research into newer immunoglobulin products, such as monoclonal antibodies.
Both Dr. Permar and Dr. Hughes highlighted the challenge of raising awareness about the danger of CMV infections during pregnancy.
“Pregnant women, and especially those who have or work with young children, who are frequently carriers of the infection, should be informed of this risk,” Dr. Permar said. She hopes universal testing of newborns will be implemented and that it enables people to recognize the frequency and burden of these infections. She remains optimistic about a vaccine.
“After 60 years of research into a CMV vaccine, I believe we are currently in a ‘golden age’ of CMV vaccine development,” she said. She noted that Moderna is about to launch a phase 3 mRNA vaccine trial for CMV. “Moreover, immune correlates of protection against CMV have been identified from previous partially effective vaccines, and animal models have improved for preclinical studies. Therefore, I believe we will have an effective and safe vaccine against this most common congenital infection in the coming years.”
The research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Center for Advancing Translational Sciences. Dr. Hughes has served on Merck’s scientific advisory board. Various coauthors have received personal fees from Medela and nonfinancial support from Hologic; personal fees from Moderna and VBI vaccines, and grants from Novavax. Dr. Permar consults for Pfizer, Moderna, Merck, Sanofi, and Dynavax on their CMV vaccine programs, and she has a sponsored research program with Merck and Moderna on CMV vaccines.
A version of this article first appeared on Medscape.com.
Administering hyperimmune globulin to pregnant women who tested positive for cytomegalovirus did not reduce CMV infections or deaths among their fetuses or newborns, according to a randomized controlled trial published online July 28 in the New England Journal of Medicine.
Up to 40,000 infants a year have congenital CMV infections, which can lead to stillbirth, neonatal death, deafness, and cognitive and motor delay. An estimated 35%-40% of fetuses of women with a primary CMV infection will develop an infection, write Brenna Hughes, MD, an associate professor of ob/gyn and chief of the division of maternal fetal medicine at Duke University, Durham, N.C., and colleagues.
Previous trials and observational studies have shown mixed results with hyperimmune globulin for the prevention of congenital CMV infection.
“It was surprising to us that none of the outcomes in this trial were in the direction of potential benefit,” Dr. Hughes told this news organization. “However, this is why it is important to do large trials in a diverse population.”
The study cohort comprised 206,082 pregnant women who were screened for CMV infection before 23 weeks’ gestation. Of those women, 712 (0.35%) tested positive for CMV. The researchers enrolled 399 women who had tested positive and randomly assigned them to receive either a monthly infusion of CMV hyperimmune globulin (100 mg/kg) or placebo until delivery. The researchers used a composite of CMV infection or, if no testing occurred, fetal/neonatal death as the primary endpoint.
The trial was stopped early for futility when data from 394 participants revealed that 22.7% of offspring in the hyperimmune globulin group and 19.4% of those in the placebo group had had a CMV infection or had died (relative risk = 1.17; P = .42).
When individual endpoints were examined, trends were detected in favor of the placebo, but they did not reach statistical significance. The incidence of death was higher in the hyperimmune globulin group (4.9%) than in the placebo group (2.6%). The rate of preterm birth was also higher in the intervention group (12.2%) than in the group that received placebo (8.3%). The incidence of birth weight below the fifth percentile was 10.3% in the intervention group and 5.4% in the placebo group.
One woman who received hyperimmune globulin experienced a severe allergic reaction to the first infusion. Additionally, more women in the hyperimmune globulin group experienced headaches and shaking chills during infusions than did those who received placebo. There were no differences in maternal outcomes between the groups. There were no thromboembolic or ischemic events in either group.
“These findings suggest CMV hyperimmune globulin should not be used for the prevention of congenital CMV in pregnant patients with primary CMV during pregnancy,” Dr. Hughes said in an interview.
“A CMV vaccine is likely to be the most effective public health measure that we can offer, and that should be at the forefront of research investments,” she said. “But some of the other medications that work against CMV should be tested on a large scale as well,” she said. For example, a small trial in Israel showed that high-dose valacyclovir in early pregnancy decreased congenital CMV, and thus the drug merits study in a larger trial, she said.
Other experts agree that developing a vaccine should be the priority.
“The ultimate goal for preventing the brain damage and birth defects caused by congenital CMV infection is a vaccine that is as effective as the rubella vaccine has been for eliminating congenital rubella syndrome and that can be given well before pregnancy,” said Sallie Permar, MD, PhD, chair of pediatrics at Weill Cornell Medicine and pediatrician-in-chief at New York–Presbyterian/Weill Cornell Medical Center and the New York–Presbyterian Komansky Children’s Hospital in New York.
“While trials of vaccines are ongoing, there is a need to have a therapeutic option, especially for the high-risk setting of a mother acquiring the virus for the first time during pregnancy,” Dr. Permar said in an interview.
Dr. Permar was not involved in this study but is involved in follow-up studies of this cohort and is conducting research on CMV maternal vaccines. She noted the need for safe, effective antiviral treatments and for research into newer immunoglobulin products, such as monoclonal antibodies.
Both Dr. Permar and Dr. Hughes highlighted the challenge of raising awareness about the danger of CMV infections during pregnancy.
“Pregnant women, and especially those who have or work with young children, who are frequently carriers of the infection, should be informed of this risk,” Dr. Permar said. She hopes universal testing of newborns will be implemented and that it enables people to recognize the frequency and burden of these infections. She remains optimistic about a vaccine.
“After 60 years of research into a CMV vaccine, I believe we are currently in a ‘golden age’ of CMV vaccine development,” she said. She noted that Moderna is about to launch a phase 3 mRNA vaccine trial for CMV. “Moreover, immune correlates of protection against CMV have been identified from previous partially effective vaccines, and animal models have improved for preclinical studies. Therefore, I believe we will have an effective and safe vaccine against this most common congenital infection in the coming years.”
The research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Center for Advancing Translational Sciences. Dr. Hughes has served on Merck’s scientific advisory board. Various coauthors have received personal fees from Medela and nonfinancial support from Hologic; personal fees from Moderna and VBI vaccines, and grants from Novavax. Dr. Permar consults for Pfizer, Moderna, Merck, Sanofi, and Dynavax on their CMV vaccine programs, and she has a sponsored research program with Merck and Moderna on CMV vaccines.
A version of this article first appeared on Medscape.com.
Administering hyperimmune globulin to pregnant women who tested positive for cytomegalovirus did not reduce CMV infections or deaths among their fetuses or newborns, according to a randomized controlled trial published online July 28 in the New England Journal of Medicine.
Up to 40,000 infants a year have congenital CMV infections, which can lead to stillbirth, neonatal death, deafness, and cognitive and motor delay. An estimated 35%-40% of fetuses of women with a primary CMV infection will develop an infection, write Brenna Hughes, MD, an associate professor of ob/gyn and chief of the division of maternal fetal medicine at Duke University, Durham, N.C., and colleagues.
Previous trials and observational studies have shown mixed results with hyperimmune globulin for the prevention of congenital CMV infection.
“It was surprising to us that none of the outcomes in this trial were in the direction of potential benefit,” Dr. Hughes told this news organization. “However, this is why it is important to do large trials in a diverse population.”
The study cohort comprised 206,082 pregnant women who were screened for CMV infection before 23 weeks’ gestation. Of those women, 712 (0.35%) tested positive for CMV. The researchers enrolled 399 women who had tested positive and randomly assigned them to receive either a monthly infusion of CMV hyperimmune globulin (100 mg/kg) or placebo until delivery. The researchers used a composite of CMV infection or, if no testing occurred, fetal/neonatal death as the primary endpoint.
The trial was stopped early for futility when data from 394 participants revealed that 22.7% of offspring in the hyperimmune globulin group and 19.4% of those in the placebo group had had a CMV infection or had died (relative risk = 1.17; P = .42).
When individual endpoints were examined, trends were detected in favor of the placebo, but they did not reach statistical significance. The incidence of death was higher in the hyperimmune globulin group (4.9%) than in the placebo group (2.6%). The rate of preterm birth was also higher in the intervention group (12.2%) than in the group that received placebo (8.3%). The incidence of birth weight below the fifth percentile was 10.3% in the intervention group and 5.4% in the placebo group.
One woman who received hyperimmune globulin experienced a severe allergic reaction to the first infusion. Additionally, more women in the hyperimmune globulin group experienced headaches and shaking chills during infusions than did those who received placebo. There were no differences in maternal outcomes between the groups. There were no thromboembolic or ischemic events in either group.
“These findings suggest CMV hyperimmune globulin should not be used for the prevention of congenital CMV in pregnant patients with primary CMV during pregnancy,” Dr. Hughes said in an interview.
“A CMV vaccine is likely to be the most effective public health measure that we can offer, and that should be at the forefront of research investments,” she said. “But some of the other medications that work against CMV should be tested on a large scale as well,” she said. For example, a small trial in Israel showed that high-dose valacyclovir in early pregnancy decreased congenital CMV, and thus the drug merits study in a larger trial, she said.
Other experts agree that developing a vaccine should be the priority.
“The ultimate goal for preventing the brain damage and birth defects caused by congenital CMV infection is a vaccine that is as effective as the rubella vaccine has been for eliminating congenital rubella syndrome and that can be given well before pregnancy,” said Sallie Permar, MD, PhD, chair of pediatrics at Weill Cornell Medicine and pediatrician-in-chief at New York–Presbyterian/Weill Cornell Medical Center and the New York–Presbyterian Komansky Children’s Hospital in New York.
“While trials of vaccines are ongoing, there is a need to have a therapeutic option, especially for the high-risk setting of a mother acquiring the virus for the first time during pregnancy,” Dr. Permar said in an interview.
Dr. Permar was not involved in this study but is involved in follow-up studies of this cohort and is conducting research on CMV maternal vaccines. She noted the need for safe, effective antiviral treatments and for research into newer immunoglobulin products, such as monoclonal antibodies.
Both Dr. Permar and Dr. Hughes highlighted the challenge of raising awareness about the danger of CMV infections during pregnancy.
“Pregnant women, and especially those who have or work with young children, who are frequently carriers of the infection, should be informed of this risk,” Dr. Permar said. She hopes universal testing of newborns will be implemented and that it enables people to recognize the frequency and burden of these infections. She remains optimistic about a vaccine.
“After 60 years of research into a CMV vaccine, I believe we are currently in a ‘golden age’ of CMV vaccine development,” she said. She noted that Moderna is about to launch a phase 3 mRNA vaccine trial for CMV. “Moreover, immune correlates of protection against CMV have been identified from previous partially effective vaccines, and animal models have improved for preclinical studies. Therefore, I believe we will have an effective and safe vaccine against this most common congenital infection in the coming years.”
The research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Center for Advancing Translational Sciences. Dr. Hughes has served on Merck’s scientific advisory board. Various coauthors have received personal fees from Medela and nonfinancial support from Hologic; personal fees from Moderna and VBI vaccines, and grants from Novavax. Dr. Permar consults for Pfizer, Moderna, Merck, Sanofi, and Dynavax on their CMV vaccine programs, and she has a sponsored research program with Merck and Moderna on CMV vaccines.
A version of this article first appeared on Medscape.com.
Traumatic Fractures Should Trigger Osteoporosis Assessment in Postmenopausal Women
Study Overview
Objective. To compare the risk of subsequent fractures after an initial traumatic or nontraumatic fracture in postmenopausal women.
Design. A prospective observational study utilizing data from the Women’s Health Initiative (WHI) Study, WHI Clinical Trials (WHI-CT), and WHI Bone Density Substudy to evaluate rates at which patients who suffered a traumatic fracture vs nontraumatic fracture develop a subsequent fracture.
Setting and participants. The WHI study, implemented at 40 United States clinical sites, enrolled 161 808 postmenopausal women aged 50 to 79 years at baseline between 1993 and 1998. The study cohort consisted of 75 335 patients who had self-reported fractures from September 1994 to December 1998 that were confirmed by the WHI Bone Density Substudy and WHI-CT. Of these participants, 253 (0.3%) were excluded because of a lack of follow-up information regarding incident fractures, and 8208 (10.9%) were excluded due to incomplete information on covariates, thus resulting in an analytic sample of 66 874 (88.8%) participants. Prospective fracture ascertainment with participants was conducted at least annually and the mechanism of fracture was assessed to differentiate traumatic vs nontraumatic incident fractures. Traumatic fractures were defined as fractures caused by motor vehicle collisions, falls from a height, falls downstairs, or sports injury. Nontraumatic fractures were defined as fractures caused by a trip and fall.
Main outcome measures. The primary outcome was an incident fracture at an anatomically distinct body part. Fractures were classified as upper extremity (carpal, elbow, lower or upper end of humerus, shaft of humerus, upper radius/ulna, or radius/ulna), lower extremity (ankle, hip, patella, pelvis, shaft of femur, tibia/fibula, or tibial plateau), or spine (lumbar and/or thoracic spine). Self-reported fractures were verified via medical chart review by WHI study physicians; hip fractures were confirmed by review of written reports of radiographic studies; and nonhip fractures were confirmed by review of radiography reports or clinical documentations.
Main results. In total, 66 874 women in the study (mean [SD] age) 63.1 (7.0) years without clinical fracture and 65.3 (7.2) years with clinical fracture at baseline were followed for 8.1 (1.6) years. Of these participants, 7142 (10.7%) experienced incident fracture during the study follow-up period (13.9 per 1000 person-years), and 721 (10.1%) of whom had a subsequent fracture. The adjusted hazard ratio (aHR) of subsequent fracture after an initial fracture was 1.49 (95% CI, 1.38-1.61, P < .001). Covariates adjusted were age, race, ethnicity, body mass index, treated diabetes, frequency of falls in the previous year, and physical function and activity. In women with initial traumatic fracture, the association between initial and subsequent fracture was increased (aHR, 1.25; 95% CI, 1.06-1.48, P = .01). Among women with initial nontraumatic fracture, the association between initial and subsequent fracture was also increased (aHR, 1.52; 95% CI, 1.37-1.68, P < .001). The confidence intervals for the 2 preceding associations for traumatic and nontraumatic initial fracture strata were overlapping.
Conclusion. Fractures, regardless of mechanism of injury, are similarly associated with an increased risk of subsequent fractures in postmenopausal women aged 50 years and older. Findings from this study provide evidence to support reevaluation of current clinical guidelines to include traumatic fracture as a trigger for osteoporosis screening.
Commentary
Osteoporosis is one of the most common age-associated disease that affects 1 in 4 women and 1 in 20 men over the age of 65.1 It increases the risk of fracture, and its clinical sequelae include reduced mobility, health decline, and increased all-cause mortality. The high prevalence of osteoporosis poses a clinical challenge as the global population continues to age. Pharmacological treatments such as bisphosphonates are highly effective in preventing or slowing bone mineral density (BMD) loss and reducing risk of fragility fractures (eg, nontraumatic fractures of the vertebra, hip, and femur) and are commonly used to mitigate adverse effects of degenerative bone changes secondary to osteoporosis.1
The high prevalence of osteoporosis and effectiveness of bisphosphonates raises the question of how to optimally identify adults at risk for osteoporosis so that pharmacologic therapy can be promptly initiated to prevent disease progression. Multiple osteoporosis screening guidelines, including those from the United States Preventive Services Task Force (USPSTF), American Association of Family Physicians, and National Osteoporosis Foundation, are widely used in the clinical setting to address this important clinical question. In general, the prevailing wisdom is to screen osteoporosis in postmenopausal women over the age of 65, women under the age of 65 who have a significant 10-year fracture risk, or women over the age of 50 who have experienced a fragility fracture.1 In the study reported by Crandall et al, it was shown that the risks of having subsequent fractures were similar after an initial traumatic or nontraumatic (fragility) fracture in postmenopausal women aged 50 years and older.2 This finding brings into question whether traumatic fractures should be viewed any differently than nontraumatic fractures in women over the age of 50 in light of evaluation for osteoporosis. Furthermore, these results suggest that most fractures in postmenopausal women may indicate decreased bone integrity, thus adding to the rationale that osteoporosis screening needs to be considered and expanded to include postmenopausal women under the age of 65 who endured a traumatic fracture.
Per current guidelines, a woman under the age of 65 is recommended for osteoporosis screening only if she has an increased 10-year fracture risk compared to women aged 65 years and older. This risk is calculated based on the World Health Organization fracture-risk algorithm (WHO FRAX) tool which uses multiple factors such as age, weight, and history of fragility fractures to predict whether an individual is at risk of developing a fracture in the next 10 years. The WHO FRAX tool does not include traumatic fractures in its risk calculation and current clinical guidelines do not account for traumatic fractures as a red flag to initiate osteoporosis screening. Therefore, postmenopausal women under the age of 65 are less likely to be screened for osteoporosis when they experience a traumatic fracture compared to a fragility fracture, despite being at a demonstrably higher risk for subsequent fracture. As an unintended consequence, this may lead to the under diagnosis of osteoporosis in postmenopausal women under the age of 65. Thus, Crandall et al conclude that a fracture due to any cause warrants follow up evaluation for osteoporosis including BMD testing in women older than 50 years of age.
Older men constitute another population who are commonly under screened for osteoporosis. The current USPSTF guidelines indicate that there is an insufficient body of evidence to screen men for osteoporosis given its lower prevalence.1 However, it is important to note that men have significantly increased mortality after a hip fracture, are less likely to be on pharmacological treatment for osteoporosis, and are under diagnosed for osteoporosis.3 Consistent with findings from the current study, Leslie et al showed that high-trauma and low-trauma fractures have similarly elevated subsequent fracture risk in both men and women over the age of 40 in a Canadian study.4 Moreover, in the same study, BMD was decreased in both men and women who suffered a fracture regardless of the injury mechanism. This finding further underscores a need to consider traumatic fractures as a risk factor for osteoporosis. Taken together, given that men are under screened and treated for osteoporosis but have increased mortality post-fracture, considerations to initiate osteoporosis evaluation should be similarly given to men who endured a traumatic fracture.
The study conducted by Crandall et al has several strengths. It is noteworthy for the large size of the WHI cohort with participants from across the United States which enables the capture of a wider range of age groups as women under the age of 65 are not common participants of osteoporosis studies. Additionally, data ascertainment and outcome adjudication utilizing medical records and physician review assure data quality. A limitation of the study is that the study cohort consists exclusively of women and therefore the findings are not generalizable to men. However, findings from this study echo those from other studies that investigate the relationship between fracture mechanisms and subsequent fracture risk in men and women.3,4 Collectively, these comparable findings highlight the need for additional research to validate traumatic fracture as a risk factor for osteoporosis and to incorporate it into clinical guidelines for osteoporosis screening.
Applications for Clinical Practice
The findings from the current study indicate that traumatic and fragility fractures may be more alike than previously recognized in regards to bone health and subsequent fracture prevention in postmenopausal women. If validated, these results may lead to changes in clinical practice whereby all fractures in postmenopausal women could trigger osteoporosis screening, assessment, and treatment if indicated for the secondary prevention of fractures.
1. US Preventive Services Task Force, Curry SJ, Krist Ah, et al. Screening for Osteoporosis to Prevent Fractures: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(24):2521–2531. doi:10.1001/jama.2018.7498
2. Crandall CJ, Larson JC, LaCroix AZ, et al. Risk of Subsequent Fractures in Postmenopausal Women After Nontraumatic vs Traumatic Fractures. JAMA Intern Med. Published online June 7, 2021. doi:10.1001/jamainternmed.2021.2617
3. Mackey DC, Lui L, Cawthon PM, et al. High-Trauma Fractures and Low Bone Mineral Density in Older Women and Men. JAMA. 2007;298(20):2381–2388. doi:10.1001/jama.298.20.2381
4. Leslie WD, Schousboe JT, Morin SN, et al. Fracture risk following high-trauma versus low-trauma fracture: a registry-based cohort study. Osteoporos Int. 2020;31(6):1059–1067. doi:10.1007/s00198-019-05274-2
Study Overview
Objective. To compare the risk of subsequent fractures after an initial traumatic or nontraumatic fracture in postmenopausal women.
Design. A prospective observational study utilizing data from the Women’s Health Initiative (WHI) Study, WHI Clinical Trials (WHI-CT), and WHI Bone Density Substudy to evaluate rates at which patients who suffered a traumatic fracture vs nontraumatic fracture develop a subsequent fracture.
Setting and participants. The WHI study, implemented at 40 United States clinical sites, enrolled 161 808 postmenopausal women aged 50 to 79 years at baseline between 1993 and 1998. The study cohort consisted of 75 335 patients who had self-reported fractures from September 1994 to December 1998 that were confirmed by the WHI Bone Density Substudy and WHI-CT. Of these participants, 253 (0.3%) were excluded because of a lack of follow-up information regarding incident fractures, and 8208 (10.9%) were excluded due to incomplete information on covariates, thus resulting in an analytic sample of 66 874 (88.8%) participants. Prospective fracture ascertainment with participants was conducted at least annually and the mechanism of fracture was assessed to differentiate traumatic vs nontraumatic incident fractures. Traumatic fractures were defined as fractures caused by motor vehicle collisions, falls from a height, falls downstairs, or sports injury. Nontraumatic fractures were defined as fractures caused by a trip and fall.
Main outcome measures. The primary outcome was an incident fracture at an anatomically distinct body part. Fractures were classified as upper extremity (carpal, elbow, lower or upper end of humerus, shaft of humerus, upper radius/ulna, or radius/ulna), lower extremity (ankle, hip, patella, pelvis, shaft of femur, tibia/fibula, or tibial plateau), or spine (lumbar and/or thoracic spine). Self-reported fractures were verified via medical chart review by WHI study physicians; hip fractures were confirmed by review of written reports of radiographic studies; and nonhip fractures were confirmed by review of radiography reports or clinical documentations.
Main results. In total, 66 874 women in the study (mean [SD] age) 63.1 (7.0) years without clinical fracture and 65.3 (7.2) years with clinical fracture at baseline were followed for 8.1 (1.6) years. Of these participants, 7142 (10.7%) experienced incident fracture during the study follow-up period (13.9 per 1000 person-years), and 721 (10.1%) of whom had a subsequent fracture. The adjusted hazard ratio (aHR) of subsequent fracture after an initial fracture was 1.49 (95% CI, 1.38-1.61, P < .001). Covariates adjusted were age, race, ethnicity, body mass index, treated diabetes, frequency of falls in the previous year, and physical function and activity. In women with initial traumatic fracture, the association between initial and subsequent fracture was increased (aHR, 1.25; 95% CI, 1.06-1.48, P = .01). Among women with initial nontraumatic fracture, the association between initial and subsequent fracture was also increased (aHR, 1.52; 95% CI, 1.37-1.68, P < .001). The confidence intervals for the 2 preceding associations for traumatic and nontraumatic initial fracture strata were overlapping.
Conclusion. Fractures, regardless of mechanism of injury, are similarly associated with an increased risk of subsequent fractures in postmenopausal women aged 50 years and older. Findings from this study provide evidence to support reevaluation of current clinical guidelines to include traumatic fracture as a trigger for osteoporosis screening.
Commentary
Osteoporosis is one of the most common age-associated disease that affects 1 in 4 women and 1 in 20 men over the age of 65.1 It increases the risk of fracture, and its clinical sequelae include reduced mobility, health decline, and increased all-cause mortality. The high prevalence of osteoporosis poses a clinical challenge as the global population continues to age. Pharmacological treatments such as bisphosphonates are highly effective in preventing or slowing bone mineral density (BMD) loss and reducing risk of fragility fractures (eg, nontraumatic fractures of the vertebra, hip, and femur) and are commonly used to mitigate adverse effects of degenerative bone changes secondary to osteoporosis.1
The high prevalence of osteoporosis and effectiveness of bisphosphonates raises the question of how to optimally identify adults at risk for osteoporosis so that pharmacologic therapy can be promptly initiated to prevent disease progression. Multiple osteoporosis screening guidelines, including those from the United States Preventive Services Task Force (USPSTF), American Association of Family Physicians, and National Osteoporosis Foundation, are widely used in the clinical setting to address this important clinical question. In general, the prevailing wisdom is to screen osteoporosis in postmenopausal women over the age of 65, women under the age of 65 who have a significant 10-year fracture risk, or women over the age of 50 who have experienced a fragility fracture.1 In the study reported by Crandall et al, it was shown that the risks of having subsequent fractures were similar after an initial traumatic or nontraumatic (fragility) fracture in postmenopausal women aged 50 years and older.2 This finding brings into question whether traumatic fractures should be viewed any differently than nontraumatic fractures in women over the age of 50 in light of evaluation for osteoporosis. Furthermore, these results suggest that most fractures in postmenopausal women may indicate decreased bone integrity, thus adding to the rationale that osteoporosis screening needs to be considered and expanded to include postmenopausal women under the age of 65 who endured a traumatic fracture.
Per current guidelines, a woman under the age of 65 is recommended for osteoporosis screening only if she has an increased 10-year fracture risk compared to women aged 65 years and older. This risk is calculated based on the World Health Organization fracture-risk algorithm (WHO FRAX) tool which uses multiple factors such as age, weight, and history of fragility fractures to predict whether an individual is at risk of developing a fracture in the next 10 years. The WHO FRAX tool does not include traumatic fractures in its risk calculation and current clinical guidelines do not account for traumatic fractures as a red flag to initiate osteoporosis screening. Therefore, postmenopausal women under the age of 65 are less likely to be screened for osteoporosis when they experience a traumatic fracture compared to a fragility fracture, despite being at a demonstrably higher risk for subsequent fracture. As an unintended consequence, this may lead to the under diagnosis of osteoporosis in postmenopausal women under the age of 65. Thus, Crandall et al conclude that a fracture due to any cause warrants follow up evaluation for osteoporosis including BMD testing in women older than 50 years of age.
Older men constitute another population who are commonly under screened for osteoporosis. The current USPSTF guidelines indicate that there is an insufficient body of evidence to screen men for osteoporosis given its lower prevalence.1 However, it is important to note that men have significantly increased mortality after a hip fracture, are less likely to be on pharmacological treatment for osteoporosis, and are under diagnosed for osteoporosis.3 Consistent with findings from the current study, Leslie et al showed that high-trauma and low-trauma fractures have similarly elevated subsequent fracture risk in both men and women over the age of 40 in a Canadian study.4 Moreover, in the same study, BMD was decreased in both men and women who suffered a fracture regardless of the injury mechanism. This finding further underscores a need to consider traumatic fractures as a risk factor for osteoporosis. Taken together, given that men are under screened and treated for osteoporosis but have increased mortality post-fracture, considerations to initiate osteoporosis evaluation should be similarly given to men who endured a traumatic fracture.
The study conducted by Crandall et al has several strengths. It is noteworthy for the large size of the WHI cohort with participants from across the United States which enables the capture of a wider range of age groups as women under the age of 65 are not common participants of osteoporosis studies. Additionally, data ascertainment and outcome adjudication utilizing medical records and physician review assure data quality. A limitation of the study is that the study cohort consists exclusively of women and therefore the findings are not generalizable to men. However, findings from this study echo those from other studies that investigate the relationship between fracture mechanisms and subsequent fracture risk in men and women.3,4 Collectively, these comparable findings highlight the need for additional research to validate traumatic fracture as a risk factor for osteoporosis and to incorporate it into clinical guidelines for osteoporosis screening.
Applications for Clinical Practice
The findings from the current study indicate that traumatic and fragility fractures may be more alike than previously recognized in regards to bone health and subsequent fracture prevention in postmenopausal women. If validated, these results may lead to changes in clinical practice whereby all fractures in postmenopausal women could trigger osteoporosis screening, assessment, and treatment if indicated for the secondary prevention of fractures.
Study Overview
Objective. To compare the risk of subsequent fractures after an initial traumatic or nontraumatic fracture in postmenopausal women.
Design. A prospective observational study utilizing data from the Women’s Health Initiative (WHI) Study, WHI Clinical Trials (WHI-CT), and WHI Bone Density Substudy to evaluate rates at which patients who suffered a traumatic fracture vs nontraumatic fracture develop a subsequent fracture.
Setting and participants. The WHI study, implemented at 40 United States clinical sites, enrolled 161 808 postmenopausal women aged 50 to 79 years at baseline between 1993 and 1998. The study cohort consisted of 75 335 patients who had self-reported fractures from September 1994 to December 1998 that were confirmed by the WHI Bone Density Substudy and WHI-CT. Of these participants, 253 (0.3%) were excluded because of a lack of follow-up information regarding incident fractures, and 8208 (10.9%) were excluded due to incomplete information on covariates, thus resulting in an analytic sample of 66 874 (88.8%) participants. Prospective fracture ascertainment with participants was conducted at least annually and the mechanism of fracture was assessed to differentiate traumatic vs nontraumatic incident fractures. Traumatic fractures were defined as fractures caused by motor vehicle collisions, falls from a height, falls downstairs, or sports injury. Nontraumatic fractures were defined as fractures caused by a trip and fall.
Main outcome measures. The primary outcome was an incident fracture at an anatomically distinct body part. Fractures were classified as upper extremity (carpal, elbow, lower or upper end of humerus, shaft of humerus, upper radius/ulna, or radius/ulna), lower extremity (ankle, hip, patella, pelvis, shaft of femur, tibia/fibula, or tibial plateau), or spine (lumbar and/or thoracic spine). Self-reported fractures were verified via medical chart review by WHI study physicians; hip fractures were confirmed by review of written reports of radiographic studies; and nonhip fractures were confirmed by review of radiography reports or clinical documentations.
Main results. In total, 66 874 women in the study (mean [SD] age) 63.1 (7.0) years without clinical fracture and 65.3 (7.2) years with clinical fracture at baseline were followed for 8.1 (1.6) years. Of these participants, 7142 (10.7%) experienced incident fracture during the study follow-up period (13.9 per 1000 person-years), and 721 (10.1%) of whom had a subsequent fracture. The adjusted hazard ratio (aHR) of subsequent fracture after an initial fracture was 1.49 (95% CI, 1.38-1.61, P < .001). Covariates adjusted were age, race, ethnicity, body mass index, treated diabetes, frequency of falls in the previous year, and physical function and activity. In women with initial traumatic fracture, the association between initial and subsequent fracture was increased (aHR, 1.25; 95% CI, 1.06-1.48, P = .01). Among women with initial nontraumatic fracture, the association between initial and subsequent fracture was also increased (aHR, 1.52; 95% CI, 1.37-1.68, P < .001). The confidence intervals for the 2 preceding associations for traumatic and nontraumatic initial fracture strata were overlapping.
Conclusion. Fractures, regardless of mechanism of injury, are similarly associated with an increased risk of subsequent fractures in postmenopausal women aged 50 years and older. Findings from this study provide evidence to support reevaluation of current clinical guidelines to include traumatic fracture as a trigger for osteoporosis screening.
Commentary
Osteoporosis is one of the most common age-associated disease that affects 1 in 4 women and 1 in 20 men over the age of 65.1 It increases the risk of fracture, and its clinical sequelae include reduced mobility, health decline, and increased all-cause mortality. The high prevalence of osteoporosis poses a clinical challenge as the global population continues to age. Pharmacological treatments such as bisphosphonates are highly effective in preventing or slowing bone mineral density (BMD) loss and reducing risk of fragility fractures (eg, nontraumatic fractures of the vertebra, hip, and femur) and are commonly used to mitigate adverse effects of degenerative bone changes secondary to osteoporosis.1
The high prevalence of osteoporosis and effectiveness of bisphosphonates raises the question of how to optimally identify adults at risk for osteoporosis so that pharmacologic therapy can be promptly initiated to prevent disease progression. Multiple osteoporosis screening guidelines, including those from the United States Preventive Services Task Force (USPSTF), American Association of Family Physicians, and National Osteoporosis Foundation, are widely used in the clinical setting to address this important clinical question. In general, the prevailing wisdom is to screen osteoporosis in postmenopausal women over the age of 65, women under the age of 65 who have a significant 10-year fracture risk, or women over the age of 50 who have experienced a fragility fracture.1 In the study reported by Crandall et al, it was shown that the risks of having subsequent fractures were similar after an initial traumatic or nontraumatic (fragility) fracture in postmenopausal women aged 50 years and older.2 This finding brings into question whether traumatic fractures should be viewed any differently than nontraumatic fractures in women over the age of 50 in light of evaluation for osteoporosis. Furthermore, these results suggest that most fractures in postmenopausal women may indicate decreased bone integrity, thus adding to the rationale that osteoporosis screening needs to be considered and expanded to include postmenopausal women under the age of 65 who endured a traumatic fracture.
Per current guidelines, a woman under the age of 65 is recommended for osteoporosis screening only if she has an increased 10-year fracture risk compared to women aged 65 years and older. This risk is calculated based on the World Health Organization fracture-risk algorithm (WHO FRAX) tool which uses multiple factors such as age, weight, and history of fragility fractures to predict whether an individual is at risk of developing a fracture in the next 10 years. The WHO FRAX tool does not include traumatic fractures in its risk calculation and current clinical guidelines do not account for traumatic fractures as a red flag to initiate osteoporosis screening. Therefore, postmenopausal women under the age of 65 are less likely to be screened for osteoporosis when they experience a traumatic fracture compared to a fragility fracture, despite being at a demonstrably higher risk for subsequent fracture. As an unintended consequence, this may lead to the under diagnosis of osteoporosis in postmenopausal women under the age of 65. Thus, Crandall et al conclude that a fracture due to any cause warrants follow up evaluation for osteoporosis including BMD testing in women older than 50 years of age.
Older men constitute another population who are commonly under screened for osteoporosis. The current USPSTF guidelines indicate that there is an insufficient body of evidence to screen men for osteoporosis given its lower prevalence.1 However, it is important to note that men have significantly increased mortality after a hip fracture, are less likely to be on pharmacological treatment for osteoporosis, and are under diagnosed for osteoporosis.3 Consistent with findings from the current study, Leslie et al showed that high-trauma and low-trauma fractures have similarly elevated subsequent fracture risk in both men and women over the age of 40 in a Canadian study.4 Moreover, in the same study, BMD was decreased in both men and women who suffered a fracture regardless of the injury mechanism. This finding further underscores a need to consider traumatic fractures as a risk factor for osteoporosis. Taken together, given that men are under screened and treated for osteoporosis but have increased mortality post-fracture, considerations to initiate osteoporosis evaluation should be similarly given to men who endured a traumatic fracture.
The study conducted by Crandall et al has several strengths. It is noteworthy for the large size of the WHI cohort with participants from across the United States which enables the capture of a wider range of age groups as women under the age of 65 are not common participants of osteoporosis studies. Additionally, data ascertainment and outcome adjudication utilizing medical records and physician review assure data quality. A limitation of the study is that the study cohort consists exclusively of women and therefore the findings are not generalizable to men. However, findings from this study echo those from other studies that investigate the relationship between fracture mechanisms and subsequent fracture risk in men and women.3,4 Collectively, these comparable findings highlight the need for additional research to validate traumatic fracture as a risk factor for osteoporosis and to incorporate it into clinical guidelines for osteoporosis screening.
Applications for Clinical Practice
The findings from the current study indicate that traumatic and fragility fractures may be more alike than previously recognized in regards to bone health and subsequent fracture prevention in postmenopausal women. If validated, these results may lead to changes in clinical practice whereby all fractures in postmenopausal women could trigger osteoporosis screening, assessment, and treatment if indicated for the secondary prevention of fractures.
1. US Preventive Services Task Force, Curry SJ, Krist Ah, et al. Screening for Osteoporosis to Prevent Fractures: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(24):2521–2531. doi:10.1001/jama.2018.7498
2. Crandall CJ, Larson JC, LaCroix AZ, et al. Risk of Subsequent Fractures in Postmenopausal Women After Nontraumatic vs Traumatic Fractures. JAMA Intern Med. Published online June 7, 2021. doi:10.1001/jamainternmed.2021.2617
3. Mackey DC, Lui L, Cawthon PM, et al. High-Trauma Fractures and Low Bone Mineral Density in Older Women and Men. JAMA. 2007;298(20):2381–2388. doi:10.1001/jama.298.20.2381
4. Leslie WD, Schousboe JT, Morin SN, et al. Fracture risk following high-trauma versus low-trauma fracture: a registry-based cohort study. Osteoporos Int. 2020;31(6):1059–1067. doi:10.1007/s00198-019-05274-2
1. US Preventive Services Task Force, Curry SJ, Krist Ah, et al. Screening for Osteoporosis to Prevent Fractures: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(24):2521–2531. doi:10.1001/jama.2018.7498
2. Crandall CJ, Larson JC, LaCroix AZ, et al. Risk of Subsequent Fractures in Postmenopausal Women After Nontraumatic vs Traumatic Fractures. JAMA Intern Med. Published online June 7, 2021. doi:10.1001/jamainternmed.2021.2617
3. Mackey DC, Lui L, Cawthon PM, et al. High-Trauma Fractures and Low Bone Mineral Density in Older Women and Men. JAMA. 2007;298(20):2381–2388. doi:10.1001/jama.298.20.2381
4. Leslie WD, Schousboe JT, Morin SN, et al. Fracture risk following high-trauma versus low-trauma fracture: a registry-based cohort study. Osteoporos Int. 2020;31(6):1059–1067. doi:10.1007/s00198-019-05274-2
Nivolumab Plus Cabozantinib Improves Outcomes Compared With Sunitinib for Advanced Renal Cell Carcinoma
Study Overview
Objective. To evaluate the efficacy and safety of the combination of nivolumab plus cabozantinib as compared with sunitinib monotherapy in the treatment of previously untreated advanced renal cell carcinoma (RCC).
Design. Multicenter, international, open-label, randomized, phase 3 trial.
Intervention. Patients were randomized in a 1:1 fashion to 1 of 2 treatment arms:
- Arm A: Nivolumab intravenously 240 mg every 2 weeks plus cabozantinib orally 40 mg once daily.
- Arm B: Sunitinib orally 50 mg daily for 4 weeks, followed by 2 weeks off therapy (6-week cycle).
Randomization was stratified by the International Metastatic RCC Database Consortium prognostic risk score (low-, intermediate-, and high-risk). Treatment was continued until disease progression or development of unacceptable toxic side effects with a maximum of 2-year duration of Nivolumab therapy.
Settings and participants. Adults with previously untreated advanced RCC with a clear cell component were eligible for enrollment. Subjects were excluded if they had active central nervous system metastases or active autoimmune disease.
Main outcome measures. The primary outcome of this study was progression-free survival (PFS) as assessed by an independent review committee. Secondary endpoints included overall survival, objective response rate, safety, and PFS as assessed by investigators. All subgroup analyses were prespecified. Efficacy was assessed in the intention-to-treat population, including all patients who underwent randomization.
Main results. A total of 651 patients underwent randomization: 323 to the nivolumab plus cabozantinib group, and 328 to the sunitinib group. Baseline demographics were balanced. The median follow-up period for overall survival (OS) was 18.1 months. The primary reason for treatment discontinuation in any group was disease progression. PFS as indicated by an independent review committee was significantly longer in the nivolumab plus cabozantinib group compared to the sunitinib group (median 16.6 months vs 8.2 months; hazard ratio [HR] 0.51, P < .001). The median OS was not reached for any group. Overall survival was longer in the nivolumab plus cabozantinib group compared to the sunitinib group (HR 0.60, 95% CI: 0.40-0.89; P = .001). The objective response rate was 55.7% with the nivolumab plus cabozantinib group versus 27.1% with sunitinib (P < .001). The complete response rate was 8% in the nivolumab plus cabozantinib group compared to 4.6% in the sunitinib group. The median time to response was 2.8 months with nivolumab plus cabozantinib and 4.2 months in the sunitinib group, while the median duration of response was 20.2 months and 11.5 months, respectively.
Nearly all patients (about 99% in each group) had an adverse event (AE). Hypertension was the most common side effect, with grade 3 or higher seen in 12.5% in the nivolumab plus cabzantinib group and 13.1% in the sunitinib group. Other grade 3 or higher side effects occurring in at least 10% of patients in any group were hyponatremia, diarrhea, palmar-plantar erythrodysesthesia, hypothyroidism, and fatigue. AEs of any cause leading to discontinuation of the therapy occurred in 19.7% in the nivolumab plus cabzantinib group vs 16.9% of the sunitinib group. One death was considered to be treatment-related (small intestinal perforation) in the nivolumab plus cabozantinib group vs 2 treatment-related deaths with sunitinib (pneumonia and respiratory distress). In the nivolumab plus cabozantinib group, 57% of the patients had a dose reduction of cabozantinib and 52% had a reduction in sunitinib dosage.
Using the Functional Assessment of Cancer Therapy-Kidney Symptoms Index, patients in the nivolumab plus cabozantinib group reported better health-related quality of life and less disease-related symptoms compared to the sunitinib group.
Commentary
The treatment landscape for frontline therapy for patients with advanced RCC has rapidly expanded over the last several years and has revolutionized cancer care. Ushered in by the results from the CheckMate 214 study highlighting the efficacy of dual checkpoint inhibition with nivolumab and ipilimumab in intermediate and poor risk patients, several subsequent trials have demonstrated improved outcomes with combination therapy with immune checkpoint inhibitors and tyrosine-kinase inhibitors (TKI). To date, data from Keynote-426 (pembrolizumab plus axitinib vs sunitinib), Javelin Renal 101 (avelumab plus axitinib vs sunitinib) and the CLEAR trial (lenvatinib plus pembrolizumab vs levatinib plus everolimus vs sunitinib) have demonstrated superiority of immune checkpoint inhibitor/TKI combinations over sunitinb in the first-line setting.1-5
The current phase 3, CheckMate 9ER trial adds yet another dynamic option for patients with advanced clear cell RCC. While cross-trial comparisons are fraught with important caveats, the median PFS of almost 16.6 months and complete response rate of 8% the nivolumab plus cabozantinib group compares favorably with other combinations. Data from the CLEAR study with the combination of lenvatinib and pembrolizumab showed a complete response rate approaching 16%. Importantly, the current study highlights improved quality of life with the combination of cabozantinib and nivolumab compared to sunitinib alone adding to the efficacy and benefits of this combination treatment.
The selection of first line therapy for patients with advanced RCC should be always guided by individual patient characteristics, and any single immune checkpoint inhibitor/TKI combination is not “superior” to any other. Perhaps more importantly is developing an understanding of the overlapping toxicity profiles of checkpoint inhibitors and TKIs. Again, this trial results are consistent with prior studies in terms of the adverse event profile which were not trivial, and almost all patients (99%) experienced AEs. It is important for oncologists to understand the management of the toxicities with these combinations and dose reductions as appropriate. It is worth noting that 19% of patients with nivolumab plus cabozantinib received glucocorticoids for management of immune-related AEs.
While long-term follow-up data will be needed to further understand the durability of response to this combination, nivolumab-cabozantinib represents an exciting new option for patients with advanced clear cell RCC. As we continue to see improvement in outcomes in clear cell histology, further work must focus on optimization of therapy in non-clear cell RCC as this is a population that is not represented in these data sets. Furthermore, future efforts should begin to explore triplet combinations and biomarker driven patient selection for upfront therapy in ordercontinue to improve outcomes in patients with advanced RCC.
Applications for Clinical Practice
The combination of nivolumab plus cabozantinib adds to the growing list of highly active checkpoint inhibitor/TKI combinations for first-line treatment of advanced RCC. With significant higher response rates, improved outcomes, and improvement in the quality of life, this combination will add another standard treatment option for patients with previously untreated advanced RCC.
1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab Versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14)1277-1290. doi:10.1056/NEJMoa1712126
2. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714
3. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8
4. Choueiri TK, Motzer RJ, Rini BI, et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020;31:1030-1039. doi:10.1016/j.annonc.2020.04.010
5, Motzer R, Alekseev B, Rha SY, et al. CLEAR Trial Investigators. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716
Study Overview
Objective. To evaluate the efficacy and safety of the combination of nivolumab plus cabozantinib as compared with sunitinib monotherapy in the treatment of previously untreated advanced renal cell carcinoma (RCC).
Design. Multicenter, international, open-label, randomized, phase 3 trial.
Intervention. Patients were randomized in a 1:1 fashion to 1 of 2 treatment arms:
- Arm A: Nivolumab intravenously 240 mg every 2 weeks plus cabozantinib orally 40 mg once daily.
- Arm B: Sunitinib orally 50 mg daily for 4 weeks, followed by 2 weeks off therapy (6-week cycle).
Randomization was stratified by the International Metastatic RCC Database Consortium prognostic risk score (low-, intermediate-, and high-risk). Treatment was continued until disease progression or development of unacceptable toxic side effects with a maximum of 2-year duration of Nivolumab therapy.
Settings and participants. Adults with previously untreated advanced RCC with a clear cell component were eligible for enrollment. Subjects were excluded if they had active central nervous system metastases or active autoimmune disease.
Main outcome measures. The primary outcome of this study was progression-free survival (PFS) as assessed by an independent review committee. Secondary endpoints included overall survival, objective response rate, safety, and PFS as assessed by investigators. All subgroup analyses were prespecified. Efficacy was assessed in the intention-to-treat population, including all patients who underwent randomization.
Main results. A total of 651 patients underwent randomization: 323 to the nivolumab plus cabozantinib group, and 328 to the sunitinib group. Baseline demographics were balanced. The median follow-up period for overall survival (OS) was 18.1 months. The primary reason for treatment discontinuation in any group was disease progression. PFS as indicated by an independent review committee was significantly longer in the nivolumab plus cabozantinib group compared to the sunitinib group (median 16.6 months vs 8.2 months; hazard ratio [HR] 0.51, P < .001). The median OS was not reached for any group. Overall survival was longer in the nivolumab plus cabozantinib group compared to the sunitinib group (HR 0.60, 95% CI: 0.40-0.89; P = .001). The objective response rate was 55.7% with the nivolumab plus cabozantinib group versus 27.1% with sunitinib (P < .001). The complete response rate was 8% in the nivolumab plus cabozantinib group compared to 4.6% in the sunitinib group. The median time to response was 2.8 months with nivolumab plus cabozantinib and 4.2 months in the sunitinib group, while the median duration of response was 20.2 months and 11.5 months, respectively.
Nearly all patients (about 99% in each group) had an adverse event (AE). Hypertension was the most common side effect, with grade 3 or higher seen in 12.5% in the nivolumab plus cabzantinib group and 13.1% in the sunitinib group. Other grade 3 or higher side effects occurring in at least 10% of patients in any group were hyponatremia, diarrhea, palmar-plantar erythrodysesthesia, hypothyroidism, and fatigue. AEs of any cause leading to discontinuation of the therapy occurred in 19.7% in the nivolumab plus cabzantinib group vs 16.9% of the sunitinib group. One death was considered to be treatment-related (small intestinal perforation) in the nivolumab plus cabozantinib group vs 2 treatment-related deaths with sunitinib (pneumonia and respiratory distress). In the nivolumab plus cabozantinib group, 57% of the patients had a dose reduction of cabozantinib and 52% had a reduction in sunitinib dosage.
Using the Functional Assessment of Cancer Therapy-Kidney Symptoms Index, patients in the nivolumab plus cabozantinib group reported better health-related quality of life and less disease-related symptoms compared to the sunitinib group.
Commentary
The treatment landscape for frontline therapy for patients with advanced RCC has rapidly expanded over the last several years and has revolutionized cancer care. Ushered in by the results from the CheckMate 214 study highlighting the efficacy of dual checkpoint inhibition with nivolumab and ipilimumab in intermediate and poor risk patients, several subsequent trials have demonstrated improved outcomes with combination therapy with immune checkpoint inhibitors and tyrosine-kinase inhibitors (TKI). To date, data from Keynote-426 (pembrolizumab plus axitinib vs sunitinib), Javelin Renal 101 (avelumab plus axitinib vs sunitinib) and the CLEAR trial (lenvatinib plus pembrolizumab vs levatinib plus everolimus vs sunitinib) have demonstrated superiority of immune checkpoint inhibitor/TKI combinations over sunitinb in the first-line setting.1-5
The current phase 3, CheckMate 9ER trial adds yet another dynamic option for patients with advanced clear cell RCC. While cross-trial comparisons are fraught with important caveats, the median PFS of almost 16.6 months and complete response rate of 8% the nivolumab plus cabozantinib group compares favorably with other combinations. Data from the CLEAR study with the combination of lenvatinib and pembrolizumab showed a complete response rate approaching 16%. Importantly, the current study highlights improved quality of life with the combination of cabozantinib and nivolumab compared to sunitinib alone adding to the efficacy and benefits of this combination treatment.
The selection of first line therapy for patients with advanced RCC should be always guided by individual patient characteristics, and any single immune checkpoint inhibitor/TKI combination is not “superior” to any other. Perhaps more importantly is developing an understanding of the overlapping toxicity profiles of checkpoint inhibitors and TKIs. Again, this trial results are consistent with prior studies in terms of the adverse event profile which were not trivial, and almost all patients (99%) experienced AEs. It is important for oncologists to understand the management of the toxicities with these combinations and dose reductions as appropriate. It is worth noting that 19% of patients with nivolumab plus cabozantinib received glucocorticoids for management of immune-related AEs.
While long-term follow-up data will be needed to further understand the durability of response to this combination, nivolumab-cabozantinib represents an exciting new option for patients with advanced clear cell RCC. As we continue to see improvement in outcomes in clear cell histology, further work must focus on optimization of therapy in non-clear cell RCC as this is a population that is not represented in these data sets. Furthermore, future efforts should begin to explore triplet combinations and biomarker driven patient selection for upfront therapy in ordercontinue to improve outcomes in patients with advanced RCC.
Applications for Clinical Practice
The combination of nivolumab plus cabozantinib adds to the growing list of highly active checkpoint inhibitor/TKI combinations for first-line treatment of advanced RCC. With significant higher response rates, improved outcomes, and improvement in the quality of life, this combination will add another standard treatment option for patients with previously untreated advanced RCC.
Study Overview
Objective. To evaluate the efficacy and safety of the combination of nivolumab plus cabozantinib as compared with sunitinib monotherapy in the treatment of previously untreated advanced renal cell carcinoma (RCC).
Design. Multicenter, international, open-label, randomized, phase 3 trial.
Intervention. Patients were randomized in a 1:1 fashion to 1 of 2 treatment arms:
- Arm A: Nivolumab intravenously 240 mg every 2 weeks plus cabozantinib orally 40 mg once daily.
- Arm B: Sunitinib orally 50 mg daily for 4 weeks, followed by 2 weeks off therapy (6-week cycle).
Randomization was stratified by the International Metastatic RCC Database Consortium prognostic risk score (low-, intermediate-, and high-risk). Treatment was continued until disease progression or development of unacceptable toxic side effects with a maximum of 2-year duration of Nivolumab therapy.
Settings and participants. Adults with previously untreated advanced RCC with a clear cell component were eligible for enrollment. Subjects were excluded if they had active central nervous system metastases or active autoimmune disease.
Main outcome measures. The primary outcome of this study was progression-free survival (PFS) as assessed by an independent review committee. Secondary endpoints included overall survival, objective response rate, safety, and PFS as assessed by investigators. All subgroup analyses were prespecified. Efficacy was assessed in the intention-to-treat population, including all patients who underwent randomization.
Main results. A total of 651 patients underwent randomization: 323 to the nivolumab plus cabozantinib group, and 328 to the sunitinib group. Baseline demographics were balanced. The median follow-up period for overall survival (OS) was 18.1 months. The primary reason for treatment discontinuation in any group was disease progression. PFS as indicated by an independent review committee was significantly longer in the nivolumab plus cabozantinib group compared to the sunitinib group (median 16.6 months vs 8.2 months; hazard ratio [HR] 0.51, P < .001). The median OS was not reached for any group. Overall survival was longer in the nivolumab plus cabozantinib group compared to the sunitinib group (HR 0.60, 95% CI: 0.40-0.89; P = .001). The objective response rate was 55.7% with the nivolumab plus cabozantinib group versus 27.1% with sunitinib (P < .001). The complete response rate was 8% in the nivolumab plus cabozantinib group compared to 4.6% in the sunitinib group. The median time to response was 2.8 months with nivolumab plus cabozantinib and 4.2 months in the sunitinib group, while the median duration of response was 20.2 months and 11.5 months, respectively.
Nearly all patients (about 99% in each group) had an adverse event (AE). Hypertension was the most common side effect, with grade 3 or higher seen in 12.5% in the nivolumab plus cabzantinib group and 13.1% in the sunitinib group. Other grade 3 or higher side effects occurring in at least 10% of patients in any group were hyponatremia, diarrhea, palmar-plantar erythrodysesthesia, hypothyroidism, and fatigue. AEs of any cause leading to discontinuation of the therapy occurred in 19.7% in the nivolumab plus cabzantinib group vs 16.9% of the sunitinib group. One death was considered to be treatment-related (small intestinal perforation) in the nivolumab plus cabozantinib group vs 2 treatment-related deaths with sunitinib (pneumonia and respiratory distress). In the nivolumab plus cabozantinib group, 57% of the patients had a dose reduction of cabozantinib and 52% had a reduction in sunitinib dosage.
Using the Functional Assessment of Cancer Therapy-Kidney Symptoms Index, patients in the nivolumab plus cabozantinib group reported better health-related quality of life and less disease-related symptoms compared to the sunitinib group.
Commentary
The treatment landscape for frontline therapy for patients with advanced RCC has rapidly expanded over the last several years and has revolutionized cancer care. Ushered in by the results from the CheckMate 214 study highlighting the efficacy of dual checkpoint inhibition with nivolumab and ipilimumab in intermediate and poor risk patients, several subsequent trials have demonstrated improved outcomes with combination therapy with immune checkpoint inhibitors and tyrosine-kinase inhibitors (TKI). To date, data from Keynote-426 (pembrolizumab plus axitinib vs sunitinib), Javelin Renal 101 (avelumab plus axitinib vs sunitinib) and the CLEAR trial (lenvatinib plus pembrolizumab vs levatinib plus everolimus vs sunitinib) have demonstrated superiority of immune checkpoint inhibitor/TKI combinations over sunitinb in the first-line setting.1-5
The current phase 3, CheckMate 9ER trial adds yet another dynamic option for patients with advanced clear cell RCC. While cross-trial comparisons are fraught with important caveats, the median PFS of almost 16.6 months and complete response rate of 8% the nivolumab plus cabozantinib group compares favorably with other combinations. Data from the CLEAR study with the combination of lenvatinib and pembrolizumab showed a complete response rate approaching 16%. Importantly, the current study highlights improved quality of life with the combination of cabozantinib and nivolumab compared to sunitinib alone adding to the efficacy and benefits of this combination treatment.
The selection of first line therapy for patients with advanced RCC should be always guided by individual patient characteristics, and any single immune checkpoint inhibitor/TKI combination is not “superior” to any other. Perhaps more importantly is developing an understanding of the overlapping toxicity profiles of checkpoint inhibitors and TKIs. Again, this trial results are consistent with prior studies in terms of the adverse event profile which were not trivial, and almost all patients (99%) experienced AEs. It is important for oncologists to understand the management of the toxicities with these combinations and dose reductions as appropriate. It is worth noting that 19% of patients with nivolumab plus cabozantinib received glucocorticoids for management of immune-related AEs.
While long-term follow-up data will be needed to further understand the durability of response to this combination, nivolumab-cabozantinib represents an exciting new option for patients with advanced clear cell RCC. As we continue to see improvement in outcomes in clear cell histology, further work must focus on optimization of therapy in non-clear cell RCC as this is a population that is not represented in these data sets. Furthermore, future efforts should begin to explore triplet combinations and biomarker driven patient selection for upfront therapy in ordercontinue to improve outcomes in patients with advanced RCC.
Applications for Clinical Practice
The combination of nivolumab plus cabozantinib adds to the growing list of highly active checkpoint inhibitor/TKI combinations for first-line treatment of advanced RCC. With significant higher response rates, improved outcomes, and improvement in the quality of life, this combination will add another standard treatment option for patients with previously untreated advanced RCC.
1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab Versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14)1277-1290. doi:10.1056/NEJMoa1712126
2. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714
3. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8
4. Choueiri TK, Motzer RJ, Rini BI, et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020;31:1030-1039. doi:10.1016/j.annonc.2020.04.010
5, Motzer R, Alekseev B, Rha SY, et al. CLEAR Trial Investigators. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716
1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab Versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14)1277-1290. doi:10.1056/NEJMoa1712126
2. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714
3. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8
4. Choueiri TK, Motzer RJ, Rini BI, et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020;31:1030-1039. doi:10.1016/j.annonc.2020.04.010
5, Motzer R, Alekseev B, Rha SY, et al. CLEAR Trial Investigators. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716
I Never Wanted To Be a Hero
I have been in the business of medicine for more than 15 years and I will never forget the initial surge of the COVID-19 pandemic in Massachusetts.
As a hospitalist, I admitted patients infected with COVID-19, followed them on the floor, and, since I had some experience working in an intensive care unit (ICU), was assigned to cover a “COVID ICU.” This wing of the hospital used to be a fancy orthopedic floor that our institution was lucky enough to have. So began the most life-changing experience in my career as a physician.
In this role, we witness death more than any of us would care to discuss. It comes with the territory, and we never expected this to change once COVID hit. However, so many patients succumbed to this disease, especially during the first surge, which made it difficult to handle emotionally. Patients that fell ill initially stayed isolated at home, optimistic they would turn the corner only to enter the hospital a week later after their conditioned worsened. After requiring a couple of liters of supplemental oxygen in the emergency room, they eventually ended up on a high flow nasal cannula in just a matter of hours.
Patients slowly got sicker and felt more helpless as the days passed, leading us to prescribe drugs that eventually proved to have no benefit. We checked countless inflammatory markers, most of which we were not even sure what to do with. Many times, we hosted a family meeting via FaceTime, holding a patient’s hand in one hand and an iPad in the other to discuss goals of care. Too often, a dark cloud hung over these discussions, a realization that there was not much else we could do.
I have always felt that helping someone have a decent and peaceful death is important, especially when the prognosis is grim, and that patient is suffering. But the sheer number of times this happened during the initial surge of the pandemic was difficult to handle. It felt like I had more of those discussions in 3 months than I did during my entire career as a hospitalist.
We helped plenty of people get better, with some heading home in a week. They thanked us, painted rocks and the sidewalks in front of the hospital displaying messages of gratitude, and sent lunches. Others, though, left the hospital 2 months later with a tube in their stomach so they could receive some form of nutrition and another in their neck to help them breathe.
These struggles were by no means special to me; other hospitalists around the world faced similar situations at one point or another during the pandemic. Working overtime, coming home late, exhausted, undressing in the garage, trying to be there for my 3 kids who were full of energy after a whole day of Zoom and doing the usual kid stuff. My house used to have strict rules about screen time. No more.
The summer months provided a bit of a COVID break, with only 1 or 2 infected patients entering my care. We went to outdoor restaurants and tried to get our lives back to “normal.” As the weather turned cold, however, things went south again. This time no more hydroxychloroquine, a drug used to fight malaria but also treat other autoimmune diseases, as it was proven eventually over many studies that it is not helpful and was potentially harmful. We instead shifted our focus to remdesivir—an antiviral drug that displayed some benefits—tocilizumab, and dexamethasone, anti-inflammatory drugs with the latter providing some positive outcomes on mortality.
Patient survival rates improved slightly, likely due to a combination of factors. We were more experienced at fighting the disease, which led to things in the hospital not being as chaotic and more time available to spend with the patients. Personal protective equipment (PPE) and tests were more readily available, and the population getting hit by the disease changed slightly with fewer elderly people from nursing homes falling ill because of social distancing, other safety measures, or having already fought the disease. Our attention turned instead to more young people that had returned to work and their social lives.
The arrival of the vaccines brought considerable relief. I remember a few decades ago debating and sometimes fighting with friends and family over who was better: Iron Man or Spider-Man. Now I found myself having the same conversation about the Pfizer and Moderna COVID vaccines.
Summer 2021 holds significantly more promise. Most of the adult population is getting vaccinated, and I am very hopeful that we are approaching the end of this nightmare. In June, our office received word that we could remove our masks if we were fully vaccinated. It felt weird, but represented another sign that things are improving. I took my kids to the mall and removed my mask. It felt odd considering how that little blue thing became part of me during the pandemic. It also felt strange to not prescribe a single dose of remdesivir for an entire month.
It feels good—and normal—to care for the patients that we neglected for a year. It has been a needed boost to see patients return to their health care providers for their colonoscopy screenings, mammograms, and managing chronic problems like coronary artery disease, congestive heart failure, or receiving chemotherapy.
I learned plenty from this pandemic and hope I am not alone. I learned to be humble. We started with a drug that was harmful, moved on to a drug that is probably neutral and eventually were able to come up with a drug that seems to decrease mortality at least in some COVID patients. I learned it is fine to try new therapies based on the best data in the hope they result in positive clinical outcomes. However, it is critical that we all keep an eye on the rapidly evolving literature and adjust our behavior accordingly.
I also learned, or relearned, that if people are desperate enough, they will drink bleach to see if it works. Others are convinced that the purpose of vaccination is to inject a microchip allowing ourselves to be tracked by some higher power. I learned that we must take the first step to prepare for the next pandemic by having a decent reserve of PPE.
It is clear synthetic messenger RNA (mRNA) technology is here to stay, and I believe it has a huge potential to change many areas of medicine. mRNA vaccines proved to be much faster to develop and probably much easier to change as the pathogen, in this case coronavirus, changes.
The technology could be used against a variety of infectious diseases to make vaccines against malaria, tuberculosis, HIV, or hepatitis. It can also be very useful for faster vaccine development needed in future possible pandemics such as influenza, Ebola, or severe acute respiratory syndrome. It may also be used for cancer treatment.
As John P. Cooke, MD, PhD, the medical director for the Center of RNA Therapeutics Program at the Houston Methodist Research Institute, said, “Most vaccines today are still viral vaccines – they are inactivated virus, so it’s potentially infectious and you have to have virus on hand. With mRNA, you’re just writing code which is going to tell the cell to make a viral protein – one part of a viral protein to stimulate an immune response. And, here’s the wonderful thing, you don’t even need the virus in hand, just its DNA code.”1
Corresponding author: Dragos Vesbianu, MD, Attending Hospitalist, Newton-Wellesley Hospital, 2014 Washington St, Newton, MA 02462; dragosv@yahoo.com.
Financial dislosures: None.
1. Houston Methodist. Messenger RNA – the Therapy of the Future. Newswise. November 16, 2020. Accessed June 25, 2021. https://www.newswise.com/coronavirus/messenger-rna-the-therapy-of-the-future/
I have been in the business of medicine for more than 15 years and I will never forget the initial surge of the COVID-19 pandemic in Massachusetts.
As a hospitalist, I admitted patients infected with COVID-19, followed them on the floor, and, since I had some experience working in an intensive care unit (ICU), was assigned to cover a “COVID ICU.” This wing of the hospital used to be a fancy orthopedic floor that our institution was lucky enough to have. So began the most life-changing experience in my career as a physician.
In this role, we witness death more than any of us would care to discuss. It comes with the territory, and we never expected this to change once COVID hit. However, so many patients succumbed to this disease, especially during the first surge, which made it difficult to handle emotionally. Patients that fell ill initially stayed isolated at home, optimistic they would turn the corner only to enter the hospital a week later after their conditioned worsened. After requiring a couple of liters of supplemental oxygen in the emergency room, they eventually ended up on a high flow nasal cannula in just a matter of hours.
Patients slowly got sicker and felt more helpless as the days passed, leading us to prescribe drugs that eventually proved to have no benefit. We checked countless inflammatory markers, most of which we were not even sure what to do with. Many times, we hosted a family meeting via FaceTime, holding a patient’s hand in one hand and an iPad in the other to discuss goals of care. Too often, a dark cloud hung over these discussions, a realization that there was not much else we could do.
I have always felt that helping someone have a decent and peaceful death is important, especially when the prognosis is grim, and that patient is suffering. But the sheer number of times this happened during the initial surge of the pandemic was difficult to handle. It felt like I had more of those discussions in 3 months than I did during my entire career as a hospitalist.
We helped plenty of people get better, with some heading home in a week. They thanked us, painted rocks and the sidewalks in front of the hospital displaying messages of gratitude, and sent lunches. Others, though, left the hospital 2 months later with a tube in their stomach so they could receive some form of nutrition and another in their neck to help them breathe.
These struggles were by no means special to me; other hospitalists around the world faced similar situations at one point or another during the pandemic. Working overtime, coming home late, exhausted, undressing in the garage, trying to be there for my 3 kids who were full of energy after a whole day of Zoom and doing the usual kid stuff. My house used to have strict rules about screen time. No more.
The summer months provided a bit of a COVID break, with only 1 or 2 infected patients entering my care. We went to outdoor restaurants and tried to get our lives back to “normal.” As the weather turned cold, however, things went south again. This time no more hydroxychloroquine, a drug used to fight malaria but also treat other autoimmune diseases, as it was proven eventually over many studies that it is not helpful and was potentially harmful. We instead shifted our focus to remdesivir—an antiviral drug that displayed some benefits—tocilizumab, and dexamethasone, anti-inflammatory drugs with the latter providing some positive outcomes on mortality.
Patient survival rates improved slightly, likely due to a combination of factors. We were more experienced at fighting the disease, which led to things in the hospital not being as chaotic and more time available to spend with the patients. Personal protective equipment (PPE) and tests were more readily available, and the population getting hit by the disease changed slightly with fewer elderly people from nursing homes falling ill because of social distancing, other safety measures, or having already fought the disease. Our attention turned instead to more young people that had returned to work and their social lives.
The arrival of the vaccines brought considerable relief. I remember a few decades ago debating and sometimes fighting with friends and family over who was better: Iron Man or Spider-Man. Now I found myself having the same conversation about the Pfizer and Moderna COVID vaccines.
Summer 2021 holds significantly more promise. Most of the adult population is getting vaccinated, and I am very hopeful that we are approaching the end of this nightmare. In June, our office received word that we could remove our masks if we were fully vaccinated. It felt weird, but represented another sign that things are improving. I took my kids to the mall and removed my mask. It felt odd considering how that little blue thing became part of me during the pandemic. It also felt strange to not prescribe a single dose of remdesivir for an entire month.
It feels good—and normal—to care for the patients that we neglected for a year. It has been a needed boost to see patients return to their health care providers for their colonoscopy screenings, mammograms, and managing chronic problems like coronary artery disease, congestive heart failure, or receiving chemotherapy.
I learned plenty from this pandemic and hope I am not alone. I learned to be humble. We started with a drug that was harmful, moved on to a drug that is probably neutral and eventually were able to come up with a drug that seems to decrease mortality at least in some COVID patients. I learned it is fine to try new therapies based on the best data in the hope they result in positive clinical outcomes. However, it is critical that we all keep an eye on the rapidly evolving literature and adjust our behavior accordingly.
I also learned, or relearned, that if people are desperate enough, they will drink bleach to see if it works. Others are convinced that the purpose of vaccination is to inject a microchip allowing ourselves to be tracked by some higher power. I learned that we must take the first step to prepare for the next pandemic by having a decent reserve of PPE.
It is clear synthetic messenger RNA (mRNA) technology is here to stay, and I believe it has a huge potential to change many areas of medicine. mRNA vaccines proved to be much faster to develop and probably much easier to change as the pathogen, in this case coronavirus, changes.
The technology could be used against a variety of infectious diseases to make vaccines against malaria, tuberculosis, HIV, or hepatitis. It can also be very useful for faster vaccine development needed in future possible pandemics such as influenza, Ebola, or severe acute respiratory syndrome. It may also be used for cancer treatment.
As John P. Cooke, MD, PhD, the medical director for the Center of RNA Therapeutics Program at the Houston Methodist Research Institute, said, “Most vaccines today are still viral vaccines – they are inactivated virus, so it’s potentially infectious and you have to have virus on hand. With mRNA, you’re just writing code which is going to tell the cell to make a viral protein – one part of a viral protein to stimulate an immune response. And, here’s the wonderful thing, you don’t even need the virus in hand, just its DNA code.”1
Corresponding author: Dragos Vesbianu, MD, Attending Hospitalist, Newton-Wellesley Hospital, 2014 Washington St, Newton, MA 02462; dragosv@yahoo.com.
Financial dislosures: None.
I have been in the business of medicine for more than 15 years and I will never forget the initial surge of the COVID-19 pandemic in Massachusetts.
As a hospitalist, I admitted patients infected with COVID-19, followed them on the floor, and, since I had some experience working in an intensive care unit (ICU), was assigned to cover a “COVID ICU.” This wing of the hospital used to be a fancy orthopedic floor that our institution was lucky enough to have. So began the most life-changing experience in my career as a physician.
In this role, we witness death more than any of us would care to discuss. It comes with the territory, and we never expected this to change once COVID hit. However, so many patients succumbed to this disease, especially during the first surge, which made it difficult to handle emotionally. Patients that fell ill initially stayed isolated at home, optimistic they would turn the corner only to enter the hospital a week later after their conditioned worsened. After requiring a couple of liters of supplemental oxygen in the emergency room, they eventually ended up on a high flow nasal cannula in just a matter of hours.
Patients slowly got sicker and felt more helpless as the days passed, leading us to prescribe drugs that eventually proved to have no benefit. We checked countless inflammatory markers, most of which we were not even sure what to do with. Many times, we hosted a family meeting via FaceTime, holding a patient’s hand in one hand and an iPad in the other to discuss goals of care. Too often, a dark cloud hung over these discussions, a realization that there was not much else we could do.
I have always felt that helping someone have a decent and peaceful death is important, especially when the prognosis is grim, and that patient is suffering. But the sheer number of times this happened during the initial surge of the pandemic was difficult to handle. It felt like I had more of those discussions in 3 months than I did during my entire career as a hospitalist.
We helped plenty of people get better, with some heading home in a week. They thanked us, painted rocks and the sidewalks in front of the hospital displaying messages of gratitude, and sent lunches. Others, though, left the hospital 2 months later with a tube in their stomach so they could receive some form of nutrition and another in their neck to help them breathe.
These struggles were by no means special to me; other hospitalists around the world faced similar situations at one point or another during the pandemic. Working overtime, coming home late, exhausted, undressing in the garage, trying to be there for my 3 kids who were full of energy after a whole day of Zoom and doing the usual kid stuff. My house used to have strict rules about screen time. No more.
The summer months provided a bit of a COVID break, with only 1 or 2 infected patients entering my care. We went to outdoor restaurants and tried to get our lives back to “normal.” As the weather turned cold, however, things went south again. This time no more hydroxychloroquine, a drug used to fight malaria but also treat other autoimmune diseases, as it was proven eventually over many studies that it is not helpful and was potentially harmful. We instead shifted our focus to remdesivir—an antiviral drug that displayed some benefits—tocilizumab, and dexamethasone, anti-inflammatory drugs with the latter providing some positive outcomes on mortality.
Patient survival rates improved slightly, likely due to a combination of factors. We were more experienced at fighting the disease, which led to things in the hospital not being as chaotic and more time available to spend with the patients. Personal protective equipment (PPE) and tests were more readily available, and the population getting hit by the disease changed slightly with fewer elderly people from nursing homes falling ill because of social distancing, other safety measures, or having already fought the disease. Our attention turned instead to more young people that had returned to work and their social lives.
The arrival of the vaccines brought considerable relief. I remember a few decades ago debating and sometimes fighting with friends and family over who was better: Iron Man or Spider-Man. Now I found myself having the same conversation about the Pfizer and Moderna COVID vaccines.
Summer 2021 holds significantly more promise. Most of the adult population is getting vaccinated, and I am very hopeful that we are approaching the end of this nightmare. In June, our office received word that we could remove our masks if we were fully vaccinated. It felt weird, but represented another sign that things are improving. I took my kids to the mall and removed my mask. It felt odd considering how that little blue thing became part of me during the pandemic. It also felt strange to not prescribe a single dose of remdesivir for an entire month.
It feels good—and normal—to care for the patients that we neglected for a year. It has been a needed boost to see patients return to their health care providers for their colonoscopy screenings, mammograms, and managing chronic problems like coronary artery disease, congestive heart failure, or receiving chemotherapy.
I learned plenty from this pandemic and hope I am not alone. I learned to be humble. We started with a drug that was harmful, moved on to a drug that is probably neutral and eventually were able to come up with a drug that seems to decrease mortality at least in some COVID patients. I learned it is fine to try new therapies based on the best data in the hope they result in positive clinical outcomes. However, it is critical that we all keep an eye on the rapidly evolving literature and adjust our behavior accordingly.
I also learned, or relearned, that if people are desperate enough, they will drink bleach to see if it works. Others are convinced that the purpose of vaccination is to inject a microchip allowing ourselves to be tracked by some higher power. I learned that we must take the first step to prepare for the next pandemic by having a decent reserve of PPE.
It is clear synthetic messenger RNA (mRNA) technology is here to stay, and I believe it has a huge potential to change many areas of medicine. mRNA vaccines proved to be much faster to develop and probably much easier to change as the pathogen, in this case coronavirus, changes.
The technology could be used against a variety of infectious diseases to make vaccines against malaria, tuberculosis, HIV, or hepatitis. It can also be very useful for faster vaccine development needed in future possible pandemics such as influenza, Ebola, or severe acute respiratory syndrome. It may also be used for cancer treatment.
As John P. Cooke, MD, PhD, the medical director for the Center of RNA Therapeutics Program at the Houston Methodist Research Institute, said, “Most vaccines today are still viral vaccines – they are inactivated virus, so it’s potentially infectious and you have to have virus on hand. With mRNA, you’re just writing code which is going to tell the cell to make a viral protein – one part of a viral protein to stimulate an immune response. And, here’s the wonderful thing, you don’t even need the virus in hand, just its DNA code.”1
Corresponding author: Dragos Vesbianu, MD, Attending Hospitalist, Newton-Wellesley Hospital, 2014 Washington St, Newton, MA 02462; dragosv@yahoo.com.
Financial dislosures: None.
1. Houston Methodist. Messenger RNA – the Therapy of the Future. Newswise. November 16, 2020. Accessed June 25, 2021. https://www.newswise.com/coronavirus/messenger-rna-the-therapy-of-the-future/
1. Houston Methodist. Messenger RNA – the Therapy of the Future. Newswise. November 16, 2020. Accessed June 25, 2021. https://www.newswise.com/coronavirus/messenger-rna-the-therapy-of-the-future/
Impact of Diagnostic Testing on Pediatric Patients With Pharyngitis: Evidence From a Large Health Plan
From the Department of Pharmaceutical and Health Economics, University of Southern California, Los Angeles, CA, (Drs. Sangha and McCombs), Department of Pediatrics, Keck School of Medicine, and Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, (Dr. Steinberg), and Leonard Schaeffer Center for Health Policy and Economics, University of Southern California, Los Angeles, CA (Dr. McCombs).
Objective: The recommended treatment for children and adolescents under 18 years of age who have a positive test for group A Streptococcus (GAS) are antibiotics using the “test and treat” strategy to detect and treat GAS for pediatric pharyngitis. This study used paid claims data to document the extent to which real-world treatment patterns are consistent with these recommendations. We document the factors correlated with testing and treatment, then examine the effects of receiving a GAS test and being treated with an antibiotic impact the likelihood of a revisit for an acute respiratory tract infection within 28 days.
Methods: This retrospective cohort study used Optum Insight Clinformatics data for medical and pharmacy claims from 2011-2013 to identify episodes of care for children and adolescents with pharyngitis around their index visit (± 6 months). The sample population included children and adolescents under 18 years of age with a diagnosis of pharyngitis. Multivariable logistic regression analyses were used to document factors associated with receipt of GAS test and antibiotic treatment. Next, we used logistic regression models to estimate the impact of test and treat recommendation on revisit risk.
Results: There were 24 685 treatment episodes for children and adolescents diagnosed with pharyngitis. Nearly 47% of these episodes included a GAS test and 48% of tested patients were prescribed an antibiotic prescription. Failing to perform a GAS test increased the risk of a revisit within 28 days by 44%. The use of antibiotics by tested and untested patients had no impact on revisit risk.
Conclusion: While the judicious use of antibiotics is important in managing pharyngitis infections and managing complications, the use of rapid diagnostic tools was found to be the determining factor in reducing revisits for pediatric patients with pharyngitis.
Keywords: pediatrics; pharyngitis; respiratory infections; acute infections; diagnostic tests; group A Streptococcus; antibiotics; revisits.
Acute pharyngitis is a common acute respiratory tract infection (ARTI) in children. Group A β-hemolytic streptococci (GABHS) is the most common bacterial etiology for pediatric pharyngitis, accounting for 15% to 30% of cases.1
Beyond clinical assessment, laboratory diagnostic testing generally plays a limited role in guiding appropriate antibiotic prescribing for patients with an ARTI.2,3 Most diagnostic tests require 2 or 3 days to result, incur additional costs, and may delay treatment.4 While these tests do not provide clear and timely guidance on which specific antibiotic is appropriate for ARTI patients, this is not the case for patients with pharyngitis.5,6,7 A rapid diagnostic test exists to identify pharyngitis patients with GABHS which accounts for 1 in 4 children with acute sore throat.1,4,6 Both the American Academy of Pediatrics and the Infectious Diseases Society of America recommend antibiotic treatment for children and adolescents under 18 years of age who have a positive test for group A Streptococcus (GAS).8,9 This “test and treat” protocol has been consistently included in the Healthcare Effectiveness Data and Information Set (HEDIS) standards over time for pediatric pharyngitis patients aged 3 to 18 years before dispensing an antibiotic.10
Sinusitis, pneumonia, and acute otitis media are considered ARTIs where antibiotic treatment is justified. Therefore, pharyngitis of unclear etiology seen with these comorbid infections may not always undergo GAS testing but move directly to the patient being prescribed antibiotics. This analysis enumerates ARTI-related comorbidities present together with the initial coded pharyngitis diagnosis to evaluate their impact on the provider’s decision to test and treat, and on revisit risk.
Antibiotic treatment for GAS patients is likely to eradicate the acute GABHS infection within 10 days. Penicillin and amoxicillin are commonly recommended because of their narrow spectrum of activity, few adverse effects, established efficacy, and modest cost. Alternative antibiotics for patients with penicillin allergy, or with polymicrobial infection seen on culture results, include a first-generation cephalosporin, clindamycin, clarithromycin (Biaxin), or azithromycin (Zithromax).1,8,11 However, while compliance with these HEDIS guidelines has been evaluated, the outcome effects of following the HEDIS “test and treat” recommendations for children with pharyngitis have not been adequately evaluated.
These outcome evaluations have increasing importance as the latest HEDIS survey has shown testing rates in commercial Preferred Provider Organizations (PPO) falling from 86.4% in 2018 to 75.9% in 2019, the lowest rate of testing since 2009, with similar reductions under 80% for Health Maintenance Organizations (HMO).10 While health plans may execute cost-benefit analyses and algorithms to forge best practices for GAS testing in children and adolescents presenting with symptoms of pharyngitis, it is important to regard the wasteful resource utilization and additional cost of revisits that may offset any gains accrued by more focused GAS testing outside the existing clinical guidelines and HEDIS measures. This may be of particular importance in documenting infection and sparing antibiotic therapy in toddlers and younger.
The objective of this study was to investigate the correlation between testing and antibiotic use on the likelihood of a revisit for an acute respiratory tract infection within 28 days. To achieve this objective, this investigation consists of 3 sequential analyses. First, we document the factors associated with the decision to test the patient for a GABHS infection using the GAS test. Next, we document the factors associated with the decision to use an antibiotic to treat the patient as a function of having tested the patient. Finally, we investigate the impact of the testing and treatment decisions on the likelihood of a revisit within 28 days.
Methods
Study design
This was a retrospective cohort study of episodes of treatment for pediatric patients with pharyngitis. Episodes were identified using data derived from the Optum Insight Clinformatics claims database provided to the University of Southern California to facilitate the training of graduate students. These data cover commercially insured patients with both medical and pharmacy benefits. Data were retrieved from the 3-year period spanning 2011-2013. An episode of care was identified based on date of the first (index) outpatient visit for a pharyngitis diagnosis (International Classification of Diseases, Ninth Revision [ICD-9]: 462, 463, 034.0). Outpatient visits were defined by visit setting: ambulatory clinics, physician offices, emergency rooms, and urgent care facilities. Each pharyngitis treatment episode was then screened for at least a 6-month enrollment in a health insurance plan prior and subsequent to the index visit using Optum enrollment data. Finally, eligible treatment episodes were restricted to children and adolescents under 18 years of age, who had an index outpatient visit for a primary diagnosis of acute pharyngitis.
A diagnostic profile was created for each episode using the diagnoses recorded for the index visit. Up to 3 diagnoses may be recorded for any outpatient visit and the first recorded diagnosis was assumed to be the primary diagnosis for that episode. Any secondary diagnoses recorded on the index visit were used to define comorbidities present at the index visit. ARTI-related comorbidities included: acute otitis media (AOM), bronchitis, sinusitis, pneumonia, and upper respiratory infection (URI). Other comorbid medical diagnoses were documented using diagnostic data from the pre-index period. Dichotomous variables for the following categories were created: mental disorders, nervous system disorders, respiratory symptoms, fever, injury and poisoning, other, or no diseases.
Prior visits for other respiratory infections in the previous 90 days were also identified for patients based on their index visit for pharyngitis. Similarly, any subsequent visits, within 28 days of the index visit, were also recorded to measure the health outcome for analysis. Practice settings include physician offices and federally qualified health centers, state and local health clinics, outpatient hospitals facilities, emergency departments, and other outpatient settings such as walk-in retail health clinic or ambulatory centers. Providers include primary care physicians (family practice, pediatricians, internal medicine), specialty care physicians (emergency medicine, preventive medicine), nonphysician providers (nurse practitioners, physician assistants) and other providers (urgent care, acute outpatient care, ambulatory care centers). Seasons of the year were determined based on the index date of the episode to account for possible seasonality in pharyngitis treatment. Lastly, a previous visits variable was created to identify whether the child had nonpharyngitis ARTI visits in the 3 months prior to the index visit.
Demographic variables were created based on enrollment and the socioeconomic data available in the Optum socioeconomic status file. These variables include patient age, race, sex, household income, geographic location, practice setting type, provider specialty, and type of insurance. An estimate of patient household income was based on algorithms using census block groups. Income categories were informed by the federal guidelines for a family of 4. A low-income family was defined as earning less than $50 000; a middle-income family earned between $50 000 and $75 000, and a high-income family earned $75 000 and above.12 Patient insurance type was categorized as HMO, Exclusive Provider Organization (EPO), Point of Service (POS), and PPO. Race was identified as White, Black, Hispanic, and Asian. Patient location was defined according to national census regions.
Outcomes
GAS test
The HEDIS measures for pharyngitis recommend using the GAS test to identify the bacterial etiology of the pharyngitis infection. Patients who received the test were identified based on Current Procedural Terminology (CPT) codes 87070-71, 87081, 87430, 87650-52, and 87880.10
Antibiotic treatment
The pharmacy administrative claims dataset was used to identify study patients who filled a prescription for an antibiotic during their pharyngitis treatment episode. Optum pharmacy data identify the medications received, specifies the date of prescription filling, National Drug Codes, and American Hospital Formulary Service (AHFS) Classification System codes for each medication. We used the AHFS Pharmacologic-Therapeutic classification of antibiotics to create dichotomous variables documenting the antibacterial used by each patient.13 These are categorized under antibacterial including penicillins, cephalosporins (first, second, third, fourth generation cephalosporins), macrolides (first generation and others), tetracyclines, sulfonamides, fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin), cephamycin, carbapenems, and β-lactam antibiotics (amoxicillin, amoxicillin/clavulanate, cephalexin, cefuroxime, cefdinir).
Revisits to physician or other provider
Revisits within 28 days were used as the measure of patient outcomes related to testing and filling of an antibiotic prescription for acute pharyngitis. Revisits may also be due to a patient returning for a follow-up, alternative treatment, worsening pharyngitis, or for another ARTI. An ARTI-related revisit also increases total resources used to treat pediatric pharyngitis patients.
Statistical analysis
Logistic regression was used for all 3 analyses conducted in this study. First, we determined the patient and treating physician characteristics that impact the decision to use GAS testing for pharyngitis. Second, we identified those factors that impact the decision to use antibiotic prescriptions among children who were diagnosed with pharyngitis adding in the dichotomous variable indicating if the patient had received a GAS test. Third, we used a logit regression analysis to document if receiving a GAS test and/or an antibiotic impacted the likelihood of a revisit by comparing revisit risk. To estimate the effect of testing and/or antibiotic use, we divided patients into 4 groups based on whether the patient received a GAS test and/or an antibiotic prescription. This specification of the analysis of revisits as an outcome focuses on adherence to HEDIS “test and treat” guidelines10:
- Patients who were not tested yet filled an antibiotic prescription. This decision was likely based on the clinician’s judgment of the patient’s signs and symptoms, and confirmational testing not performed.
- Patients who were not tested and did not fill an antibiotic prescription. Apparently, in the clinician’s judgment the patient’s signs and symptoms were such that the infection did not warrant treatment and the clinical presentation did not necessitate the GAS test to confirm the recorded diagnosis of pharyngitis.
- Patients who were tested and received antibiotic prescription, likely because the test was positive for GABHS.
- Patients who were tested and did not receive antibiotic prescription.
We tested for statistically significant differences in baseline characteristics across these 4 patient groups using t tests for continuous variables and χ2 tests for categorical variables. Odds ratios (OR) and CI were computed for the influential variables included the regression analyses.
We conducted a sensitivity analysis using a model specification which included the dichotomous variables for testing and for treatment, and the interaction term between these variables to assess if treatment effects varied in tested and untested patients. We also estimated this model of revisit risk using revisits within 7 days as the outcome variable.
All analyses were completed using STATA/IC 13 (StataCorp, College Station, TX).
Results
There were 24 685 treatment episodes for children diagnosed with pharyngitis. Nearly 47% of these episodes included GAS testing and 47% of the tested patients filled an antibiotic prescription. Similarly, 53% of patients were not tested and 49% of untested patients filled an antibiotic prescription. As a result, the 4 groups identified for analysis were evenly distributed: untested and no prescription (26.9%), untested and prescription (26.3%), tested and prescription (21.9%), and tested and no prescription (24.9%) (Figure).
Table 1 presents the descriptive statistics for these 4 patient groups. Note first that the rate of revisits within 28 days is under 5% across all groups. Second, the 2 tested groups have a lower revisit rate than the untested groups: the tested and treated have a revisit rate of 3.3%, and the tested and untreated have a revisit rate of 2.4%, while both the untested groups have a revisit rate of nearly 5%. These small absolute differences in revisit rates across groups were statistically significant.
Factors associated with receiving GAS test
Several factors were found to impact the decision to test (Table 2). Only 9.7% of children were reported to have any ARTI coinfection. As expected, these comorbidities resulted in a significantly lower likelihood of receiving the GAS test: AOM, bronchitis, sinusitis, pneumonia, and URI as comorbid infections had a 48%, 41%, 37%, 63%, and 13% lower likelihood of receiving the GAS test, respectively, than those with no comorbidities. Similarly, children with fever and respiratory symptoms were 35% and 45% less likely to receiving the GAS test, respectively. This is consistent with our expectation that comorbid ARTI infections will lead many providers to forgo testing.
Provider type and patient age also plays a role in receipt of the GAS test. Relative to outpatient facility providers, primary care physicians were 24% more likely and specialty physicians were 38% less likely of employing the GAS test. The child’s age played a significant role in receipt of the GAS test. Children aged 1 to 5 years and 5 to 12 years were 15% and 14% more likely to receive the test compared to children older than 12 years.
Pharyngitis patients have disproportionately higher odds of receiving a GAS test in most regions of the country compared to the Pacific region. For instance, children in the Mid-Atlantic region have 51% higher odds of receiving a GAS test while children in New England have 80% higher odds of receiving the same test.
Black children have 11% lower odds of receiving the GAS test compared to White children. Both middle-income and high-income children have 12% and 32% higher odds of receiving the test compared to low-income children. Compared to office-based visits, children visiting a clinic were twice as likely to receive a GAS test while those seen in the emergency room have 43% lower odds of receiving a GAS test. Hospital outpatient departments, which account for less than 1% of all visits, rarely used a GAS test which could be a statistical artifact due to small sample size. Lastly, insurance and season of the year had no significant impact of receipt of a GAS test.
Factors associated with receiving antibiotic prescription
Surprisingly, receiving the GAS test has a small but insignificant impact on the likelihood that the patient will receive an antibiotic prescription (Table 3) (Adjusted OR = 1.055, P = .07). After controlling for receipt of a GAS test, children with AOM and sinusitis comorbidities have an increased likelihood of being prescribed an antibiotic. Children with URI have a lower likelihood of being prescribed an antibiotic. Additionally, relative to primary care physicians, children visiting nonphysician providers for pharyngitis were more likely to be prescribed an antibiotic.
Children under 12 years of age were more likely to use an antibiotic compared to children 12 years and older. Geographically, there is some evidence of regional variation in antibiotic use as well. Children in the south Atlantic, west-south central, and southeast central regions had a significantly lower odds of being prescribed an antibiotic respectively than pharyngitis patients in the Pacific region. Black children had a 10% lower likelihood of being prescribed an antibiotic compared to White children, possibly related to their lower rate of GAS testing. Compared to office-based visits, children visiting a clinic were less likely to use an antibiotic. Household income, insurance type, and season had no significant impact on revisit risk.
Effects of GAS test and antibiotic prescriptions on likelihood of revisits
The multivariate analysis of the risk of a revisit within 28 days is presented in Table 4. Children with pharyngitis who tested and did not receive an antibiotic serve as the reference comparison group for this analysis to illustrate the impact of using the GAS test and treatment with an antibiotic. The results in Table 4 are quite clear: patients who receive the GAS test were significantly less likely to have a revisit within 28 days. Moreover, within the group of patients who were tested, those not receiving an antibiotic, presumedly because their GAS test was negative, experienced the lowest risk of a revisit. This result is consistent with the data in Table 1. Moreover, using an antibiotic had no impact on the likelihood of a revisit in patients not receiving the GAS test. This result is also consistent with Table 1.
Other results from the analysis of revisit risk may be of interest to clinicians. Pharyngitis patients with a prior episode of treatment within 90 days for an acute respiratory tract infection were more than 7 times more likely to experience a revisit within 28 days of the pharyngitis diagnosis than patients without a history of recent ARTI infections. Age is also a risk factor in likelihood of initiating a revisit. Children under 1 year and children aged 1 to 5 years were more likely to have a revisit than children aged more than 12 years. Compared to White children, Black children were 25% (P = .04) less likely to have a revisit. The care setting also has a significant impact on revisit risk. Children visiting outpatient hospital and other care settings had a significantly higher revisit risk than those visiting a physician’s office. Lastly, household income, geographic region, season, medical comorbidities, gender, and insurance type have no significant impact on revisit risk.
Sensitivity analysis
The results from the analysis of 7-day and 28-day revisit risk are summarized in Table 5. These results indicate that patients who were tested had a more significant decrease in revisit risk at 7 days (72%) than was evident at 28 days (47% reduction). Receiving an antibiotic, with or without the test, had no impact on revisit risk.
Discussion
Published data on revisits for pharyngitis are lacking with the concentration of prior research focused more on systemic complications of undertreated GABHS disease or on identifying carrier status. Our study results suggest that GAS testing is the most important factor in reducing revisit risk. Being prescribed an antibiotic, on its own, does not have a significant impact on the risk of a revisit. However, once the GAS test is used, the decision not to use an antibiotic was correlated with the lowest revisit rate, likely because the source of the pharyngitis infection was viral and more likely to resolve without a revisit. Prior studies have reported variable rates of testing among children with pharyngitis prescribed an antibiotic, ranging from 23% to 91%,14,15 with testing important toward more appropriate antibiotic use.16 More recently, among more than 67 000 patients aged 3 to 21 years presenting with sore throat and receiving a GAS test, 32.6% were positive.17
Our analysis found that more than 46% of pediatric pharyngitis patients were given the rapid GAS test. While this testing rate is substantially lower than HEDIS recommendations and lower than testing rates achieved by several health maintenance organizations,10 it is similar to the 53% of children receiving such testing in a recent National Ambulatory Medical Care Survey.18 Furthermore, we found that when antibiotics are prescribed following a GAS test, the revisit risk is not significantly reduced, possibly because antibiotics lower revisit risk when informed by diagnostic testing tools that determine the infectious organism. This is supported by a similar population analysis in which we observed reduced revisit rates in children with AOM managed with antibiotics within 3 days of index diagnosis.19
Several other factors also affect the likelihood of a child receiving the GAS test. Children aged 1 to 12 years were significantly more likely to receive the GAS test than children over the age of 12. This included children in the 1 to 5 years old bracket who had a 15% higher likelihood of undergoing a GAS test, despite children less than 3 years of age as not recommended targets for GAS testing.20 As expected, children with reported ARTI-associated comorbidities were also less likely to receive a GAS test. Additionally, specialty care physicians were less inclined to implement the GAS test, possibly because of diagnostic confidence without testing or referral after GAS was ruled out. Black and low-income children had statistically lower odds of receiving the test, even after controlling for other factors, and yet were less likely to consume a revisit. As the overall data suggested more revisits in those not tested, further study is needed to examine if race or income discrepancies are equity based. Finally, children in the Pacific region, compared to the rest of the nation, were the least likely to receive a GAS test and yet there were no significant differences in revisit rates by region. Regional differences in antibiotic use were also observed in our study, as has been seen by others.21
After statistically controlling for having received the diagnostic GAS test and filled a prescription for an antibiotic, there are multitude of factors that independently affect the revisit risk, the most important of which if which was a history of an ARTI infection in the prior 90 days. While prior visit history had no impact on the likelihood of being tested or filling an antibiotic, patients with prior visits were more than 7 times more likely to consume a revisit. This was not reflected in nor related to comorbid ARTIs as these patients did not have statistically higher revisits than those with pharyngitis as the sole-coded diagnosis. Moreover, speculation for bacterial etiology of primary or superinfection based on a recent history of ARTI accounting for revisits seems unlikely as it did not yield greater antibiotic use in that group. Further analysis is required to determine the clinical and behavioral factors that promote for prior ARTI history as a major factor in revisit risk after an index visit for pharyngitis.
Children aged between 1 and 5 years, though 15% more likely to be tested than those aged 12 through 17 years, were also 39% more likely to initiate a revisit compared to older children when statistically controlling for other covariates. This perhaps suggests longer illness, wrong diagnosis, delay in appropriate treatment, or more caution by parents and providers in this age group. Justification for testing children less than 3 years of age who are outside of the HEDIS suggested age group, when clinical judgement does not point to another infection source, can result in positivity rates between 22% and 30% as previously observed.22,23 Patients visiting nonphysician providers and outpatient facility providers were less likely to have a revisit than those visiting primary and specialty care physicians, though slightly higher propensity for antibiotic prescriptions was seen for nonphysician providers. Pediatricians have been noted to be less likely to prescribe antibiotics without GAS testing than nonpediatric providers, and more guidelines-compliant in prescribing.24
Recommendations to not test children under 3 years of age are based on the lack of acute rheumatic fever and other complications in this age group together with more frequent viral syndromes. Selectivity in applying clinical criteria to testing can be attempted to separate bacterial from viral illness. Postnasal drainage/rhinorrhea, hoarse voice, and cough have been used successfully to identify those with viral illness and less need for testing, with greater certainty of low risk for GABHS in those over 11 years of age without tonsillar exudates, cervical adenopathy, or fever.17 However, the marginal benefits of those who have all 3 features of viral illness versus none in identifying GAS positivity was 23.3% vs 37.6% - helpful, but certainly not diminishing the need for testing. These constitutional findings of viral URI also do not exclude the GAS carrier state that features these symptoms.25 Others have reinforced the doubt of pharyngeal exudates as the premier diagnostic finding for test-positive GAS.26
This study had several limitations. The Optum claims dataset only contains ICD-9 codes for diagnoses. It does not include data on infection severity and clinical findings related to symptoms, thus empiric treatment warranted based in clinical severity is not assessed. Antibiotics are commonly available as generics and very inexpensive. Patients may fill and pay for these prescriptions directly, in which case, a claim for payment may not be filed with Optum. This could result in an undercount of treated patients in our study.
There is no corresponding problem of missing medical claims for GAS testing which were obtained from the CPT codes within the Optum claims data set. However, we elected not to verify the test results due to these data being missing for 75% of the study population. Nevertheless, this study’s focus was less about justifying antibiotic treatment, but dealt with the outcomes generated by testing and treatment. Toward that end, we used CPT codes to identify a revisit, and while those can at times be affected by financial reimbursement incentives, differences related to revisits in the 4 patient groups should not be subject to bias.
Conclusion
This study used data from real world practices to document the patterns of GAS testing and antibiotic use in pediatric pharyngitis patients. Revisit rates were under 5% for all patient groups and the use of rapid diagnostic tools were found to be the determining factor in further reducing the risk of revisits. This supports the need for compliance with the HEDIS quality metric for pharyngitis to the recommended levels of rapid testing which have been falling in recent years. Use of more accurate antigen and newer molecular detection testing methods may help further delineate important factors in determining pediatric pharyngitis treatment and need for revisits.27
Corresponding author: Jeffrey McCombs, MD, University of Southern California School of Pharmacy, Department of Pharmaceutical and Health Economics, Leonard D. Schaeffer Center for Health Policy & Economics, 635 Downey Way, Verna & Peter Dauterive Hall 310, Los Angeles, CA 90089-3333; jmccombs@usc.edu.
Financial disclosures: None.
1. Choby BA. Diagnosis and treatment of streptococcal pharyngitis. Am Fam Physician. 2009;79(5):383-390.
2. Briel M, Schuetz P, Mueller B, et al. Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract infections in primary care. Arch of Intern Med. 2008;168(18):2000-2008. doi: 10.1001/archinte.168.18.2000
3. Maltezou HC, Tsagris V, Antoniadou A, et al. Evaluation of a rapid antigen detection test in the diagnosis of streptococcal pharyngitis in children and its impact on antibiotic prescription. J Antimicrob Chemother. 2008;62(6):1407-1412. doi: 10.1093/jac/dkn376
4. Neuner JM, Hamel MB, Phillips RS, et al. Diagnosis and management of adults with pharyngitis: a cost-effectiveness analysis. Ann Intern Med. 2003;139(2):113-122. doi:10.7326/0003-4819-139-2-200307150-00011
5. Gerber MA, Baltimore RS, Eaton CB, et al. Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2009;119(11):1541-1551. doi: 10.1161/CIRCULATIONAHA.109.191959
6. Gieseker KE, Roe MH, MacKenzie T, Todd JK. Evaluating the American Academy of Pediatrics diagnostic standard for Streptococcus pyogenes pharyngitis: backup culture versus repeat rapid antigen testing. Pediatrics. 2003;111(6):e666-e670. doi: 10.1542/peds.111.6.e666
7. Shapiro DJ, Lindgren CE, Neuman MI, Fine AM. Viral features and testing for Streptococcal pharyngitis. Pediatrics. 2017;139(5):e20163403. doi: 10.1542/peds.2016-3403
8. Shulman ST, Bisno AL, Clegg H, et al. Clinical practice guideline for the diagnosis and management of group A Streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis. 2012;55(10):e86–e102. doi: 10.1093/cid/cis629
9. Mangione-Smith R, McGlynn EA, Elliott MN, et al. Parent expectations for antibiotics, physician-parent communication, and satisfaction. Arch Pediatr Adolesc Med. 2001;155(7):800–806. doi: 10.1001/archpedi.155.7.800
10. Appropriate Testing for Children with Pharyngitis. HEDIS Measures and Technical Resources. National Committee for Quality Assurance. Accessed February 12, 2021. https://www.ncqa.org/hedis/measures/appropriate-testing-for-children-with-pharyngitis/
11. Linder JA, Bates DW, Lee GM, Finkelstein JA. Antibiotic treatment of children with sore throat. JAMA. 2005;294(18):2315-2322. doi: 10.1001/jama.294.18.2315
12. Crimmel BL. Health Insurance Coverage and Income Levels for the US Noninstitutionalized Population Under Age 65, 2001. Medical Expenditure Panel Survey, Agency for Healthcare Research and Quality. 2004. https://meps.ahrq.gov/data_files/publications/st40/stat40.pd
13. AHFS/ASHP. American Hospital Formulary Service Drug Information. 2012. AHFS drug information. 00--. Accessed January 4, 2021.
14. Mainous AG 3rd, Zoorob, RJ, Kohrs FP, Hagen MD. Streptococcal diagnostic testing and antibiotics prescribed for pediatric tonsillopharyngitis. Pediatr Infect Dis J. 1996;15(9):806-810. doi: 10.1097/00006454-199609000-00014
15. Benin AL, Vitkauskas G, Thornquist E, et al. Improving diagnostic testing and reducing overuse of antibiotics for children with pharyngitis: a useful role for the electronic medical record. Pediatr Infect Dis J. 2003;22(12):1043-1047. doi: 10.1097/01.inf.0000100577.76542.af
16. Luo R, Sickler J, Vahidnia F, et al. Diagnosis and Management of Group a Streptococcal Pharyngitis in the United States, 2011-2015. BMC Infect Dis. 2019;19(1):193-201. doi: 10.1186/s12879-019-3835-4
17. Shapiro DJ, Barak-Corren Y, Neuman MI, et al. Identifying Patients at Lowest Risk for Streptococcal Pharyngitis: A National Validation Study. J Pediatr. 2020;220:132-138.e2. doi: 10.1016/j.jpeds.2020.01.030. Epub 2020 Feb 14
18. Shapiro DJ, King LM, Fleming-Dutra KE, et al. Association between use of diagnostic tests and antibiotic prescribing for pharyngitis in the United States. Infect Control Hosp Epidemiol. 2020;41(4):479-481. doi: 10.1017/ice.2020.29
19. Sangha K, Steinberg I, McCombs JS. The impact of antibiotic treatment time and class of antibiotic for acute otitis media infections on the risk of revisits. Abs PDG4. Value in Health. 2019; 22:S163.
20. Ahluwalia T, Jain S, Norton L, Meade J, et al. Reducing Streptococcal Testing in Patients < 3 Years Old in an Emergency Department. Pediatrics. 2019;144(4):e20190174. doi: 10.1542/peds.2019-0174
21. McKay R, Mah A, Law MR, et al. Systematic Review of Factors Associated with Antibiotic Prescribing for Respiratory Tract Infections. Antimicrob Agents Chemother. 2016;60(7):4106-4118. doi: 10.1128/AAC.00209-16
22. Woods WA, Carter CT, Schlager TA. Detection of group A streptococci in children under 3 years of age with pharyngitis. Pediatr Emerg Care. 1999;15(5):338-340. doi: 10.1097/00006565-199910000-00011
23. Mendes N, Miguéis C, Lindo J, et al. Retrospective study of group A Streptococcus oropharyngeal infection diagnosis using a rapid antigenic detection test in a paediatric population from the central region of Portugal. Eur J Clin Microbiol Infect Dis. 2021;40(6):1235-1243. doi: 10.1007/s10096-021-04157-x
24. Frost HM, McLean HQ, Chow BDW. Variability in Antibiotic Prescribing for Upper Respiratory Illnesses by Provider Specialty. J Pediatr. 2018;203:76-85.e8. doi: 10.1016/j.jpeds.2018.07.044.
25. Rick AM, Zaheer HA, Martin JM. Clinical Features of Group A Streptococcus in Children With Pharyngitis: Carriers versus Acute Infection. Pediatr Infect Dis J. 2020;39(6):483-488. doi: 10.1097/INF.0000000000002602
26. Nadeau NL, Fine AM, Kimia A. Improving the prediction of streptococcal pharyngitis; time to move past exudate alone [published online ahead of print, 2020 Aug 16]. Am J Emerg Med. 2020;S0735-6757(20)30709-9. doi: 10.1016/j.ajem.2020.08.023
27. Mustafa Z, Ghaffari M. Diagnostic Methods, Clinical Guidelines, and Antibiotic Treatment for Group A Streptococcal Pharyngitis: A Narrative Review. Front Cell Infect Microbiol. 2020;10:563627. doi: 10.3389/fcimb.2020.563627
From the Department of Pharmaceutical and Health Economics, University of Southern California, Los Angeles, CA, (Drs. Sangha and McCombs), Department of Pediatrics, Keck School of Medicine, and Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, (Dr. Steinberg), and Leonard Schaeffer Center for Health Policy and Economics, University of Southern California, Los Angeles, CA (Dr. McCombs).
Objective: The recommended treatment for children and adolescents under 18 years of age who have a positive test for group A Streptococcus (GAS) are antibiotics using the “test and treat” strategy to detect and treat GAS for pediatric pharyngitis. This study used paid claims data to document the extent to which real-world treatment patterns are consistent with these recommendations. We document the factors correlated with testing and treatment, then examine the effects of receiving a GAS test and being treated with an antibiotic impact the likelihood of a revisit for an acute respiratory tract infection within 28 days.
Methods: This retrospective cohort study used Optum Insight Clinformatics data for medical and pharmacy claims from 2011-2013 to identify episodes of care for children and adolescents with pharyngitis around their index visit (± 6 months). The sample population included children and adolescents under 18 years of age with a diagnosis of pharyngitis. Multivariable logistic regression analyses were used to document factors associated with receipt of GAS test and antibiotic treatment. Next, we used logistic regression models to estimate the impact of test and treat recommendation on revisit risk.
Results: There were 24 685 treatment episodes for children and adolescents diagnosed with pharyngitis. Nearly 47% of these episodes included a GAS test and 48% of tested patients were prescribed an antibiotic prescription. Failing to perform a GAS test increased the risk of a revisit within 28 days by 44%. The use of antibiotics by tested and untested patients had no impact on revisit risk.
Conclusion: While the judicious use of antibiotics is important in managing pharyngitis infections and managing complications, the use of rapid diagnostic tools was found to be the determining factor in reducing revisits for pediatric patients with pharyngitis.
Keywords: pediatrics; pharyngitis; respiratory infections; acute infections; diagnostic tests; group A Streptococcus; antibiotics; revisits.
Acute pharyngitis is a common acute respiratory tract infection (ARTI) in children. Group A β-hemolytic streptococci (GABHS) is the most common bacterial etiology for pediatric pharyngitis, accounting for 15% to 30% of cases.1
Beyond clinical assessment, laboratory diagnostic testing generally plays a limited role in guiding appropriate antibiotic prescribing for patients with an ARTI.2,3 Most diagnostic tests require 2 or 3 days to result, incur additional costs, and may delay treatment.4 While these tests do not provide clear and timely guidance on which specific antibiotic is appropriate for ARTI patients, this is not the case for patients with pharyngitis.5,6,7 A rapid diagnostic test exists to identify pharyngitis patients with GABHS which accounts for 1 in 4 children with acute sore throat.1,4,6 Both the American Academy of Pediatrics and the Infectious Diseases Society of America recommend antibiotic treatment for children and adolescents under 18 years of age who have a positive test for group A Streptococcus (GAS).8,9 This “test and treat” protocol has been consistently included in the Healthcare Effectiveness Data and Information Set (HEDIS) standards over time for pediatric pharyngitis patients aged 3 to 18 years before dispensing an antibiotic.10
Sinusitis, pneumonia, and acute otitis media are considered ARTIs where antibiotic treatment is justified. Therefore, pharyngitis of unclear etiology seen with these comorbid infections may not always undergo GAS testing but move directly to the patient being prescribed antibiotics. This analysis enumerates ARTI-related comorbidities present together with the initial coded pharyngitis diagnosis to evaluate their impact on the provider’s decision to test and treat, and on revisit risk.
Antibiotic treatment for GAS patients is likely to eradicate the acute GABHS infection within 10 days. Penicillin and amoxicillin are commonly recommended because of their narrow spectrum of activity, few adverse effects, established efficacy, and modest cost. Alternative antibiotics for patients with penicillin allergy, or with polymicrobial infection seen on culture results, include a first-generation cephalosporin, clindamycin, clarithromycin (Biaxin), or azithromycin (Zithromax).1,8,11 However, while compliance with these HEDIS guidelines has been evaluated, the outcome effects of following the HEDIS “test and treat” recommendations for children with pharyngitis have not been adequately evaluated.
These outcome evaluations have increasing importance as the latest HEDIS survey has shown testing rates in commercial Preferred Provider Organizations (PPO) falling from 86.4% in 2018 to 75.9% in 2019, the lowest rate of testing since 2009, with similar reductions under 80% for Health Maintenance Organizations (HMO).10 While health plans may execute cost-benefit analyses and algorithms to forge best practices for GAS testing in children and adolescents presenting with symptoms of pharyngitis, it is important to regard the wasteful resource utilization and additional cost of revisits that may offset any gains accrued by more focused GAS testing outside the existing clinical guidelines and HEDIS measures. This may be of particular importance in documenting infection and sparing antibiotic therapy in toddlers and younger.
The objective of this study was to investigate the correlation between testing and antibiotic use on the likelihood of a revisit for an acute respiratory tract infection within 28 days. To achieve this objective, this investigation consists of 3 sequential analyses. First, we document the factors associated with the decision to test the patient for a GABHS infection using the GAS test. Next, we document the factors associated with the decision to use an antibiotic to treat the patient as a function of having tested the patient. Finally, we investigate the impact of the testing and treatment decisions on the likelihood of a revisit within 28 days.
Methods
Study design
This was a retrospective cohort study of episodes of treatment for pediatric patients with pharyngitis. Episodes were identified using data derived from the Optum Insight Clinformatics claims database provided to the University of Southern California to facilitate the training of graduate students. These data cover commercially insured patients with both medical and pharmacy benefits. Data were retrieved from the 3-year period spanning 2011-2013. An episode of care was identified based on date of the first (index) outpatient visit for a pharyngitis diagnosis (International Classification of Diseases, Ninth Revision [ICD-9]: 462, 463, 034.0). Outpatient visits were defined by visit setting: ambulatory clinics, physician offices, emergency rooms, and urgent care facilities. Each pharyngitis treatment episode was then screened for at least a 6-month enrollment in a health insurance plan prior and subsequent to the index visit using Optum enrollment data. Finally, eligible treatment episodes were restricted to children and adolescents under 18 years of age, who had an index outpatient visit for a primary diagnosis of acute pharyngitis.
A diagnostic profile was created for each episode using the diagnoses recorded for the index visit. Up to 3 diagnoses may be recorded for any outpatient visit and the first recorded diagnosis was assumed to be the primary diagnosis for that episode. Any secondary diagnoses recorded on the index visit were used to define comorbidities present at the index visit. ARTI-related comorbidities included: acute otitis media (AOM), bronchitis, sinusitis, pneumonia, and upper respiratory infection (URI). Other comorbid medical diagnoses were documented using diagnostic data from the pre-index period. Dichotomous variables for the following categories were created: mental disorders, nervous system disorders, respiratory symptoms, fever, injury and poisoning, other, or no diseases.
Prior visits for other respiratory infections in the previous 90 days were also identified for patients based on their index visit for pharyngitis. Similarly, any subsequent visits, within 28 days of the index visit, were also recorded to measure the health outcome for analysis. Practice settings include physician offices and federally qualified health centers, state and local health clinics, outpatient hospitals facilities, emergency departments, and other outpatient settings such as walk-in retail health clinic or ambulatory centers. Providers include primary care physicians (family practice, pediatricians, internal medicine), specialty care physicians (emergency medicine, preventive medicine), nonphysician providers (nurse practitioners, physician assistants) and other providers (urgent care, acute outpatient care, ambulatory care centers). Seasons of the year were determined based on the index date of the episode to account for possible seasonality in pharyngitis treatment. Lastly, a previous visits variable was created to identify whether the child had nonpharyngitis ARTI visits in the 3 months prior to the index visit.
Demographic variables were created based on enrollment and the socioeconomic data available in the Optum socioeconomic status file. These variables include patient age, race, sex, household income, geographic location, practice setting type, provider specialty, and type of insurance. An estimate of patient household income was based on algorithms using census block groups. Income categories were informed by the federal guidelines for a family of 4. A low-income family was defined as earning less than $50 000; a middle-income family earned between $50 000 and $75 000, and a high-income family earned $75 000 and above.12 Patient insurance type was categorized as HMO, Exclusive Provider Organization (EPO), Point of Service (POS), and PPO. Race was identified as White, Black, Hispanic, and Asian. Patient location was defined according to national census regions.
Outcomes
GAS test
The HEDIS measures for pharyngitis recommend using the GAS test to identify the bacterial etiology of the pharyngitis infection. Patients who received the test were identified based on Current Procedural Terminology (CPT) codes 87070-71, 87081, 87430, 87650-52, and 87880.10
Antibiotic treatment
The pharmacy administrative claims dataset was used to identify study patients who filled a prescription for an antibiotic during their pharyngitis treatment episode. Optum pharmacy data identify the medications received, specifies the date of prescription filling, National Drug Codes, and American Hospital Formulary Service (AHFS) Classification System codes for each medication. We used the AHFS Pharmacologic-Therapeutic classification of antibiotics to create dichotomous variables documenting the antibacterial used by each patient.13 These are categorized under antibacterial including penicillins, cephalosporins (first, second, third, fourth generation cephalosporins), macrolides (first generation and others), tetracyclines, sulfonamides, fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin), cephamycin, carbapenems, and β-lactam antibiotics (amoxicillin, amoxicillin/clavulanate, cephalexin, cefuroxime, cefdinir).
Revisits to physician or other provider
Revisits within 28 days were used as the measure of patient outcomes related to testing and filling of an antibiotic prescription for acute pharyngitis. Revisits may also be due to a patient returning for a follow-up, alternative treatment, worsening pharyngitis, or for another ARTI. An ARTI-related revisit also increases total resources used to treat pediatric pharyngitis patients.
Statistical analysis
Logistic regression was used for all 3 analyses conducted in this study. First, we determined the patient and treating physician characteristics that impact the decision to use GAS testing for pharyngitis. Second, we identified those factors that impact the decision to use antibiotic prescriptions among children who were diagnosed with pharyngitis adding in the dichotomous variable indicating if the patient had received a GAS test. Third, we used a logit regression analysis to document if receiving a GAS test and/or an antibiotic impacted the likelihood of a revisit by comparing revisit risk. To estimate the effect of testing and/or antibiotic use, we divided patients into 4 groups based on whether the patient received a GAS test and/or an antibiotic prescription. This specification of the analysis of revisits as an outcome focuses on adherence to HEDIS “test and treat” guidelines10:
- Patients who were not tested yet filled an antibiotic prescription. This decision was likely based on the clinician’s judgment of the patient’s signs and symptoms, and confirmational testing not performed.
- Patients who were not tested and did not fill an antibiotic prescription. Apparently, in the clinician’s judgment the patient’s signs and symptoms were such that the infection did not warrant treatment and the clinical presentation did not necessitate the GAS test to confirm the recorded diagnosis of pharyngitis.
- Patients who were tested and received antibiotic prescription, likely because the test was positive for GABHS.
- Patients who were tested and did not receive antibiotic prescription.
We tested for statistically significant differences in baseline characteristics across these 4 patient groups using t tests for continuous variables and χ2 tests for categorical variables. Odds ratios (OR) and CI were computed for the influential variables included the regression analyses.
We conducted a sensitivity analysis using a model specification which included the dichotomous variables for testing and for treatment, and the interaction term between these variables to assess if treatment effects varied in tested and untested patients. We also estimated this model of revisit risk using revisits within 7 days as the outcome variable.
All analyses were completed using STATA/IC 13 (StataCorp, College Station, TX).
Results
There were 24 685 treatment episodes for children diagnosed with pharyngitis. Nearly 47% of these episodes included GAS testing and 47% of the tested patients filled an antibiotic prescription. Similarly, 53% of patients were not tested and 49% of untested patients filled an antibiotic prescription. As a result, the 4 groups identified for analysis were evenly distributed: untested and no prescription (26.9%), untested and prescription (26.3%), tested and prescription (21.9%), and tested and no prescription (24.9%) (Figure).
Table 1 presents the descriptive statistics for these 4 patient groups. Note first that the rate of revisits within 28 days is under 5% across all groups. Second, the 2 tested groups have a lower revisit rate than the untested groups: the tested and treated have a revisit rate of 3.3%, and the tested and untreated have a revisit rate of 2.4%, while both the untested groups have a revisit rate of nearly 5%. These small absolute differences in revisit rates across groups were statistically significant.
Factors associated with receiving GAS test
Several factors were found to impact the decision to test (Table 2). Only 9.7% of children were reported to have any ARTI coinfection. As expected, these comorbidities resulted in a significantly lower likelihood of receiving the GAS test: AOM, bronchitis, sinusitis, pneumonia, and URI as comorbid infections had a 48%, 41%, 37%, 63%, and 13% lower likelihood of receiving the GAS test, respectively, than those with no comorbidities. Similarly, children with fever and respiratory symptoms were 35% and 45% less likely to receiving the GAS test, respectively. This is consistent with our expectation that comorbid ARTI infections will lead many providers to forgo testing.
Provider type and patient age also plays a role in receipt of the GAS test. Relative to outpatient facility providers, primary care physicians were 24% more likely and specialty physicians were 38% less likely of employing the GAS test. The child’s age played a significant role in receipt of the GAS test. Children aged 1 to 5 years and 5 to 12 years were 15% and 14% more likely to receive the test compared to children older than 12 years.
Pharyngitis patients have disproportionately higher odds of receiving a GAS test in most regions of the country compared to the Pacific region. For instance, children in the Mid-Atlantic region have 51% higher odds of receiving a GAS test while children in New England have 80% higher odds of receiving the same test.
Black children have 11% lower odds of receiving the GAS test compared to White children. Both middle-income and high-income children have 12% and 32% higher odds of receiving the test compared to low-income children. Compared to office-based visits, children visiting a clinic were twice as likely to receive a GAS test while those seen in the emergency room have 43% lower odds of receiving a GAS test. Hospital outpatient departments, which account for less than 1% of all visits, rarely used a GAS test which could be a statistical artifact due to small sample size. Lastly, insurance and season of the year had no significant impact of receipt of a GAS test.
Factors associated with receiving antibiotic prescription
Surprisingly, receiving the GAS test has a small but insignificant impact on the likelihood that the patient will receive an antibiotic prescription (Table 3) (Adjusted OR = 1.055, P = .07). After controlling for receipt of a GAS test, children with AOM and sinusitis comorbidities have an increased likelihood of being prescribed an antibiotic. Children with URI have a lower likelihood of being prescribed an antibiotic. Additionally, relative to primary care physicians, children visiting nonphysician providers for pharyngitis were more likely to be prescribed an antibiotic.
Children under 12 years of age were more likely to use an antibiotic compared to children 12 years and older. Geographically, there is some evidence of regional variation in antibiotic use as well. Children in the south Atlantic, west-south central, and southeast central regions had a significantly lower odds of being prescribed an antibiotic respectively than pharyngitis patients in the Pacific region. Black children had a 10% lower likelihood of being prescribed an antibiotic compared to White children, possibly related to their lower rate of GAS testing. Compared to office-based visits, children visiting a clinic were less likely to use an antibiotic. Household income, insurance type, and season had no significant impact on revisit risk.
Effects of GAS test and antibiotic prescriptions on likelihood of revisits
The multivariate analysis of the risk of a revisit within 28 days is presented in Table 4. Children with pharyngitis who tested and did not receive an antibiotic serve as the reference comparison group for this analysis to illustrate the impact of using the GAS test and treatment with an antibiotic. The results in Table 4 are quite clear: patients who receive the GAS test were significantly less likely to have a revisit within 28 days. Moreover, within the group of patients who were tested, those not receiving an antibiotic, presumedly because their GAS test was negative, experienced the lowest risk of a revisit. This result is consistent with the data in Table 1. Moreover, using an antibiotic had no impact on the likelihood of a revisit in patients not receiving the GAS test. This result is also consistent with Table 1.
Other results from the analysis of revisit risk may be of interest to clinicians. Pharyngitis patients with a prior episode of treatment within 90 days for an acute respiratory tract infection were more than 7 times more likely to experience a revisit within 28 days of the pharyngitis diagnosis than patients without a history of recent ARTI infections. Age is also a risk factor in likelihood of initiating a revisit. Children under 1 year and children aged 1 to 5 years were more likely to have a revisit than children aged more than 12 years. Compared to White children, Black children were 25% (P = .04) less likely to have a revisit. The care setting also has a significant impact on revisit risk. Children visiting outpatient hospital and other care settings had a significantly higher revisit risk than those visiting a physician’s office. Lastly, household income, geographic region, season, medical comorbidities, gender, and insurance type have no significant impact on revisit risk.
Sensitivity analysis
The results from the analysis of 7-day and 28-day revisit risk are summarized in Table 5. These results indicate that patients who were tested had a more significant decrease in revisit risk at 7 days (72%) than was evident at 28 days (47% reduction). Receiving an antibiotic, with or without the test, had no impact on revisit risk.
Discussion
Published data on revisits for pharyngitis are lacking with the concentration of prior research focused more on systemic complications of undertreated GABHS disease or on identifying carrier status. Our study results suggest that GAS testing is the most important factor in reducing revisit risk. Being prescribed an antibiotic, on its own, does not have a significant impact on the risk of a revisit. However, once the GAS test is used, the decision not to use an antibiotic was correlated with the lowest revisit rate, likely because the source of the pharyngitis infection was viral and more likely to resolve without a revisit. Prior studies have reported variable rates of testing among children with pharyngitis prescribed an antibiotic, ranging from 23% to 91%,14,15 with testing important toward more appropriate antibiotic use.16 More recently, among more than 67 000 patients aged 3 to 21 years presenting with sore throat and receiving a GAS test, 32.6% were positive.17
Our analysis found that more than 46% of pediatric pharyngitis patients were given the rapid GAS test. While this testing rate is substantially lower than HEDIS recommendations and lower than testing rates achieved by several health maintenance organizations,10 it is similar to the 53% of children receiving such testing in a recent National Ambulatory Medical Care Survey.18 Furthermore, we found that when antibiotics are prescribed following a GAS test, the revisit risk is not significantly reduced, possibly because antibiotics lower revisit risk when informed by diagnostic testing tools that determine the infectious organism. This is supported by a similar population analysis in which we observed reduced revisit rates in children with AOM managed with antibiotics within 3 days of index diagnosis.19
Several other factors also affect the likelihood of a child receiving the GAS test. Children aged 1 to 12 years were significantly more likely to receive the GAS test than children over the age of 12. This included children in the 1 to 5 years old bracket who had a 15% higher likelihood of undergoing a GAS test, despite children less than 3 years of age as not recommended targets for GAS testing.20 As expected, children with reported ARTI-associated comorbidities were also less likely to receive a GAS test. Additionally, specialty care physicians were less inclined to implement the GAS test, possibly because of diagnostic confidence without testing or referral after GAS was ruled out. Black and low-income children had statistically lower odds of receiving the test, even after controlling for other factors, and yet were less likely to consume a revisit. As the overall data suggested more revisits in those not tested, further study is needed to examine if race or income discrepancies are equity based. Finally, children in the Pacific region, compared to the rest of the nation, were the least likely to receive a GAS test and yet there were no significant differences in revisit rates by region. Regional differences in antibiotic use were also observed in our study, as has been seen by others.21
After statistically controlling for having received the diagnostic GAS test and filled a prescription for an antibiotic, there are multitude of factors that independently affect the revisit risk, the most important of which if which was a history of an ARTI infection in the prior 90 days. While prior visit history had no impact on the likelihood of being tested or filling an antibiotic, patients with prior visits were more than 7 times more likely to consume a revisit. This was not reflected in nor related to comorbid ARTIs as these patients did not have statistically higher revisits than those with pharyngitis as the sole-coded diagnosis. Moreover, speculation for bacterial etiology of primary or superinfection based on a recent history of ARTI accounting for revisits seems unlikely as it did not yield greater antibiotic use in that group. Further analysis is required to determine the clinical and behavioral factors that promote for prior ARTI history as a major factor in revisit risk after an index visit for pharyngitis.
Children aged between 1 and 5 years, though 15% more likely to be tested than those aged 12 through 17 years, were also 39% more likely to initiate a revisit compared to older children when statistically controlling for other covariates. This perhaps suggests longer illness, wrong diagnosis, delay in appropriate treatment, or more caution by parents and providers in this age group. Justification for testing children less than 3 years of age who are outside of the HEDIS suggested age group, when clinical judgement does not point to another infection source, can result in positivity rates between 22% and 30% as previously observed.22,23 Patients visiting nonphysician providers and outpatient facility providers were less likely to have a revisit than those visiting primary and specialty care physicians, though slightly higher propensity for antibiotic prescriptions was seen for nonphysician providers. Pediatricians have been noted to be less likely to prescribe antibiotics without GAS testing than nonpediatric providers, and more guidelines-compliant in prescribing.24
Recommendations to not test children under 3 years of age are based on the lack of acute rheumatic fever and other complications in this age group together with more frequent viral syndromes. Selectivity in applying clinical criteria to testing can be attempted to separate bacterial from viral illness. Postnasal drainage/rhinorrhea, hoarse voice, and cough have been used successfully to identify those with viral illness and less need for testing, with greater certainty of low risk for GABHS in those over 11 years of age without tonsillar exudates, cervical adenopathy, or fever.17 However, the marginal benefits of those who have all 3 features of viral illness versus none in identifying GAS positivity was 23.3% vs 37.6% - helpful, but certainly not diminishing the need for testing. These constitutional findings of viral URI also do not exclude the GAS carrier state that features these symptoms.25 Others have reinforced the doubt of pharyngeal exudates as the premier diagnostic finding for test-positive GAS.26
This study had several limitations. The Optum claims dataset only contains ICD-9 codes for diagnoses. It does not include data on infection severity and clinical findings related to symptoms, thus empiric treatment warranted based in clinical severity is not assessed. Antibiotics are commonly available as generics and very inexpensive. Patients may fill and pay for these prescriptions directly, in which case, a claim for payment may not be filed with Optum. This could result in an undercount of treated patients in our study.
There is no corresponding problem of missing medical claims for GAS testing which were obtained from the CPT codes within the Optum claims data set. However, we elected not to verify the test results due to these data being missing for 75% of the study population. Nevertheless, this study’s focus was less about justifying antibiotic treatment, but dealt with the outcomes generated by testing and treatment. Toward that end, we used CPT codes to identify a revisit, and while those can at times be affected by financial reimbursement incentives, differences related to revisits in the 4 patient groups should not be subject to bias.
Conclusion
This study used data from real world practices to document the patterns of GAS testing and antibiotic use in pediatric pharyngitis patients. Revisit rates were under 5% for all patient groups and the use of rapid diagnostic tools were found to be the determining factor in further reducing the risk of revisits. This supports the need for compliance with the HEDIS quality metric for pharyngitis to the recommended levels of rapid testing which have been falling in recent years. Use of more accurate antigen and newer molecular detection testing methods may help further delineate important factors in determining pediatric pharyngitis treatment and need for revisits.27
Corresponding author: Jeffrey McCombs, MD, University of Southern California School of Pharmacy, Department of Pharmaceutical and Health Economics, Leonard D. Schaeffer Center for Health Policy & Economics, 635 Downey Way, Verna & Peter Dauterive Hall 310, Los Angeles, CA 90089-3333; jmccombs@usc.edu.
Financial disclosures: None.
From the Department of Pharmaceutical and Health Economics, University of Southern California, Los Angeles, CA, (Drs. Sangha and McCombs), Department of Pediatrics, Keck School of Medicine, and Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, (Dr. Steinberg), and Leonard Schaeffer Center for Health Policy and Economics, University of Southern California, Los Angeles, CA (Dr. McCombs).
Objective: The recommended treatment for children and adolescents under 18 years of age who have a positive test for group A Streptococcus (GAS) are antibiotics using the “test and treat” strategy to detect and treat GAS for pediatric pharyngitis. This study used paid claims data to document the extent to which real-world treatment patterns are consistent with these recommendations. We document the factors correlated with testing and treatment, then examine the effects of receiving a GAS test and being treated with an antibiotic impact the likelihood of a revisit for an acute respiratory tract infection within 28 days.
Methods: This retrospective cohort study used Optum Insight Clinformatics data for medical and pharmacy claims from 2011-2013 to identify episodes of care for children and adolescents with pharyngitis around their index visit (± 6 months). The sample population included children and adolescents under 18 years of age with a diagnosis of pharyngitis. Multivariable logistic regression analyses were used to document factors associated with receipt of GAS test and antibiotic treatment. Next, we used logistic regression models to estimate the impact of test and treat recommendation on revisit risk.
Results: There were 24 685 treatment episodes for children and adolescents diagnosed with pharyngitis. Nearly 47% of these episodes included a GAS test and 48% of tested patients were prescribed an antibiotic prescription. Failing to perform a GAS test increased the risk of a revisit within 28 days by 44%. The use of antibiotics by tested and untested patients had no impact on revisit risk.
Conclusion: While the judicious use of antibiotics is important in managing pharyngitis infections and managing complications, the use of rapid diagnostic tools was found to be the determining factor in reducing revisits for pediatric patients with pharyngitis.
Keywords: pediatrics; pharyngitis; respiratory infections; acute infections; diagnostic tests; group A Streptococcus; antibiotics; revisits.
Acute pharyngitis is a common acute respiratory tract infection (ARTI) in children. Group A β-hemolytic streptococci (GABHS) is the most common bacterial etiology for pediatric pharyngitis, accounting for 15% to 30% of cases.1
Beyond clinical assessment, laboratory diagnostic testing generally plays a limited role in guiding appropriate antibiotic prescribing for patients with an ARTI.2,3 Most diagnostic tests require 2 or 3 days to result, incur additional costs, and may delay treatment.4 While these tests do not provide clear and timely guidance on which specific antibiotic is appropriate for ARTI patients, this is not the case for patients with pharyngitis.5,6,7 A rapid diagnostic test exists to identify pharyngitis patients with GABHS which accounts for 1 in 4 children with acute sore throat.1,4,6 Both the American Academy of Pediatrics and the Infectious Diseases Society of America recommend antibiotic treatment for children and adolescents under 18 years of age who have a positive test for group A Streptococcus (GAS).8,9 This “test and treat” protocol has been consistently included in the Healthcare Effectiveness Data and Information Set (HEDIS) standards over time for pediatric pharyngitis patients aged 3 to 18 years before dispensing an antibiotic.10
Sinusitis, pneumonia, and acute otitis media are considered ARTIs where antibiotic treatment is justified. Therefore, pharyngitis of unclear etiology seen with these comorbid infections may not always undergo GAS testing but move directly to the patient being prescribed antibiotics. This analysis enumerates ARTI-related comorbidities present together with the initial coded pharyngitis diagnosis to evaluate their impact on the provider’s decision to test and treat, and on revisit risk.
Antibiotic treatment for GAS patients is likely to eradicate the acute GABHS infection within 10 days. Penicillin and amoxicillin are commonly recommended because of their narrow spectrum of activity, few adverse effects, established efficacy, and modest cost. Alternative antibiotics for patients with penicillin allergy, or with polymicrobial infection seen on culture results, include a first-generation cephalosporin, clindamycin, clarithromycin (Biaxin), or azithromycin (Zithromax).1,8,11 However, while compliance with these HEDIS guidelines has been evaluated, the outcome effects of following the HEDIS “test and treat” recommendations for children with pharyngitis have not been adequately evaluated.
These outcome evaluations have increasing importance as the latest HEDIS survey has shown testing rates in commercial Preferred Provider Organizations (PPO) falling from 86.4% in 2018 to 75.9% in 2019, the lowest rate of testing since 2009, with similar reductions under 80% for Health Maintenance Organizations (HMO).10 While health plans may execute cost-benefit analyses and algorithms to forge best practices for GAS testing in children and adolescents presenting with symptoms of pharyngitis, it is important to regard the wasteful resource utilization and additional cost of revisits that may offset any gains accrued by more focused GAS testing outside the existing clinical guidelines and HEDIS measures. This may be of particular importance in documenting infection and sparing antibiotic therapy in toddlers and younger.
The objective of this study was to investigate the correlation between testing and antibiotic use on the likelihood of a revisit for an acute respiratory tract infection within 28 days. To achieve this objective, this investigation consists of 3 sequential analyses. First, we document the factors associated with the decision to test the patient for a GABHS infection using the GAS test. Next, we document the factors associated with the decision to use an antibiotic to treat the patient as a function of having tested the patient. Finally, we investigate the impact of the testing and treatment decisions on the likelihood of a revisit within 28 days.
Methods
Study design
This was a retrospective cohort study of episodes of treatment for pediatric patients with pharyngitis. Episodes were identified using data derived from the Optum Insight Clinformatics claims database provided to the University of Southern California to facilitate the training of graduate students. These data cover commercially insured patients with both medical and pharmacy benefits. Data were retrieved from the 3-year period spanning 2011-2013. An episode of care was identified based on date of the first (index) outpatient visit for a pharyngitis diagnosis (International Classification of Diseases, Ninth Revision [ICD-9]: 462, 463, 034.0). Outpatient visits were defined by visit setting: ambulatory clinics, physician offices, emergency rooms, and urgent care facilities. Each pharyngitis treatment episode was then screened for at least a 6-month enrollment in a health insurance plan prior and subsequent to the index visit using Optum enrollment data. Finally, eligible treatment episodes were restricted to children and adolescents under 18 years of age, who had an index outpatient visit for a primary diagnosis of acute pharyngitis.
A diagnostic profile was created for each episode using the diagnoses recorded for the index visit. Up to 3 diagnoses may be recorded for any outpatient visit and the first recorded diagnosis was assumed to be the primary diagnosis for that episode. Any secondary diagnoses recorded on the index visit were used to define comorbidities present at the index visit. ARTI-related comorbidities included: acute otitis media (AOM), bronchitis, sinusitis, pneumonia, and upper respiratory infection (URI). Other comorbid medical diagnoses were documented using diagnostic data from the pre-index period. Dichotomous variables for the following categories were created: mental disorders, nervous system disorders, respiratory symptoms, fever, injury and poisoning, other, or no diseases.
Prior visits for other respiratory infections in the previous 90 days were also identified for patients based on their index visit for pharyngitis. Similarly, any subsequent visits, within 28 days of the index visit, were also recorded to measure the health outcome for analysis. Practice settings include physician offices and federally qualified health centers, state and local health clinics, outpatient hospitals facilities, emergency departments, and other outpatient settings such as walk-in retail health clinic or ambulatory centers. Providers include primary care physicians (family practice, pediatricians, internal medicine), specialty care physicians (emergency medicine, preventive medicine), nonphysician providers (nurse practitioners, physician assistants) and other providers (urgent care, acute outpatient care, ambulatory care centers). Seasons of the year were determined based on the index date of the episode to account for possible seasonality in pharyngitis treatment. Lastly, a previous visits variable was created to identify whether the child had nonpharyngitis ARTI visits in the 3 months prior to the index visit.
Demographic variables were created based on enrollment and the socioeconomic data available in the Optum socioeconomic status file. These variables include patient age, race, sex, household income, geographic location, practice setting type, provider specialty, and type of insurance. An estimate of patient household income was based on algorithms using census block groups. Income categories were informed by the federal guidelines for a family of 4. A low-income family was defined as earning less than $50 000; a middle-income family earned between $50 000 and $75 000, and a high-income family earned $75 000 and above.12 Patient insurance type was categorized as HMO, Exclusive Provider Organization (EPO), Point of Service (POS), and PPO. Race was identified as White, Black, Hispanic, and Asian. Patient location was defined according to national census regions.
Outcomes
GAS test
The HEDIS measures for pharyngitis recommend using the GAS test to identify the bacterial etiology of the pharyngitis infection. Patients who received the test were identified based on Current Procedural Terminology (CPT) codes 87070-71, 87081, 87430, 87650-52, and 87880.10
Antibiotic treatment
The pharmacy administrative claims dataset was used to identify study patients who filled a prescription for an antibiotic during their pharyngitis treatment episode. Optum pharmacy data identify the medications received, specifies the date of prescription filling, National Drug Codes, and American Hospital Formulary Service (AHFS) Classification System codes for each medication. We used the AHFS Pharmacologic-Therapeutic classification of antibiotics to create dichotomous variables documenting the antibacterial used by each patient.13 These are categorized under antibacterial including penicillins, cephalosporins (first, second, third, fourth generation cephalosporins), macrolides (first generation and others), tetracyclines, sulfonamides, fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin), cephamycin, carbapenems, and β-lactam antibiotics (amoxicillin, amoxicillin/clavulanate, cephalexin, cefuroxime, cefdinir).
Revisits to physician or other provider
Revisits within 28 days were used as the measure of patient outcomes related to testing and filling of an antibiotic prescription for acute pharyngitis. Revisits may also be due to a patient returning for a follow-up, alternative treatment, worsening pharyngitis, or for another ARTI. An ARTI-related revisit also increases total resources used to treat pediatric pharyngitis patients.
Statistical analysis
Logistic regression was used for all 3 analyses conducted in this study. First, we determined the patient and treating physician characteristics that impact the decision to use GAS testing for pharyngitis. Second, we identified those factors that impact the decision to use antibiotic prescriptions among children who were diagnosed with pharyngitis adding in the dichotomous variable indicating if the patient had received a GAS test. Third, we used a logit regression analysis to document if receiving a GAS test and/or an antibiotic impacted the likelihood of a revisit by comparing revisit risk. To estimate the effect of testing and/or antibiotic use, we divided patients into 4 groups based on whether the patient received a GAS test and/or an antibiotic prescription. This specification of the analysis of revisits as an outcome focuses on adherence to HEDIS “test and treat” guidelines10:
- Patients who were not tested yet filled an antibiotic prescription. This decision was likely based on the clinician’s judgment of the patient’s signs and symptoms, and confirmational testing not performed.
- Patients who were not tested and did not fill an antibiotic prescription. Apparently, in the clinician’s judgment the patient’s signs and symptoms were such that the infection did not warrant treatment and the clinical presentation did not necessitate the GAS test to confirm the recorded diagnosis of pharyngitis.
- Patients who were tested and received antibiotic prescription, likely because the test was positive for GABHS.
- Patients who were tested and did not receive antibiotic prescription.
We tested for statistically significant differences in baseline characteristics across these 4 patient groups using t tests for continuous variables and χ2 tests for categorical variables. Odds ratios (OR) and CI were computed for the influential variables included the regression analyses.
We conducted a sensitivity analysis using a model specification which included the dichotomous variables for testing and for treatment, and the interaction term between these variables to assess if treatment effects varied in tested and untested patients. We also estimated this model of revisit risk using revisits within 7 days as the outcome variable.
All analyses were completed using STATA/IC 13 (StataCorp, College Station, TX).
Results
There were 24 685 treatment episodes for children diagnosed with pharyngitis. Nearly 47% of these episodes included GAS testing and 47% of the tested patients filled an antibiotic prescription. Similarly, 53% of patients were not tested and 49% of untested patients filled an antibiotic prescription. As a result, the 4 groups identified for analysis were evenly distributed: untested and no prescription (26.9%), untested and prescription (26.3%), tested and prescription (21.9%), and tested and no prescription (24.9%) (Figure).
Table 1 presents the descriptive statistics for these 4 patient groups. Note first that the rate of revisits within 28 days is under 5% across all groups. Second, the 2 tested groups have a lower revisit rate than the untested groups: the tested and treated have a revisit rate of 3.3%, and the tested and untreated have a revisit rate of 2.4%, while both the untested groups have a revisit rate of nearly 5%. These small absolute differences in revisit rates across groups were statistically significant.
Factors associated with receiving GAS test
Several factors were found to impact the decision to test (Table 2). Only 9.7% of children were reported to have any ARTI coinfection. As expected, these comorbidities resulted in a significantly lower likelihood of receiving the GAS test: AOM, bronchitis, sinusitis, pneumonia, and URI as comorbid infections had a 48%, 41%, 37%, 63%, and 13% lower likelihood of receiving the GAS test, respectively, than those with no comorbidities. Similarly, children with fever and respiratory symptoms were 35% and 45% less likely to receiving the GAS test, respectively. This is consistent with our expectation that comorbid ARTI infections will lead many providers to forgo testing.
Provider type and patient age also plays a role in receipt of the GAS test. Relative to outpatient facility providers, primary care physicians were 24% more likely and specialty physicians were 38% less likely of employing the GAS test. The child’s age played a significant role in receipt of the GAS test. Children aged 1 to 5 years and 5 to 12 years were 15% and 14% more likely to receive the test compared to children older than 12 years.
Pharyngitis patients have disproportionately higher odds of receiving a GAS test in most regions of the country compared to the Pacific region. For instance, children in the Mid-Atlantic region have 51% higher odds of receiving a GAS test while children in New England have 80% higher odds of receiving the same test.
Black children have 11% lower odds of receiving the GAS test compared to White children. Both middle-income and high-income children have 12% and 32% higher odds of receiving the test compared to low-income children. Compared to office-based visits, children visiting a clinic were twice as likely to receive a GAS test while those seen in the emergency room have 43% lower odds of receiving a GAS test. Hospital outpatient departments, which account for less than 1% of all visits, rarely used a GAS test which could be a statistical artifact due to small sample size. Lastly, insurance and season of the year had no significant impact of receipt of a GAS test.
Factors associated with receiving antibiotic prescription
Surprisingly, receiving the GAS test has a small but insignificant impact on the likelihood that the patient will receive an antibiotic prescription (Table 3) (Adjusted OR = 1.055, P = .07). After controlling for receipt of a GAS test, children with AOM and sinusitis comorbidities have an increased likelihood of being prescribed an antibiotic. Children with URI have a lower likelihood of being prescribed an antibiotic. Additionally, relative to primary care physicians, children visiting nonphysician providers for pharyngitis were more likely to be prescribed an antibiotic.
Children under 12 years of age were more likely to use an antibiotic compared to children 12 years and older. Geographically, there is some evidence of regional variation in antibiotic use as well. Children in the south Atlantic, west-south central, and southeast central regions had a significantly lower odds of being prescribed an antibiotic respectively than pharyngitis patients in the Pacific region. Black children had a 10% lower likelihood of being prescribed an antibiotic compared to White children, possibly related to their lower rate of GAS testing. Compared to office-based visits, children visiting a clinic were less likely to use an antibiotic. Household income, insurance type, and season had no significant impact on revisit risk.
Effects of GAS test and antibiotic prescriptions on likelihood of revisits
The multivariate analysis of the risk of a revisit within 28 days is presented in Table 4. Children with pharyngitis who tested and did not receive an antibiotic serve as the reference comparison group for this analysis to illustrate the impact of using the GAS test and treatment with an antibiotic. The results in Table 4 are quite clear: patients who receive the GAS test were significantly less likely to have a revisit within 28 days. Moreover, within the group of patients who were tested, those not receiving an antibiotic, presumedly because their GAS test was negative, experienced the lowest risk of a revisit. This result is consistent with the data in Table 1. Moreover, using an antibiotic had no impact on the likelihood of a revisit in patients not receiving the GAS test. This result is also consistent with Table 1.
Other results from the analysis of revisit risk may be of interest to clinicians. Pharyngitis patients with a prior episode of treatment within 90 days for an acute respiratory tract infection were more than 7 times more likely to experience a revisit within 28 days of the pharyngitis diagnosis than patients without a history of recent ARTI infections. Age is also a risk factor in likelihood of initiating a revisit. Children under 1 year and children aged 1 to 5 years were more likely to have a revisit than children aged more than 12 years. Compared to White children, Black children were 25% (P = .04) less likely to have a revisit. The care setting also has a significant impact on revisit risk. Children visiting outpatient hospital and other care settings had a significantly higher revisit risk than those visiting a physician’s office. Lastly, household income, geographic region, season, medical comorbidities, gender, and insurance type have no significant impact on revisit risk.
Sensitivity analysis
The results from the analysis of 7-day and 28-day revisit risk are summarized in Table 5. These results indicate that patients who were tested had a more significant decrease in revisit risk at 7 days (72%) than was evident at 28 days (47% reduction). Receiving an antibiotic, with or without the test, had no impact on revisit risk.
Discussion
Published data on revisits for pharyngitis are lacking with the concentration of prior research focused more on systemic complications of undertreated GABHS disease or on identifying carrier status. Our study results suggest that GAS testing is the most important factor in reducing revisit risk. Being prescribed an antibiotic, on its own, does not have a significant impact on the risk of a revisit. However, once the GAS test is used, the decision not to use an antibiotic was correlated with the lowest revisit rate, likely because the source of the pharyngitis infection was viral and more likely to resolve without a revisit. Prior studies have reported variable rates of testing among children with pharyngitis prescribed an antibiotic, ranging from 23% to 91%,14,15 with testing important toward more appropriate antibiotic use.16 More recently, among more than 67 000 patients aged 3 to 21 years presenting with sore throat and receiving a GAS test, 32.6% were positive.17
Our analysis found that more than 46% of pediatric pharyngitis patients were given the rapid GAS test. While this testing rate is substantially lower than HEDIS recommendations and lower than testing rates achieved by several health maintenance organizations,10 it is similar to the 53% of children receiving such testing in a recent National Ambulatory Medical Care Survey.18 Furthermore, we found that when antibiotics are prescribed following a GAS test, the revisit risk is not significantly reduced, possibly because antibiotics lower revisit risk when informed by diagnostic testing tools that determine the infectious organism. This is supported by a similar population analysis in which we observed reduced revisit rates in children with AOM managed with antibiotics within 3 days of index diagnosis.19
Several other factors also affect the likelihood of a child receiving the GAS test. Children aged 1 to 12 years were significantly more likely to receive the GAS test than children over the age of 12. This included children in the 1 to 5 years old bracket who had a 15% higher likelihood of undergoing a GAS test, despite children less than 3 years of age as not recommended targets for GAS testing.20 As expected, children with reported ARTI-associated comorbidities were also less likely to receive a GAS test. Additionally, specialty care physicians were less inclined to implement the GAS test, possibly because of diagnostic confidence without testing or referral after GAS was ruled out. Black and low-income children had statistically lower odds of receiving the test, even after controlling for other factors, and yet were less likely to consume a revisit. As the overall data suggested more revisits in those not tested, further study is needed to examine if race or income discrepancies are equity based. Finally, children in the Pacific region, compared to the rest of the nation, were the least likely to receive a GAS test and yet there were no significant differences in revisit rates by region. Regional differences in antibiotic use were also observed in our study, as has been seen by others.21
After statistically controlling for having received the diagnostic GAS test and filled a prescription for an antibiotic, there are multitude of factors that independently affect the revisit risk, the most important of which if which was a history of an ARTI infection in the prior 90 days. While prior visit history had no impact on the likelihood of being tested or filling an antibiotic, patients with prior visits were more than 7 times more likely to consume a revisit. This was not reflected in nor related to comorbid ARTIs as these patients did not have statistically higher revisits than those with pharyngitis as the sole-coded diagnosis. Moreover, speculation for bacterial etiology of primary or superinfection based on a recent history of ARTI accounting for revisits seems unlikely as it did not yield greater antibiotic use in that group. Further analysis is required to determine the clinical and behavioral factors that promote for prior ARTI history as a major factor in revisit risk after an index visit for pharyngitis.
Children aged between 1 and 5 years, though 15% more likely to be tested than those aged 12 through 17 years, were also 39% more likely to initiate a revisit compared to older children when statistically controlling for other covariates. This perhaps suggests longer illness, wrong diagnosis, delay in appropriate treatment, or more caution by parents and providers in this age group. Justification for testing children less than 3 years of age who are outside of the HEDIS suggested age group, when clinical judgement does not point to another infection source, can result in positivity rates between 22% and 30% as previously observed.22,23 Patients visiting nonphysician providers and outpatient facility providers were less likely to have a revisit than those visiting primary and specialty care physicians, though slightly higher propensity for antibiotic prescriptions was seen for nonphysician providers. Pediatricians have been noted to be less likely to prescribe antibiotics without GAS testing than nonpediatric providers, and more guidelines-compliant in prescribing.24
Recommendations to not test children under 3 years of age are based on the lack of acute rheumatic fever and other complications in this age group together with more frequent viral syndromes. Selectivity in applying clinical criteria to testing can be attempted to separate bacterial from viral illness. Postnasal drainage/rhinorrhea, hoarse voice, and cough have been used successfully to identify those with viral illness and less need for testing, with greater certainty of low risk for GABHS in those over 11 years of age without tonsillar exudates, cervical adenopathy, or fever.17 However, the marginal benefits of those who have all 3 features of viral illness versus none in identifying GAS positivity was 23.3% vs 37.6% - helpful, but certainly not diminishing the need for testing. These constitutional findings of viral URI also do not exclude the GAS carrier state that features these symptoms.25 Others have reinforced the doubt of pharyngeal exudates as the premier diagnostic finding for test-positive GAS.26
This study had several limitations. The Optum claims dataset only contains ICD-9 codes for diagnoses. It does not include data on infection severity and clinical findings related to symptoms, thus empiric treatment warranted based in clinical severity is not assessed. Antibiotics are commonly available as generics and very inexpensive. Patients may fill and pay for these prescriptions directly, in which case, a claim for payment may not be filed with Optum. This could result in an undercount of treated patients in our study.
There is no corresponding problem of missing medical claims for GAS testing which were obtained from the CPT codes within the Optum claims data set. However, we elected not to verify the test results due to these data being missing for 75% of the study population. Nevertheless, this study’s focus was less about justifying antibiotic treatment, but dealt with the outcomes generated by testing and treatment. Toward that end, we used CPT codes to identify a revisit, and while those can at times be affected by financial reimbursement incentives, differences related to revisits in the 4 patient groups should not be subject to bias.
Conclusion
This study used data from real world practices to document the patterns of GAS testing and antibiotic use in pediatric pharyngitis patients. Revisit rates were under 5% for all patient groups and the use of rapid diagnostic tools were found to be the determining factor in further reducing the risk of revisits. This supports the need for compliance with the HEDIS quality metric for pharyngitis to the recommended levels of rapid testing which have been falling in recent years. Use of more accurate antigen and newer molecular detection testing methods may help further delineate important factors in determining pediatric pharyngitis treatment and need for revisits.27
Corresponding author: Jeffrey McCombs, MD, University of Southern California School of Pharmacy, Department of Pharmaceutical and Health Economics, Leonard D. Schaeffer Center for Health Policy & Economics, 635 Downey Way, Verna & Peter Dauterive Hall 310, Los Angeles, CA 90089-3333; jmccombs@usc.edu.
Financial disclosures: None.
1. Choby BA. Diagnosis and treatment of streptococcal pharyngitis. Am Fam Physician. 2009;79(5):383-390.
2. Briel M, Schuetz P, Mueller B, et al. Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract infections in primary care. Arch of Intern Med. 2008;168(18):2000-2008. doi: 10.1001/archinte.168.18.2000
3. Maltezou HC, Tsagris V, Antoniadou A, et al. Evaluation of a rapid antigen detection test in the diagnosis of streptococcal pharyngitis in children and its impact on antibiotic prescription. J Antimicrob Chemother. 2008;62(6):1407-1412. doi: 10.1093/jac/dkn376
4. Neuner JM, Hamel MB, Phillips RS, et al. Diagnosis and management of adults with pharyngitis: a cost-effectiveness analysis. Ann Intern Med. 2003;139(2):113-122. doi:10.7326/0003-4819-139-2-200307150-00011
5. Gerber MA, Baltimore RS, Eaton CB, et al. Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2009;119(11):1541-1551. doi: 10.1161/CIRCULATIONAHA.109.191959
6. Gieseker KE, Roe MH, MacKenzie T, Todd JK. Evaluating the American Academy of Pediatrics diagnostic standard for Streptococcus pyogenes pharyngitis: backup culture versus repeat rapid antigen testing. Pediatrics. 2003;111(6):e666-e670. doi: 10.1542/peds.111.6.e666
7. Shapiro DJ, Lindgren CE, Neuman MI, Fine AM. Viral features and testing for Streptococcal pharyngitis. Pediatrics. 2017;139(5):e20163403. doi: 10.1542/peds.2016-3403
8. Shulman ST, Bisno AL, Clegg H, et al. Clinical practice guideline for the diagnosis and management of group A Streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis. 2012;55(10):e86–e102. doi: 10.1093/cid/cis629
9. Mangione-Smith R, McGlynn EA, Elliott MN, et al. Parent expectations for antibiotics, physician-parent communication, and satisfaction. Arch Pediatr Adolesc Med. 2001;155(7):800–806. doi: 10.1001/archpedi.155.7.800
10. Appropriate Testing for Children with Pharyngitis. HEDIS Measures and Technical Resources. National Committee for Quality Assurance. Accessed February 12, 2021. https://www.ncqa.org/hedis/measures/appropriate-testing-for-children-with-pharyngitis/
11. Linder JA, Bates DW, Lee GM, Finkelstein JA. Antibiotic treatment of children with sore throat. JAMA. 2005;294(18):2315-2322. doi: 10.1001/jama.294.18.2315
12. Crimmel BL. Health Insurance Coverage and Income Levels for the US Noninstitutionalized Population Under Age 65, 2001. Medical Expenditure Panel Survey, Agency for Healthcare Research and Quality. 2004. https://meps.ahrq.gov/data_files/publications/st40/stat40.pd
13. AHFS/ASHP. American Hospital Formulary Service Drug Information. 2012. AHFS drug information. 00--. Accessed January 4, 2021.
14. Mainous AG 3rd, Zoorob, RJ, Kohrs FP, Hagen MD. Streptococcal diagnostic testing and antibiotics prescribed for pediatric tonsillopharyngitis. Pediatr Infect Dis J. 1996;15(9):806-810. doi: 10.1097/00006454-199609000-00014
15. Benin AL, Vitkauskas G, Thornquist E, et al. Improving diagnostic testing and reducing overuse of antibiotics for children with pharyngitis: a useful role for the electronic medical record. Pediatr Infect Dis J. 2003;22(12):1043-1047. doi: 10.1097/01.inf.0000100577.76542.af
16. Luo R, Sickler J, Vahidnia F, et al. Diagnosis and Management of Group a Streptococcal Pharyngitis in the United States, 2011-2015. BMC Infect Dis. 2019;19(1):193-201. doi: 10.1186/s12879-019-3835-4
17. Shapiro DJ, Barak-Corren Y, Neuman MI, et al. Identifying Patients at Lowest Risk for Streptococcal Pharyngitis: A National Validation Study. J Pediatr. 2020;220:132-138.e2. doi: 10.1016/j.jpeds.2020.01.030. Epub 2020 Feb 14
18. Shapiro DJ, King LM, Fleming-Dutra KE, et al. Association between use of diagnostic tests and antibiotic prescribing for pharyngitis in the United States. Infect Control Hosp Epidemiol. 2020;41(4):479-481. doi: 10.1017/ice.2020.29
19. Sangha K, Steinberg I, McCombs JS. The impact of antibiotic treatment time and class of antibiotic for acute otitis media infections on the risk of revisits. Abs PDG4. Value in Health. 2019; 22:S163.
20. Ahluwalia T, Jain S, Norton L, Meade J, et al. Reducing Streptococcal Testing in Patients < 3 Years Old in an Emergency Department. Pediatrics. 2019;144(4):e20190174. doi: 10.1542/peds.2019-0174
21. McKay R, Mah A, Law MR, et al. Systematic Review of Factors Associated with Antibiotic Prescribing for Respiratory Tract Infections. Antimicrob Agents Chemother. 2016;60(7):4106-4118. doi: 10.1128/AAC.00209-16
22. Woods WA, Carter CT, Schlager TA. Detection of group A streptococci in children under 3 years of age with pharyngitis. Pediatr Emerg Care. 1999;15(5):338-340. doi: 10.1097/00006565-199910000-00011
23. Mendes N, Miguéis C, Lindo J, et al. Retrospective study of group A Streptococcus oropharyngeal infection diagnosis using a rapid antigenic detection test in a paediatric population from the central region of Portugal. Eur J Clin Microbiol Infect Dis. 2021;40(6):1235-1243. doi: 10.1007/s10096-021-04157-x
24. Frost HM, McLean HQ, Chow BDW. Variability in Antibiotic Prescribing for Upper Respiratory Illnesses by Provider Specialty. J Pediatr. 2018;203:76-85.e8. doi: 10.1016/j.jpeds.2018.07.044.
25. Rick AM, Zaheer HA, Martin JM. Clinical Features of Group A Streptococcus in Children With Pharyngitis: Carriers versus Acute Infection. Pediatr Infect Dis J. 2020;39(6):483-488. doi: 10.1097/INF.0000000000002602
26. Nadeau NL, Fine AM, Kimia A. Improving the prediction of streptococcal pharyngitis; time to move past exudate alone [published online ahead of print, 2020 Aug 16]. Am J Emerg Med. 2020;S0735-6757(20)30709-9. doi: 10.1016/j.ajem.2020.08.023
27. Mustafa Z, Ghaffari M. Diagnostic Methods, Clinical Guidelines, and Antibiotic Treatment for Group A Streptococcal Pharyngitis: A Narrative Review. Front Cell Infect Microbiol. 2020;10:563627. doi: 10.3389/fcimb.2020.563627
1. Choby BA. Diagnosis and treatment of streptococcal pharyngitis. Am Fam Physician. 2009;79(5):383-390.
2. Briel M, Schuetz P, Mueller B, et al. Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract infections in primary care. Arch of Intern Med. 2008;168(18):2000-2008. doi: 10.1001/archinte.168.18.2000
3. Maltezou HC, Tsagris V, Antoniadou A, et al. Evaluation of a rapid antigen detection test in the diagnosis of streptococcal pharyngitis in children and its impact on antibiotic prescription. J Antimicrob Chemother. 2008;62(6):1407-1412. doi: 10.1093/jac/dkn376
4. Neuner JM, Hamel MB, Phillips RS, et al. Diagnosis and management of adults with pharyngitis: a cost-effectiveness analysis. Ann Intern Med. 2003;139(2):113-122. doi:10.7326/0003-4819-139-2-200307150-00011
5. Gerber MA, Baltimore RS, Eaton CB, et al. Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2009;119(11):1541-1551. doi: 10.1161/CIRCULATIONAHA.109.191959
6. Gieseker KE, Roe MH, MacKenzie T, Todd JK. Evaluating the American Academy of Pediatrics diagnostic standard for Streptococcus pyogenes pharyngitis: backup culture versus repeat rapid antigen testing. Pediatrics. 2003;111(6):e666-e670. doi: 10.1542/peds.111.6.e666
7. Shapiro DJ, Lindgren CE, Neuman MI, Fine AM. Viral features and testing for Streptococcal pharyngitis. Pediatrics. 2017;139(5):e20163403. doi: 10.1542/peds.2016-3403
8. Shulman ST, Bisno AL, Clegg H, et al. Clinical practice guideline for the diagnosis and management of group A Streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis. 2012;55(10):e86–e102. doi: 10.1093/cid/cis629
9. Mangione-Smith R, McGlynn EA, Elliott MN, et al. Parent expectations for antibiotics, physician-parent communication, and satisfaction. Arch Pediatr Adolesc Med. 2001;155(7):800–806. doi: 10.1001/archpedi.155.7.800
10. Appropriate Testing for Children with Pharyngitis. HEDIS Measures and Technical Resources. National Committee for Quality Assurance. Accessed February 12, 2021. https://www.ncqa.org/hedis/measures/appropriate-testing-for-children-with-pharyngitis/
11. Linder JA, Bates DW, Lee GM, Finkelstein JA. Antibiotic treatment of children with sore throat. JAMA. 2005;294(18):2315-2322. doi: 10.1001/jama.294.18.2315
12. Crimmel BL. Health Insurance Coverage and Income Levels for the US Noninstitutionalized Population Under Age 65, 2001. Medical Expenditure Panel Survey, Agency for Healthcare Research and Quality. 2004. https://meps.ahrq.gov/data_files/publications/st40/stat40.pd
13. AHFS/ASHP. American Hospital Formulary Service Drug Information. 2012. AHFS drug information. 00--. Accessed January 4, 2021.
14. Mainous AG 3rd, Zoorob, RJ, Kohrs FP, Hagen MD. Streptococcal diagnostic testing and antibiotics prescribed for pediatric tonsillopharyngitis. Pediatr Infect Dis J. 1996;15(9):806-810. doi: 10.1097/00006454-199609000-00014
15. Benin AL, Vitkauskas G, Thornquist E, et al. Improving diagnostic testing and reducing overuse of antibiotics for children with pharyngitis: a useful role for the electronic medical record. Pediatr Infect Dis J. 2003;22(12):1043-1047. doi: 10.1097/01.inf.0000100577.76542.af
16. Luo R, Sickler J, Vahidnia F, et al. Diagnosis and Management of Group a Streptococcal Pharyngitis in the United States, 2011-2015. BMC Infect Dis. 2019;19(1):193-201. doi: 10.1186/s12879-019-3835-4
17. Shapiro DJ, Barak-Corren Y, Neuman MI, et al. Identifying Patients at Lowest Risk for Streptococcal Pharyngitis: A National Validation Study. J Pediatr. 2020;220:132-138.e2. doi: 10.1016/j.jpeds.2020.01.030. Epub 2020 Feb 14
18. Shapiro DJ, King LM, Fleming-Dutra KE, et al. Association between use of diagnostic tests and antibiotic prescribing for pharyngitis in the United States. Infect Control Hosp Epidemiol. 2020;41(4):479-481. doi: 10.1017/ice.2020.29
19. Sangha K, Steinberg I, McCombs JS. The impact of antibiotic treatment time and class of antibiotic for acute otitis media infections on the risk of revisits. Abs PDG4. Value in Health. 2019; 22:S163.
20. Ahluwalia T, Jain S, Norton L, Meade J, et al. Reducing Streptococcal Testing in Patients < 3 Years Old in an Emergency Department. Pediatrics. 2019;144(4):e20190174. doi: 10.1542/peds.2019-0174
21. McKay R, Mah A, Law MR, et al. Systematic Review of Factors Associated with Antibiotic Prescribing for Respiratory Tract Infections. Antimicrob Agents Chemother. 2016;60(7):4106-4118. doi: 10.1128/AAC.00209-16
22. Woods WA, Carter CT, Schlager TA. Detection of group A streptococci in children under 3 years of age with pharyngitis. Pediatr Emerg Care. 1999;15(5):338-340. doi: 10.1097/00006565-199910000-00011
23. Mendes N, Miguéis C, Lindo J, et al. Retrospective study of group A Streptococcus oropharyngeal infection diagnosis using a rapid antigenic detection test in a paediatric population from the central region of Portugal. Eur J Clin Microbiol Infect Dis. 2021;40(6):1235-1243. doi: 10.1007/s10096-021-04157-x
24. Frost HM, McLean HQ, Chow BDW. Variability in Antibiotic Prescribing for Upper Respiratory Illnesses by Provider Specialty. J Pediatr. 2018;203:76-85.e8. doi: 10.1016/j.jpeds.2018.07.044.
25. Rick AM, Zaheer HA, Martin JM. Clinical Features of Group A Streptococcus in Children With Pharyngitis: Carriers versus Acute Infection. Pediatr Infect Dis J. 2020;39(6):483-488. doi: 10.1097/INF.0000000000002602
26. Nadeau NL, Fine AM, Kimia A. Improving the prediction of streptococcal pharyngitis; time to move past exudate alone [published online ahead of print, 2020 Aug 16]. Am J Emerg Med. 2020;S0735-6757(20)30709-9. doi: 10.1016/j.ajem.2020.08.023
27. Mustafa Z, Ghaffari M. Diagnostic Methods, Clinical Guidelines, and Antibiotic Treatment for Group A Streptococcal Pharyngitis: A Narrative Review. Front Cell Infect Microbiol. 2020;10:563627. doi: 10.3389/fcimb.2020.563627