In order for percutaneous coronary intervention (PCI) to shine, compared with meds alone in patients with type-2 diabetes and stable coronary disease (CAD), it needs help from aggressive control of LDL cholesterol (LDL-C) levels, suggests a patient-level meta-analysis of three major randomized trials.

Performing PCI in such patients with diabetes conferred further benefit over optimal medical therapy (OMT) for major adverse cardiac or cerebrovascular events (MACCE) only among those whose LDL-C levels had been pushed below the guidelines-specified threshold of 70 mg/dL within 1 year.

At that level of LDL-C control, PCI, compared with the meds-alone strategy, was followed by a nearly 40% drop in 4-year risk for the composite endpoint, which consisted of death from any cause or nonfatal myocardial infarction (MI) or stroke.

Also for patients reaching a 1-year LDL-C of <70 mg/dL, the risk of MACCE was similar for those who had been assigned to coronary bypass surgery (CABG), compared with PCI. But that risk was significantly lower for the CABG group among those reaching LDL-C levels above that threshold.

“The strategy of revascularization with the LDL lowering, that’s the combination that seems to be a winner” in such patients with diabetes and stable CAD, lead author Michael E. Farkouh, MD, MSc, said in an interview.

If their LDL-C “stays above 70 mg/dL, they don’t really enjoy any benefit of PCI. It’s a message to our interventional community to really drive that LDL down,” said Dr. Farkouh, of the University of Toronto. “Not only with statins, but perhaps with PCSK9 inhibitors, ezetimibe, and other therapies to lower that LDL-C.”

The analysis, published Nov. 2 in the Journal of the American College of Cardiology, pooled more than 4,000 patients with diabetes and stable CAD randomized in the BARI 2D, FREEDOM, and COURAGE trials.

The new study adds a twist to an ongoing theme throughout some meta-analyses and clinical trials like ISCHEMIA since the results of COURAGE were unveiled 13 years ago. The latter trial famously saw no significant difference in death, MI, or stroke in patients with stable CAD assigned to OMT with or without PCI. That set off years of controversy about the relative merits of the revascularization and meds-only strategies in stable CAD that persists today.

But, Dr. Farkouh proposed, whether PCI improves clinical outcomes, compared with meds alone, at least in patients with diabetes, may be tied to the success of LDL-C-lowering therapies in reaching that goal, which in the current study was below 70 mg/dL.

“In this analysis of pooled data from the three major trials, we demonstrate that attaining that level of LDL-C at 1 year portends a better outcome for PCI” in patients with diabetes and stable CAD, he said.

The findings “probably need to be studied further, but it is compelling to think that if we can drive the LDL-C down by one year after the procedure, we have better outcomes with PCI,” compared with a meds-only strategy in patients with diabetes and stable CAD. “That really vindicates a lot of those who believe in PCI,” Dr. Farkouh said.

“What’s surprising to me is, if the patient has an LDL less than 70, why is it that there is a benefit of PCI, compared to medical therapy alone? Because they’re already so aggressively managed, you would think there shouldn’t be a benefit,” Sripal Bangalore, MD, MHA, New York University, said in an interview. “For me, that part is difficult to understand.”

The finding somewhat contradicts the results of ISCHEMIA, in which OMT – including LDL-C-lowering therapy – was considered more aggressive than usually managed in practice, Bangalore said. Yet the trial saw no outcomes difference between PCI and the more conservative approach, leading some to speculate that PCI may be a better choice when, for whatever reason, medical therapy isn’t optimal.

The observed superiority of PCI over meds-only at the lowest LDL-C levels is, according to Dr. Banagalore, “more likely because of residual confounding, given the fact that they’re combining three different trials, which are aimed to address different sets of questions.” He was an investigator with the FREEDOM and ISCHEMIA trials but isn’t associated with the current report.

The main message from this observational analysis is that “of course, we want to get the LDL as low as possible in these patients with demonstrated cardiovascular disease and diabetes,” Donald M. Lloyd-Jones, MD, ScM, Northwestern University, Chicago, said in an interview. “Every one of these patients should be shooting for as low an LDL as possible.”

Regardless of revascularization strategy, he said, “we have to get people on a high-intensity statin, or at least their maximally targeted dose, and have a careful and thoughtful conversation about whether they need additional lowering with, perhaps, ezetimibe, if they’re not below the thresholds we’d like to see them at, in this case, 70 mg/dL.”

Still, the current findings that the relative effects of PCI and CABG in these patients may vary by degree of LDL-C reduction “are interesting, but would have to be tested a little bit more directly,” said Dr. Lloyd-Jones, who is not affiliated with the analysis.

An accompanying editorial, which also acknowledges the study’s limitations, says its results “are relevant for clinical practice and may pave the way toward the generation of novel personalized medicine models that can optimize care of patients with type-2 diabetes.” 

They “support the concept of an individualized treatment strategy that accounts for a patient’s LDL-C level to estimate clinical outcomes and expected treatment effects after therapeutic interventions,” say the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.

“For daily practice, these results also underscore the importance of follow-up LDL-C measurements, both as a risk stratifier and as an indicator for therapy adjustments,” they write, noting that “current guidelines provide no formal recommendation on when to check LDL-C after PCI.”

The meta-analysis followed a total of 4050 patients with diabetes and stable CAD from the three randomized trials, those with evaluable baseline and follow-up LDL-C measurements, for a median of 4 years after the 1-year LDL-C assessment. At that time, at least 90% of patients in each of the trials had statin prescriptions, the group reported.

At one year, 34.5% of the total cohort had an LDL-C <70 mg/dL; their mean was 55.8 mg/dL.

And 42.2% had an LDL-C from 70 mg/dL to <100 mg/dL; their mean was 83.4 mg/dL. Compared with patients with an LDL-C <70 mg/dL, their adjusted hazard ratio for the composite endpoint was not elevated at 1.07 (95% CI, 0.86-1.32, P = .54).

Finally, 23.2% had an LDL-C ≥100 mg/dL; the mean was 123.0 mg/dL. Compared with the group with the lowest 1-year LDL-C, their adjusted HR for MACCE was increased at 1.46 (95% CI, 1.15 - 1.85, P = .002).

That HR among the 42.3% of patients in the PCI cohort, compared with the 33.3% assigned to meds only, climbed significantly only among those in the lowest 1-year LDL-C stratum: HR, 0.61 (95% CI, 0.40-0.91, P = .016). Corresponding HRs in the mid-range and highest 1-year LDL strata were close to unity and nonsignificant at P = .71 and P = .98, respectively.

On the other hand, the 24.4% of patients assigned to CABG showed better MACCE outcomes than those in the meds-only group across all three 1-year LDL-C strata.

The risk of MACCE wasn’t significantly altered by CABG, compared with PCI among patients achieving a 1-year LDL-C less than 70 mg/dL. However, it fell by about one-half for CABG vs. PCI in both the mid-range and highest 1-year LDL-C strata, P = .003 and P = .022, respectively.

Dr. Bangalore said he’s entirely behind the results of the study’s comparison of PCI and CABG. “It’s exactly the hypothesis that I’ve been putting forward, that if you want to achieve results as good as CABG, do PCI with aggressive medical therapy.” That means second-generation drug-eluting stents for the target lesions, “and aggressive medical therapy to address all of the nontarget lesions, specifically in diabetics.”

It’s possible, Dr. Lloyd-Jones said, that there is “no longer a dichotomy between revascularization strategies,” with respect to clinical outcomes, in such patients who maintain an LDL less than 70 mg/dL, as the study suggests.

“But I wonder, if it had continued for another 4 years of follow-up, whether we would see the CABG patients start to have more events,” such that the CABG advantage goes away at higher LDL-C levels, he proposed.

Or, Dr. Lloyd-Jones speculated, if all patients had achieved LDL-C below 70 mg/dL, “would there be such a difference between the PCI and CABG groups? My bet would be that it would be small or abolished.”

Dr. Farkouh discloses receiving research grants from Amgen, Novo Nordisk, and Novartis. Disclosures for the other study authors can be found with the original article. Editorialist Dr. Navarese discloses receiving consulting fees or honoraria from Abbott, AstraZeneca, Amgen, Bayer, Sanofi, and Pfizer; and grants from Abbott and Amgen. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

In order for percutaneous coronary intervention (PCI) to shine, compared with meds alone in patients with type-2 diabetes and stable coronary disease (CAD), it needs help from aggressive control of LDL cholesterol (LDL-C) levels, suggests a patient-level meta-analysis of three major randomized trials.

Performing PCI in such patients with diabetes conferred further benefit over optimal medical therapy (OMT) for major adverse cardiac or cerebrovascular events (MACCE) only among those whose LDL-C levels had been pushed below the guidelines-specified threshold of 70 mg/dL within 1 year.

At that level of LDL-C control, PCI, compared with the meds-alone strategy, was followed by a nearly 40% drop in 4-year risk for the composite endpoint, which consisted of death from any cause or nonfatal myocardial infarction (MI) or stroke.

Also for patients reaching a 1-year LDL-C of <70 mg/dL, the risk of MACCE was similar for those who had been assigned to coronary bypass surgery (CABG), compared with PCI. But that risk was significantly lower for the CABG group among those reaching LDL-C levels above that threshold.

“The strategy of revascularization with the LDL lowering, that’s the combination that seems to be a winner” in such patients with diabetes and stable CAD, lead author Michael E. Farkouh, MD, MSc, said in an interview.

If their LDL-C “stays above 70 mg/dL, they don’t really enjoy any benefit of PCI. It’s a message to our interventional community to really drive that LDL down,” said Dr. Farkouh, of the University of Toronto. “Not only with statins, but perhaps with PCSK9 inhibitors, ezetimibe, and other therapies to lower that LDL-C.”

The analysis, published Nov. 2 in the Journal of the American College of Cardiology, pooled more than 4,000 patients with diabetes and stable CAD randomized in the BARI 2D, FREEDOM, and COURAGE trials.

The new study adds a twist to an ongoing theme throughout some meta-analyses and clinical trials like ISCHEMIA since the results of COURAGE were unveiled 13 years ago. The latter trial famously saw no significant difference in death, MI, or stroke in patients with stable CAD assigned to OMT with or without PCI. That set off years of controversy about the relative merits of the revascularization and meds-only strategies in stable CAD that persists today.

But, Dr. Farkouh proposed, whether PCI improves clinical outcomes, compared with meds alone, at least in patients with diabetes, may be tied to the success of LDL-C-lowering therapies in reaching that goal, which in the current study was below 70 mg/dL.

“In this analysis of pooled data from the three major trials, we demonstrate that attaining that level of LDL-C at 1 year portends a better outcome for PCI” in patients with diabetes and stable CAD, he said.

The findings “probably need to be studied further, but it is compelling to think that if we can drive the LDL-C down by one year after the procedure, we have better outcomes with PCI,” compared with a meds-only strategy in patients with diabetes and stable CAD. “That really vindicates a lot of those who believe in PCI,” Dr. Farkouh said.

“What’s surprising to me is, if the patient has an LDL less than 70, why is it that there is a benefit of PCI, compared to medical therapy alone? Because they’re already so aggressively managed, you would think there shouldn’t be a benefit,” Sripal Bangalore, MD, MHA, New York University, said in an interview. “For me, that part is difficult to understand.”

The finding somewhat contradicts the results of ISCHEMIA, in which OMT – including LDL-C-lowering therapy – was considered more aggressive than usually managed in practice, Bangalore said. Yet the trial saw no outcomes difference between PCI and the more conservative approach, leading some to speculate that PCI may be a better choice when, for whatever reason, medical therapy isn’t optimal.

The observed superiority of PCI over meds-only at the lowest LDL-C levels is, according to Dr. Banagalore, “more likely because of residual confounding, given the fact that they’re combining three different trials, which are aimed to address different sets of questions.” He was an investigator with the FREEDOM and ISCHEMIA trials but isn’t associated with the current report.

The main message from this observational analysis is that “of course, we want to get the LDL as low as possible in these patients with demonstrated cardiovascular disease and diabetes,” Donald M. Lloyd-Jones, MD, ScM, Northwestern University, Chicago, said in an interview. “Every one of these patients should be shooting for as low an LDL as possible.”

Regardless of revascularization strategy, he said, “we have to get people on a high-intensity statin, or at least their maximally targeted dose, and have a careful and thoughtful conversation about whether they need additional lowering with, perhaps, ezetimibe, if they’re not below the thresholds we’d like to see them at, in this case, 70 mg/dL.”

Still, the current findings that the relative effects of PCI and CABG in these patients may vary by degree of LDL-C reduction “are interesting, but would have to be tested a little bit more directly,” said Dr. Lloyd-Jones, who is not affiliated with the analysis.

An accompanying editorial, which also acknowledges the study’s limitations, says its results “are relevant for clinical practice and may pave the way toward the generation of novel personalized medicine models that can optimize care of patients with type-2 diabetes.” 

They “support the concept of an individualized treatment strategy that accounts for a patient’s LDL-C level to estimate clinical outcomes and expected treatment effects after therapeutic interventions,” say the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.

“For daily practice, these results also underscore the importance of follow-up LDL-C measurements, both as a risk stratifier and as an indicator for therapy adjustments,” they write, noting that “current guidelines provide no formal recommendation on when to check LDL-C after PCI.”

The meta-analysis followed a total of 4050 patients with diabetes and stable CAD from the three randomized trials, those with evaluable baseline and follow-up LDL-C measurements, for a median of 4 years after the 1-year LDL-C assessment. At that time, at least 90% of patients in each of the trials had statin prescriptions, the group reported.

At one year, 34.5% of the total cohort had an LDL-C <70 mg/dL; their mean was 55.8 mg/dL.

And 42.2% had an LDL-C from 70 mg/dL to <100 mg/dL; their mean was 83.4 mg/dL. Compared with patients with an LDL-C <70 mg/dL, their adjusted hazard ratio for the composite endpoint was not elevated at 1.07 (95% CI, 0.86-1.32, P = .54).

Finally, 23.2% had an LDL-C ≥100 mg/dL; the mean was 123.0 mg/dL. Compared with the group with the lowest 1-year LDL-C, their adjusted HR for MACCE was increased at 1.46 (95% CI, 1.15 - 1.85, P = .002).

That HR among the 42.3% of patients in the PCI cohort, compared with the 33.3% assigned to meds only, climbed significantly only among those in the lowest 1-year LDL-C stratum: HR, 0.61 (95% CI, 0.40-0.91, P = .016). Corresponding HRs in the mid-range and highest 1-year LDL strata were close to unity and nonsignificant at P = .71 and P = .98, respectively.

On the other hand, the 24.4% of patients assigned to CABG showed better MACCE outcomes than those in the meds-only group across all three 1-year LDL-C strata.

The risk of MACCE wasn’t significantly altered by CABG, compared with PCI among patients achieving a 1-year LDL-C less than 70 mg/dL. However, it fell by about one-half for CABG vs. PCI in both the mid-range and highest 1-year LDL-C strata, P = .003 and P = .022, respectively.

Dr. Bangalore said he’s entirely behind the results of the study’s comparison of PCI and CABG. “It’s exactly the hypothesis that I’ve been putting forward, that if you want to achieve results as good as CABG, do PCI with aggressive medical therapy.” That means second-generation drug-eluting stents for the target lesions, “and aggressive medical therapy to address all of the nontarget lesions, specifically in diabetics.”

It’s possible, Dr. Lloyd-Jones said, that there is “no longer a dichotomy between revascularization strategies,” with respect to clinical outcomes, in such patients who maintain an LDL less than 70 mg/dL, as the study suggests.

“But I wonder, if it had continued for another 4 years of follow-up, whether we would see the CABG patients start to have more events,” such that the CABG advantage goes away at higher LDL-C levels, he proposed.

Or, Dr. Lloyd-Jones speculated, if all patients had achieved LDL-C below 70 mg/dL, “would there be such a difference between the PCI and CABG groups? My bet would be that it would be small or abolished.”

Dr. Farkouh discloses receiving research grants from Amgen, Novo Nordisk, and Novartis. Disclosures for the other study authors can be found with the original article. Editorialist Dr. Navarese discloses receiving consulting fees or honoraria from Abbott, AstraZeneca, Amgen, Bayer, Sanofi, and Pfizer; and grants from Abbott and Amgen. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

In order for percutaneous coronary intervention (PCI) to shine, compared with meds alone in patients with type-2 diabetes and stable coronary disease (CAD), it needs help from aggressive control of LDL cholesterol (LDL-C) levels, suggests a patient-level meta-analysis of three major randomized trials.

Performing PCI in such patients with diabetes conferred further benefit over optimal medical therapy (OMT) for major adverse cardiac or cerebrovascular events (MACCE) only among those whose LDL-C levels had been pushed below the guidelines-specified threshold of 70 mg/dL within 1 year.

At that level of LDL-C control, PCI, compared with the meds-alone strategy, was followed by a nearly 40% drop in 4-year risk for the composite endpoint, which consisted of death from any cause or nonfatal myocardial infarction (MI) or stroke.

Also for patients reaching a 1-year LDL-C of <70 mg/dL, the risk of MACCE was similar for those who had been assigned to coronary bypass surgery (CABG), compared with PCI. But that risk was significantly lower for the CABG group among those reaching LDL-C levels above that threshold.

“The strategy of revascularization with the LDL lowering, that’s the combination that seems to be a winner” in such patients with diabetes and stable CAD, lead author Michael E. Farkouh, MD, MSc, said in an interview.

If their LDL-C “stays above 70 mg/dL, they don’t really enjoy any benefit of PCI. It’s a message to our interventional community to really drive that LDL down,” said Dr. Farkouh, of the University of Toronto. “Not only with statins, but perhaps with PCSK9 inhibitors, ezetimibe, and other therapies to lower that LDL-C.”

The analysis, published Nov. 2 in the Journal of the American College of Cardiology, pooled more than 4,000 patients with diabetes and stable CAD randomized in the BARI 2D, FREEDOM, and COURAGE trials.

The new study adds a twist to an ongoing theme throughout some meta-analyses and clinical trials like ISCHEMIA since the results of COURAGE were unveiled 13 years ago. The latter trial famously saw no significant difference in death, MI, or stroke in patients with stable CAD assigned to OMT with or without PCI. That set off years of controversy about the relative merits of the revascularization and meds-only strategies in stable CAD that persists today.

But, Dr. Farkouh proposed, whether PCI improves clinical outcomes, compared with meds alone, at least in patients with diabetes, may be tied to the success of LDL-C-lowering therapies in reaching that goal, which in the current study was below 70 mg/dL.

“In this analysis of pooled data from the three major trials, we demonstrate that attaining that level of LDL-C at 1 year portends a better outcome for PCI” in patients with diabetes and stable CAD, he said.

The findings “probably need to be studied further, but it is compelling to think that if we can drive the LDL-C down by one year after the procedure, we have better outcomes with PCI,” compared with a meds-only strategy in patients with diabetes and stable CAD. “That really vindicates a lot of those who believe in PCI,” Dr. Farkouh said.

“What’s surprising to me is, if the patient has an LDL less than 70, why is it that there is a benefit of PCI, compared to medical therapy alone? Because they’re already so aggressively managed, you would think there shouldn’t be a benefit,” Sripal Bangalore, MD, MHA, New York University, said in an interview. “For me, that part is difficult to understand.”

The finding somewhat contradicts the results of ISCHEMIA, in which OMT – including LDL-C-lowering therapy – was considered more aggressive than usually managed in practice, Bangalore said. Yet the trial saw no outcomes difference between PCI and the more conservative approach, leading some to speculate that PCI may be a better choice when, for whatever reason, medical therapy isn’t optimal.

The observed superiority of PCI over meds-only at the lowest LDL-C levels is, according to Dr. Banagalore, “more likely because of residual confounding, given the fact that they’re combining three different trials, which are aimed to address different sets of questions.” He was an investigator with the FREEDOM and ISCHEMIA trials but isn’t associated with the current report.

The main message from this observational analysis is that “of course, we want to get the LDL as low as possible in these patients with demonstrated cardiovascular disease and diabetes,” Donald M. Lloyd-Jones, MD, ScM, Northwestern University, Chicago, said in an interview. “Every one of these patients should be shooting for as low an LDL as possible.”

Regardless of revascularization strategy, he said, “we have to get people on a high-intensity statin, or at least their maximally targeted dose, and have a careful and thoughtful conversation about whether they need additional lowering with, perhaps, ezetimibe, if they’re not below the thresholds we’d like to see them at, in this case, 70 mg/dL.”

Still, the current findings that the relative effects of PCI and CABG in these patients may vary by degree of LDL-C reduction “are interesting, but would have to be tested a little bit more directly,” said Dr. Lloyd-Jones, who is not affiliated with the analysis.

An accompanying editorial, which also acknowledges the study’s limitations, says its results “are relevant for clinical practice and may pave the way toward the generation of novel personalized medicine models that can optimize care of patients with type-2 diabetes.” 

They “support the concept of an individualized treatment strategy that accounts for a patient’s LDL-C level to estimate clinical outcomes and expected treatment effects after therapeutic interventions,” say the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.

“For daily practice, these results also underscore the importance of follow-up LDL-C measurements, both as a risk stratifier and as an indicator for therapy adjustments,” they write, noting that “current guidelines provide no formal recommendation on when to check LDL-C after PCI.”

The meta-analysis followed a total of 4050 patients with diabetes and stable CAD from the three randomized trials, those with evaluable baseline and follow-up LDL-C measurements, for a median of 4 years after the 1-year LDL-C assessment. At that time, at least 90% of patients in each of the trials had statin prescriptions, the group reported.

At one year, 34.5% of the total cohort had an LDL-C <70 mg/dL; their mean was 55.8 mg/dL.

And 42.2% had an LDL-C from 70 mg/dL to <100 mg/dL; their mean was 83.4 mg/dL. Compared with patients with an LDL-C <70 mg/dL, their adjusted hazard ratio for the composite endpoint was not elevated at 1.07 (95% CI, 0.86-1.32, P = .54).

Finally, 23.2% had an LDL-C ≥100 mg/dL; the mean was 123.0 mg/dL. Compared with the group with the lowest 1-year LDL-C, their adjusted HR for MACCE was increased at 1.46 (95% CI, 1.15 - 1.85, P = .002).

That HR among the 42.3% of patients in the PCI cohort, compared with the 33.3% assigned to meds only, climbed significantly only among those in the lowest 1-year LDL-C stratum: HR, 0.61 (95% CI, 0.40-0.91, P = .016). Corresponding HRs in the mid-range and highest 1-year LDL strata were close to unity and nonsignificant at P = .71 and P = .98, respectively.

On the other hand, the 24.4% of patients assigned to CABG showed better MACCE outcomes than those in the meds-only group across all three 1-year LDL-C strata.

The risk of MACCE wasn’t significantly altered by CABG, compared with PCI among patients achieving a 1-year LDL-C less than 70 mg/dL. However, it fell by about one-half for CABG vs. PCI in both the mid-range and highest 1-year LDL-C strata, P = .003 and P = .022, respectively.

Dr. Bangalore said he’s entirely behind the results of the study’s comparison of PCI and CABG. “It’s exactly the hypothesis that I’ve been putting forward, that if you want to achieve results as good as CABG, do PCI with aggressive medical therapy.” That means second-generation drug-eluting stents for the target lesions, “and aggressive medical therapy to address all of the nontarget lesions, specifically in diabetics.”

It’s possible, Dr. Lloyd-Jones said, that there is “no longer a dichotomy between revascularization strategies,” with respect to clinical outcomes, in such patients who maintain an LDL less than 70 mg/dL, as the study suggests.

“But I wonder, if it had continued for another 4 years of follow-up, whether we would see the CABG patients start to have more events,” such that the CABG advantage goes away at higher LDL-C levels, he proposed.

Or, Dr. Lloyd-Jones speculated, if all patients had achieved LDL-C below 70 mg/dL, “would there be such a difference between the PCI and CABG groups? My bet would be that it would be small or abolished.”

Dr. Farkouh discloses receiving research grants from Amgen, Novo Nordisk, and Novartis. Disclosures for the other study authors can be found with the original article. Editorialist Dr. Navarese discloses receiving consulting fees or honoraria from Abbott, AstraZeneca, Amgen, Bayer, Sanofi, and Pfizer; and grants from Abbott and Amgen. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

“I would argue that the most important reason to care about climate change is because of our children,” Saul Hymes, MD, said at the annual meeting of the American Academy of Pediatrics, held virtually this year.

Cynthia Goldsmith/CDC photo #10073

“Being able to point out to people how climate change harms the health of their children and affects their children’s risk of infections is a particularly effective argument to make,” said Dr. Hymes, a pediatric infectious diseases specialist at Stony Brook (N.Y.) University.

Rachel Boykan, MD, a pediatrician at the university, found Dr. Hymes’ presentation excellent and highly relevant to issues all health care workers treating children face, even beyond infectious disease.

“It was data focused but also understandable for a broad audience,” Dr. Boykan, who was not involved in the presentation, said in an interview. “He explained the science of climate change in a way that all physicians, but especially pediatricians, would find relevant. I suspect if people who were listening didn’t already prioritize the issues of climate change, they certainly did after hearing the talk.”

She also appreciated that Dr. Hymes addressed how climate change affects everyone in both their professional and personal lives.

“We need to be prepared to address the clinical issues that ensue after a natural disaster, and we need to be advocates for change so that we can slow down the climate changes we are all dealing with,” said Dr. Boykan, adding that the presentation was also inspiring. “He presented many different viewpoints and many ways to be involved and to be an advocate. I would think that a good number of people who were there would be energized to do something differently to combat climate change.”
 

The multitudinous impacts of climate change

The impact of climate change on human health is broad and far-reaching, Dr. Hymes said. It doesn’t require much imagination to recognize that rising global temperatures can lead to prolonged extreme heat waves that can cause heat-related deaths and illnesses. But other effects can be more gradual or subtle. Changes in outdoor air quality can affect weather patterns, pollen counts, and air pollution that can increase risk of asthma, allergies, as well as acute and chronic respiratory and cardiovascular disease.

Sea level rise, more frequent and severe hurricanes, storm surges, and extreme precipitation all can lead to contaminated water and destruction of essential infrastructure. In addition to drowning and injuries from the storms themselves, these changes have mental health consequences, and can lead to gastrointestinal and other illnesses, including water-borne infectious disease. The distribution and prevalence of vector-borne diseases also will shift with changes in temperature, precipitation, and other weather patterns.
 

Distribution, prevalence of vector-borne diseases shift with climate change

One of the most common bacteria transmitted by vectors in the United States is Borrelia burgdorferi, the cause of Lyme disease. Transmitted by deer ticks, Lyme disease is listed by the Environmental Protection Agency as an indicator of climate change’s impact on human health and is becoming more common every year. Cases doubled from 1990 to 2014, from 4 to 8 cases per 100,000 people.

CDC/ Dr. Amanda Loftis, Dr. William Nicholson, Dr. Will Reeves, Dr. Chris Paddock

Increases were most dramatic in the Northeast, where Lyme disease is endemic. States such as Maine, Vermont, and New Hampshire all saw increases of 80-100 more cases per 100,000 people. Evidence now shows that Lyme disease is moving north as the climate warms. Toronto, for example, has seen more than a 400% increase in cases in less than a decade, from 128 cases per 100,000 people in 2009 to 700 cases per 100,000 in 2015.

“It’s a known phenomenon that climate change affects more northerly latitudes disproportionately to more than southerly latitudes,” Dr. Hymes said. He shared a 2013 study providing evidence that climate change is expanding the range of Lyme disease. Even when controlling for other confounding factors, the research found that areas being warmed proportionately more by climate change also are experiencing greater Lyme incidence. While Lyme cases declined in several Western and Deep South states, it significantly increased in nearly every Northeast state as well as Idaho, Arizona, and states in the northern Midwest near the Great Lakes.

Courtesy CDC

“We find that this impact of climate change on the movement of vectors like ticks affects more than just Lyme disease,” Dr. Hymes said. Amblyomma americanum, the Lone Star tick, has historically been restricted to the southern United States but is now found further north, even up to New England. It carries bacteria that can cause multiple illnesses, including ehrlichiosis, heartland virus, and tularemia.

An alpha-gal meat allergy associated with this tick can lead to anaphylaxis about 6 hours after a person eats red meat or pork. Prevalence of this allergy, first reported in Georgia in 1989-1991, has been increasing and moving further north, and the Lone Star tick is a particularly heat-tolerant and heat-loving tick.

Climate change also affects how long during the year people are at risk. Lyme disease, for example, typically lasted from April/May to October, when ticks then hibernated during the cold weather. But the warming climate has expanded Lyme season: Local Lyme cases have begun occurring into November through January on Long Island over the past 5 years.

Courtesy Megan Lobdell

The impact of seasonal changes on infectious diseases overall is difficult to predict. The seasons for cold weather diseases such as influenza and respiratory syncytial virus, for example, may become shorter or milder while viruses more common in the summer, such as enteroviruses, may become a risk year-round.
 

Natural disasters pose multiple risks

Natural disasters can pose immediate dangers to families and have a significant impact on mental health, but that’s not their only potential impact.

“Severe weather events such as hurricanes, floods, and tornadoes are well established in the climate change literature as an effect of increased temperatures and more volatile weather systems, but they also have a significant effect on infectious diseases and on children in particular,” Dr. Hymes said. “Hurricanes and flash floods can cause increases in infectious disease outbreaks through a variety of different ways.”

They can bring saltwater, freshwater, and sometimes soil organisms into the food and water supplies, and lead to sewage contamination from overloaded sewers, overflowing storm drains, and loss of power or pumps. Displaced animal vectors, such as rats, can lead to spread of other diseases, such as plague, hantavirus, typhus, and rabies.

Examples of saltwater organisms include Vibrio, Aeromonas, and Mycobacterium marinum, all of which can cause infections in wounds and/or diarrheal illness or bacteremia. Similarly, organisms from freshwater and soil that can cause serious illness or death include Aeromonas, Pseudomonas, Amebiasis, Giardia, and Legionella. Without access to clean water, or with contamination from overflowing sewage, cryptosporidium, Escherichia coli, salmonella, typhoid, norovirus, hepatitis A and E, and even cholera can also become problems as well.

In Houston following Hurricane Harvey, for example, cellulitis cases doubled and included infections from organisms different from the usual suspects. Scrapes and cuts that occurred during the storm also festered sooner.

Cases of disease linked to Hurricane Katrina in a Centers for Disease Control and Prevention report included 6 cases of cholera, 17 cases of other vibrio – including five that resulted in death – and reported cases of norovirus, Escherichia coli, salmonella, and influenza and pneumonia from overcrowding of evacuees.
 

You can help in a variety of ways

You can play several key roles as the world’s climate changes, starting with preparing for the changes. You should familiarize themselves with new and emerging infections, or those that have been around a while but not seen in your areas, such as Lyme, Zika, and Dengue.

“If you haven’t seen them already, you likely will due to movements of vector-borne infections that can occur due to climate change,” Dr. Hymes said. “You also want to expect the usual common diseases, but maybe at unsuspected times,” he added. “If you have a pediatric patient who looks like they have Coxsackie virus but it’s February, if it’s been a warm February, it may very well be Coxsackie virus.”

Following natural disasters such as floods, hurricanes and tornadoes, consider who your patients are. If they’re evacuees, are they living in overcrowded conditions? Do they have access to clean water? If not, explain the need to boil water if they can, or to use iodine tablets or a portable pump filter. Consider that some infections may involve unexpected or odd organisms, such as legionella pneumonia or vibrio cellulitis, and contact your local infectious disease doctor as needed.

You also can make personal lifestyle changes that, while small, can add up in the aggregate in reducing carbon footprints, such as purchasing an electric or hybrid car and converting their homes to solar power.

“For very little money, you can purchase carbon offsets,” Dr. Hymes said, such as $10-$15 a month for wind power offsets with home electricity or $5-$10 a month for car or plane travel.

“But really, the most important thing we can do as pediatricians is educate,” Dr. Hymes said. “Taking opportunities every day in your office to educate your patients and educate your colleagues about the importance of climate change in our patients’ health and our own children’s health is super, super important.”

Dr. Hymes and Dr. Boykan had no relevant financial disclosures.

“I would argue that the most important reason to care about climate change is because of our children,” Saul Hymes, MD, said at the annual meeting of the American Academy of Pediatrics, held virtually this year.

Cynthia Goldsmith/CDC photo #10073

“Being able to point out to people how climate change harms the health of their children and affects their children’s risk of infections is a particularly effective argument to make,” said Dr. Hymes, a pediatric infectious diseases specialist at Stony Brook (N.Y.) University.

Rachel Boykan, MD, a pediatrician at the university, found Dr. Hymes’ presentation excellent and highly relevant to issues all health care workers treating children face, even beyond infectious disease.

“It was data focused but also understandable for a broad audience,” Dr. Boykan, who was not involved in the presentation, said in an interview. “He explained the science of climate change in a way that all physicians, but especially pediatricians, would find relevant. I suspect if people who were listening didn’t already prioritize the issues of climate change, they certainly did after hearing the talk.”

She also appreciated that Dr. Hymes addressed how climate change affects everyone in both their professional and personal lives.

“We need to be prepared to address the clinical issues that ensue after a natural disaster, and we need to be advocates for change so that we can slow down the climate changes we are all dealing with,” said Dr. Boykan, adding that the presentation was also inspiring. “He presented many different viewpoints and many ways to be involved and to be an advocate. I would think that a good number of people who were there would be energized to do something differently to combat climate change.”
 

The multitudinous impacts of climate change

The impact of climate change on human health is broad and far-reaching, Dr. Hymes said. It doesn’t require much imagination to recognize that rising global temperatures can lead to prolonged extreme heat waves that can cause heat-related deaths and illnesses. But other effects can be more gradual or subtle. Changes in outdoor air quality can affect weather patterns, pollen counts, and air pollution that can increase risk of asthma, allergies, as well as acute and chronic respiratory and cardiovascular disease.

Sea level rise, more frequent and severe hurricanes, storm surges, and extreme precipitation all can lead to contaminated water and destruction of essential infrastructure. In addition to drowning and injuries from the storms themselves, these changes have mental health consequences, and can lead to gastrointestinal and other illnesses, including water-borne infectious disease. The distribution and prevalence of vector-borne diseases also will shift with changes in temperature, precipitation, and other weather patterns.
 

Distribution, prevalence of vector-borne diseases shift with climate change

One of the most common bacteria transmitted by vectors in the United States is Borrelia burgdorferi, the cause of Lyme disease. Transmitted by deer ticks, Lyme disease is listed by the Environmental Protection Agency as an indicator of climate change’s impact on human health and is becoming more common every year. Cases doubled from 1990 to 2014, from 4 to 8 cases per 100,000 people.

CDC/ Dr. Amanda Loftis, Dr. William Nicholson, Dr. Will Reeves, Dr. Chris Paddock

Increases were most dramatic in the Northeast, where Lyme disease is endemic. States such as Maine, Vermont, and New Hampshire all saw increases of 80-100 more cases per 100,000 people. Evidence now shows that Lyme disease is moving north as the climate warms. Toronto, for example, has seen more than a 400% increase in cases in less than a decade, from 128 cases per 100,000 people in 2009 to 700 cases per 100,000 in 2015.

“It’s a known phenomenon that climate change affects more northerly latitudes disproportionately to more than southerly latitudes,” Dr. Hymes said. He shared a 2013 study providing evidence that climate change is expanding the range of Lyme disease. Even when controlling for other confounding factors, the research found that areas being warmed proportionately more by climate change also are experiencing greater Lyme incidence. While Lyme cases declined in several Western and Deep South states, it significantly increased in nearly every Northeast state as well as Idaho, Arizona, and states in the northern Midwest near the Great Lakes.

Courtesy CDC

“We find that this impact of climate change on the movement of vectors like ticks affects more than just Lyme disease,” Dr. Hymes said. Amblyomma americanum, the Lone Star tick, has historically been restricted to the southern United States but is now found further north, even up to New England. It carries bacteria that can cause multiple illnesses, including ehrlichiosis, heartland virus, and tularemia.

An alpha-gal meat allergy associated with this tick can lead to anaphylaxis about 6 hours after a person eats red meat or pork. Prevalence of this allergy, first reported in Georgia in 1989-1991, has been increasing and moving further north, and the Lone Star tick is a particularly heat-tolerant and heat-loving tick.

Climate change also affects how long during the year people are at risk. Lyme disease, for example, typically lasted from April/May to October, when ticks then hibernated during the cold weather. But the warming climate has expanded Lyme season: Local Lyme cases have begun occurring into November through January on Long Island over the past 5 years.

Courtesy Megan Lobdell

The impact of seasonal changes on infectious diseases overall is difficult to predict. The seasons for cold weather diseases such as influenza and respiratory syncytial virus, for example, may become shorter or milder while viruses more common in the summer, such as enteroviruses, may become a risk year-round.
 

Natural disasters pose multiple risks

Natural disasters can pose immediate dangers to families and have a significant impact on mental health, but that’s not their only potential impact.

“Severe weather events such as hurricanes, floods, and tornadoes are well established in the climate change literature as an effect of increased temperatures and more volatile weather systems, but they also have a significant effect on infectious diseases and on children in particular,” Dr. Hymes said. “Hurricanes and flash floods can cause increases in infectious disease outbreaks through a variety of different ways.”

They can bring saltwater, freshwater, and sometimes soil organisms into the food and water supplies, and lead to sewage contamination from overloaded sewers, overflowing storm drains, and loss of power or pumps. Displaced animal vectors, such as rats, can lead to spread of other diseases, such as plague, hantavirus, typhus, and rabies.

Examples of saltwater organisms include Vibrio, Aeromonas, and Mycobacterium marinum, all of which can cause infections in wounds and/or diarrheal illness or bacteremia. Similarly, organisms from freshwater and soil that can cause serious illness or death include Aeromonas, Pseudomonas, Amebiasis, Giardia, and Legionella. Without access to clean water, or with contamination from overflowing sewage, cryptosporidium, Escherichia coli, salmonella, typhoid, norovirus, hepatitis A and E, and even cholera can also become problems as well.

In Houston following Hurricane Harvey, for example, cellulitis cases doubled and included infections from organisms different from the usual suspects. Scrapes and cuts that occurred during the storm also festered sooner.

Cases of disease linked to Hurricane Katrina in a Centers for Disease Control and Prevention report included 6 cases of cholera, 17 cases of other vibrio – including five that resulted in death – and reported cases of norovirus, Escherichia coli, salmonella, and influenza and pneumonia from overcrowding of evacuees.
 

You can help in a variety of ways

You can play several key roles as the world’s climate changes, starting with preparing for the changes. You should familiarize themselves with new and emerging infections, or those that have been around a while but not seen in your areas, such as Lyme, Zika, and Dengue.

“If you haven’t seen them already, you likely will due to movements of vector-borne infections that can occur due to climate change,” Dr. Hymes said. “You also want to expect the usual common diseases, but maybe at unsuspected times,” he added. “If you have a pediatric patient who looks like they have Coxsackie virus but it’s February, if it’s been a warm February, it may very well be Coxsackie virus.”

Following natural disasters such as floods, hurricanes and tornadoes, consider who your patients are. If they’re evacuees, are they living in overcrowded conditions? Do they have access to clean water? If not, explain the need to boil water if they can, or to use iodine tablets or a portable pump filter. Consider that some infections may involve unexpected or odd organisms, such as legionella pneumonia or vibrio cellulitis, and contact your local infectious disease doctor as needed.

You also can make personal lifestyle changes that, while small, can add up in the aggregate in reducing carbon footprints, such as purchasing an electric or hybrid car and converting their homes to solar power.

“For very little money, you can purchase carbon offsets,” Dr. Hymes said, such as $10-$15 a month for wind power offsets with home electricity or $5-$10 a month for car or plane travel.

“But really, the most important thing we can do as pediatricians is educate,” Dr. Hymes said. “Taking opportunities every day in your office to educate your patients and educate your colleagues about the importance of climate change in our patients’ health and our own children’s health is super, super important.”

Dr. Hymes and Dr. Boykan had no relevant financial disclosures.

“I would argue that the most important reason to care about climate change is because of our children,” Saul Hymes, MD, said at the annual meeting of the American Academy of Pediatrics, held virtually this year.

Cynthia Goldsmith/CDC photo #10073

“Being able to point out to people how climate change harms the health of their children and affects their children’s risk of infections is a particularly effective argument to make,” said Dr. Hymes, a pediatric infectious diseases specialist at Stony Brook (N.Y.) University.

Rachel Boykan, MD, a pediatrician at the university, found Dr. Hymes’ presentation excellent and highly relevant to issues all health care workers treating children face, even beyond infectious disease.

“It was data focused but also understandable for a broad audience,” Dr. Boykan, who was not involved in the presentation, said in an interview. “He explained the science of climate change in a way that all physicians, but especially pediatricians, would find relevant. I suspect if people who were listening didn’t already prioritize the issues of climate change, they certainly did after hearing the talk.”

She also appreciated that Dr. Hymes addressed how climate change affects everyone in both their professional and personal lives.

“We need to be prepared to address the clinical issues that ensue after a natural disaster, and we need to be advocates for change so that we can slow down the climate changes we are all dealing with,” said Dr. Boykan, adding that the presentation was also inspiring. “He presented many different viewpoints and many ways to be involved and to be an advocate. I would think that a good number of people who were there would be energized to do something differently to combat climate change.”
 

The multitudinous impacts of climate change

The impact of climate change on human health is broad and far-reaching, Dr. Hymes said. It doesn’t require much imagination to recognize that rising global temperatures can lead to prolonged extreme heat waves that can cause heat-related deaths and illnesses. But other effects can be more gradual or subtle. Changes in outdoor air quality can affect weather patterns, pollen counts, and air pollution that can increase risk of asthma, allergies, as well as acute and chronic respiratory and cardiovascular disease.

Sea level rise, more frequent and severe hurricanes, storm surges, and extreme precipitation all can lead to contaminated water and destruction of essential infrastructure. In addition to drowning and injuries from the storms themselves, these changes have mental health consequences, and can lead to gastrointestinal and other illnesses, including water-borne infectious disease. The distribution and prevalence of vector-borne diseases also will shift with changes in temperature, precipitation, and other weather patterns.
 

Distribution, prevalence of vector-borne diseases shift with climate change

One of the most common bacteria transmitted by vectors in the United States is Borrelia burgdorferi, the cause of Lyme disease. Transmitted by deer ticks, Lyme disease is listed by the Environmental Protection Agency as an indicator of climate change’s impact on human health and is becoming more common every year. Cases doubled from 1990 to 2014, from 4 to 8 cases per 100,000 people.

CDC/ Dr. Amanda Loftis, Dr. William Nicholson, Dr. Will Reeves, Dr. Chris Paddock

Increases were most dramatic in the Northeast, where Lyme disease is endemic. States such as Maine, Vermont, and New Hampshire all saw increases of 80-100 more cases per 100,000 people. Evidence now shows that Lyme disease is moving north as the climate warms. Toronto, for example, has seen more than a 400% increase in cases in less than a decade, from 128 cases per 100,000 people in 2009 to 700 cases per 100,000 in 2015.

“It’s a known phenomenon that climate change affects more northerly latitudes disproportionately to more than southerly latitudes,” Dr. Hymes said. He shared a 2013 study providing evidence that climate change is expanding the range of Lyme disease. Even when controlling for other confounding factors, the research found that areas being warmed proportionately more by climate change also are experiencing greater Lyme incidence. While Lyme cases declined in several Western and Deep South states, it significantly increased in nearly every Northeast state as well as Idaho, Arizona, and states in the northern Midwest near the Great Lakes.

Courtesy CDC

“We find that this impact of climate change on the movement of vectors like ticks affects more than just Lyme disease,” Dr. Hymes said. Amblyomma americanum, the Lone Star tick, has historically been restricted to the southern United States but is now found further north, even up to New England. It carries bacteria that can cause multiple illnesses, including ehrlichiosis, heartland virus, and tularemia.

An alpha-gal meat allergy associated with this tick can lead to anaphylaxis about 6 hours after a person eats red meat or pork. Prevalence of this allergy, first reported in Georgia in 1989-1991, has been increasing and moving further north, and the Lone Star tick is a particularly heat-tolerant and heat-loving tick.

Climate change also affects how long during the year people are at risk. Lyme disease, for example, typically lasted from April/May to October, when ticks then hibernated during the cold weather. But the warming climate has expanded Lyme season: Local Lyme cases have begun occurring into November through January on Long Island over the past 5 years.

Courtesy Megan Lobdell

The impact of seasonal changes on infectious diseases overall is difficult to predict. The seasons for cold weather diseases such as influenza and respiratory syncytial virus, for example, may become shorter or milder while viruses more common in the summer, such as enteroviruses, may become a risk year-round.
 

Natural disasters pose multiple risks

Natural disasters can pose immediate dangers to families and have a significant impact on mental health, but that’s not their only potential impact.

“Severe weather events such as hurricanes, floods, and tornadoes are well established in the climate change literature as an effect of increased temperatures and more volatile weather systems, but they also have a significant effect on infectious diseases and on children in particular,” Dr. Hymes said. “Hurricanes and flash floods can cause increases in infectious disease outbreaks through a variety of different ways.”

They can bring saltwater, freshwater, and sometimes soil organisms into the food and water supplies, and lead to sewage contamination from overloaded sewers, overflowing storm drains, and loss of power or pumps. Displaced animal vectors, such as rats, can lead to spread of other diseases, such as plague, hantavirus, typhus, and rabies.

Examples of saltwater organisms include Vibrio, Aeromonas, and Mycobacterium marinum, all of which can cause infections in wounds and/or diarrheal illness or bacteremia. Similarly, organisms from freshwater and soil that can cause serious illness or death include Aeromonas, Pseudomonas, Amebiasis, Giardia, and Legionella. Without access to clean water, or with contamination from overflowing sewage, cryptosporidium, Escherichia coli, salmonella, typhoid, norovirus, hepatitis A and E, and even cholera can also become problems as well.

In Houston following Hurricane Harvey, for example, cellulitis cases doubled and included infections from organisms different from the usual suspects. Scrapes and cuts that occurred during the storm also festered sooner.

Cases of disease linked to Hurricane Katrina in a Centers for Disease Control and Prevention report included 6 cases of cholera, 17 cases of other vibrio – including five that resulted in death – and reported cases of norovirus, Escherichia coli, salmonella, and influenza and pneumonia from overcrowding of evacuees.
 

You can help in a variety of ways

You can play several key roles as the world’s climate changes, starting with preparing for the changes. You should familiarize themselves with new and emerging infections, or those that have been around a while but not seen in your areas, such as Lyme, Zika, and Dengue.

“If you haven’t seen them already, you likely will due to movements of vector-borne infections that can occur due to climate change,” Dr. Hymes said. “You also want to expect the usual common diseases, but maybe at unsuspected times,” he added. “If you have a pediatric patient who looks like they have Coxsackie virus but it’s February, if it’s been a warm February, it may very well be Coxsackie virus.”

Following natural disasters such as floods, hurricanes and tornadoes, consider who your patients are. If they’re evacuees, are they living in overcrowded conditions? Do they have access to clean water? If not, explain the need to boil water if they can, or to use iodine tablets or a portable pump filter. Consider that some infections may involve unexpected or odd organisms, such as legionella pneumonia or vibrio cellulitis, and contact your local infectious disease doctor as needed.

You also can make personal lifestyle changes that, while small, can add up in the aggregate in reducing carbon footprints, such as purchasing an electric or hybrid car and converting their homes to solar power.

“For very little money, you can purchase carbon offsets,” Dr. Hymes said, such as $10-$15 a month for wind power offsets with home electricity or $5-$10 a month for car or plane travel.

“But really, the most important thing we can do as pediatricians is educate,” Dr. Hymes said. “Taking opportunities every day in your office to educate your patients and educate your colleagues about the importance of climate change in our patients’ health and our own children’s health is super, super important.”

Dr. Hymes and Dr. Boykan had no relevant financial disclosures.

Pruritus, defined as a sensation that induces a desire to scratch¹ and classified as acute or chronic (lasting > 6 weeks),² is one of the most common complaints among primary care patients: Approximately 1% of ambulatory visits in the United States are linked to pruritus.³

Chronic pruritus impairs quality of life; its impact has been compared to that of chronic pain.⁴ Treatment should therefore be instituted promptly. Although this condition might appear benign, chronic pruritus can be a symptom of a serious condition, as we describe here. When persistent pruritus is refractory to treatment, systemic causes should be fully explored.

In this article, we discuss the pathogenesis and management of pruritus without skin eruption in the adult nonpregnant patient. We also present practice recommendations to help you determine whether your patient’s pruritus is indicative of a serious systemic condition.

An incomplete understanding of the pathophysiology of pruritus

The pathophysiology of pruritus is not fully understood. It is generally recognized, however, that pruritus starts in the peripheral nerves located in the dermal–epidermal junction of the skin.⁵ The sensation is then transmitted along unmyelinated slow-conducting C fibers to the dorsal horn of the spinal cord.^5,6 There are 2 types of C fibers that transmit the itch impulse⁶: A histamine-dependent type and a non-­histamine-dependent type, which might explain why pruritus can be refractory to antihistamine treatment.⁶

Once the itch impulse has moved from the spinal cord, it travels along the spinothalamic tract up to the contralateral thalamus.¹ From there, the impulse ascends to the cerebral cortex.¹ In the cortex, the impulse triggers multiple areas of the brain, such as those responsible for sensation, motor function, reward, memory, and emotion.⁷

Although this condition might appear benign, chronic pruritus can be a symptom of a serious condition.

Several chemical mediators have been found to be peripheral and central inducers of pruritus: histamine, endogenous opioids, substance P, and serotonin.² There are indications that certain receptors, such as mu-opioid receptors and kappa-opioid receptors, are key contributors to itch as well.²

A diverse etiology

The International Forum for the Study of Itch (IFSI) has established 6 main categories of causes of pruritus(TABLE 1)²:

• dermatologic
• systemic
• neurologic
• psychogenic
• mixed
• other.

Continue to: In this review...

In this review, we focus on the work-up and management of 3 of those categories: systemic, neurologic, and psychogenic causes of pruritus.

Systemic causes

Research has shown that 14% to 24% of patients who seek the care of a dermatologist for chronic itch without skin lesions have a systemic illness.⁸

Renal disease. Approximately 40% of patients with end-stage renal disease who are on hemodialysis or peritoneal dialysis have uremic pruritus.2 The itch is mostly generalized but can be pronounced on the back. For most patients, the itch is worse at night, causing a major impact on quality of life.⁶

Liver disease. In hepatic disease, there is often impairment in the secretion of bile, which can lead to cholestatic pruritus.² This condition commonly affects the hands and feet first; later, it becomes generalized.² Cholestatic pruritus can be elicited by tight-fitting clothing. Relief is not achieved by scratching.⁹ This type of itch effects 70% of patients with primary biliary cirrhosis and 15% of patients with hepatitis C infection.⁹

Hematologic disorders. Pruritus is a hallmark symptom of polycythemia rubra vera. Almost 50% of patients with this disorder report pruritus that occurs after exposure to water⁹; aquagenic pruritus can precede the formal diagnosis of polycythemia rubra vera by years.² It has been speculated that platelet aggregation in this disorder leads to release of serotonin and histamine, which, in turn, causes itch.⁹

Continue to: Endocrine disorders

Endocrine disorders. Approximately 4% to 11% of patients with thyrotoxicosis have pruritus.¹ It has been suggested that vasodilation, increased skin temperature, and a decreased itch threshold from untreated Graves disease might be inciting factors.

Malignancy. In generalized chronic pruritus without a known cause, strongly consider the likelihood of underlying malignancy^8,10; for 10% of these patients, their chronic pruritus is a paraneoplastic sign. Paraneoplastic pruritus is characterized as an itch that predates clinical onset, or occurs early in the course, of a malignancy.⁹ The condition is most strongly linked to cancers of the liver, gallbladder, biliary tract, hematologic system, and skin.¹¹

Palpate the liver, spleen, lymph nodes, and thyroid for organomegaly, which could indicate a serious systemic condition as the cause of pruritus.

Chronic pruritus affects 30% of patients with Hodgkin lymphoma.⁹ General pruritus can precede this diagnosis by months, even years.¹ In Hodgkin lymphoma patients who are in remission, a return of pruritic symptoms can be a harbinger of recurrence.⁹

Neurologic causes

A recent study found that 8% to 15% of patients referred to a dermatology clinic for chronic pruritus without skin eruption had underlying neurologic pathology.¹² Although the specific mechanisms of neuropathic itch are still poorly understood, it has been theorized that the itch emanates from neuronal damage, which can come from peripheral or central nervous system lesions.⁹

Brachioradial pruritus. There are divergent theories about the etiology of brachioradial pruritus. One hypothesis is that the condition is caused by cervical nerve-root impingement at the level of C5-C8 that leads to nerve damage²; another is that chronic exposure to sunlight causes injury to peripheral cutaneous nerves.² Brachioradial pruritus is localized to the dorsolateral forearm; it can also involve the neck, back, shoulder, upper arm, and chest, unilaterally and bilaterally. This pruritus can be intermittent and become worse upon exposure to sunlight.²

Continue to: Notalgia paresthetica

Notalgia paresthetica. This condition might also cause neuropathic pruritus as a consequence of nerve impingement. The itch of notalgia paresthesia is located on the skin, medial to the scapular border on the upper or mid-back.² It has been postulated that the itch is caused by nerve entrapment of the posterior rami of spinal nerves arising from T2-T6.⁹ However, another theory suggests that the itch is caused by damage to peripheral nerves.⁹ The itch of notalgia paresthetica can wax and wane.²

Poststroke pruritus. Brain lesions, most often caused by stroke, can cause neuropathic itch. One of the best-known syndromes related to poststroke itch is Wallenberg syndrome (ischemia from a lateral medullary infarction), which typically presents with itch, thermalgic hypoesthesia of the face, cerebellar dysfunction, nausea, and vomiting.⁷

Shingles. More than one-half of patients who develop postherpetic neuralgia as a consequence of a herpes zoster infection also develop neuropathic pruritus.⁹ It is thought that postherpetic pruritus shares a comparable pathophysiology with postherpetic neuralgia, in which neurons involved in itch stimuli become damaged.⁷

Diabetes mellitus. Pruritus from diabetes can be classified as systemic or neuropathic. Diabetes is one of the most common causes of small-fiber polyneuropathy, which can cause neuropathic pruritus.¹³

Multiple sclerosis. Central nervous system lesions that affect sensory pathways can lead to neuropathic itch in multiple sclerosis. Patients can have severe episodes of generalized pruritus. It has been hypothesized that the neuropathic itch in multiple sclerosis is induced by activation of artificial synapses in demyelinated areas.²

Continue to: Psychogenic pruritus

Chronic pruritus can be a comorbidity of psychiatric illness. A retrospective study found that pruritus occurs in 32% to 42% of psychiatric inpatients.¹⁴ Depression, anxiety, bipolar disorders, obsessive–compulsive disorders, somatoform disorders, psychosis, and substance abuse all have a strong link to psychogenic excoriation.¹⁵ Psychogenic excoriation, which can cause secondary skin lesions, occurs in psychiatric patients who excessively pick and scratch normal skin because they perceive an itch sensation or have a delusion of infestation.² Affected skin can be marked by scattered crusted lesions (FIGURE) anywhere on the body that the patient can reach—most commonly, the extremities.²

Delusion of infestation. Patients with a delusion of infestation have a strong belief that their body is infected by some kind of insect or microorganism.¹⁶ Before a diagnosis of delusion of infestation can be made, other organic causes must be excluded, including withdrawal from such substances as cocaine, amphetamines, and alcohol.¹⁶ Patients with a delusion of infestation can have, and maintain, a symptomatic response with continuing use of an atypical antipsychotic agent, including risperidone and olanzapine.¹⁷

Evaluation and diagnostic work-up

A thorough medical history, review of systems, medication review, social history, and family history are important when evaluating a patient with chronic pruritus.¹⁸ These items can be valuable in formulating a differential diagnosis, even before a physical examination.

Physical examination. The physical exam should include detailed inspection of the entire skin and hair¹⁸; such a comprehensive physical exam can determine whether the source of the itch is cutaneous.⁷ This, in turn, can help further narrow the differential diagnosis. It is crucial that the physical exam include palpation of the liver, spleen, lymph nodes, and thyroid for organomegaly,⁸ which could indicate a serious systemic condition, such as lymphoma.

The ice-pack sign—in which an ice pack applied to the pruritic area provides immediate relief—is considered pathognomonic for brachioradial pruritus.

The ice-pack sign—in which an ice pack is applied to the pruritic area, the patient experiences immediate relief of pruritus, and the itch returns soon after the ice pack is removed—is considered pathognomonic for brachioradial pruritus.¹⁹

Continue to: Chronic pruritus with abnormal findings...

Chronic pruritus with abnormal findings on the physical exam should prompt an initial work-up.¹⁸ Also consider an initial work-up for a patient with chronic pruritus whose symptom has not been relieved with conservative treatment.¹⁸

Laboratory testing. The initial laboratory work-up could include any of the following evaluations: complete blood count, measurement of thyroid-stimulating hormone, comprehensive metabolic panel (liver function, renal function, and the serum glucose level) and the erythrocyte sedimentation rate (TABLE 2).¹⁸ If warranted by the evaluation and physical exam, blood work can also include serologic studies for human immunodeficiency virus infection and ­hepatitis.¹⁷

Imaging. Chest radiography should be performed if there is suspicion of malignancy, such as lymphoma.⁷ Although brachioradial pruritus and notalgia paresthetica have been postulated to be caused by impingement of spinal nerves, obtaining spinal imaging, such as magnetic resonance imaging, as part of the initial work-up is not recommended; because spinal images might not show evidence of spinal disease, obtaining spinal imaging is not a requirement before treating brachioradial pruritus and notalgia paresthetica. Do consider spinal imaging, however, for patients in whom brachioradial pruritus or notalgia paresthetica is suspected and conservative treatment has not produced a response.

Treatment: Nondrug approaches, topicals, systemic agents

Start conservatively. Treatment of pruritus should begin with behavior modification and nonpharmacotherapeutic options (TABLE 3⁸). Educate the patient that scratching might cause secondary skin lesions; empowering them with that knowledge is sometimes enough to help break the scratching cycling—especially if the patient combines behavior modification with proper skin hydration with an emollient. To prevent secondary skin lesions through involuntary scratching, consider recommending that lesions be covered with an occlusive dressing or protective clothing.¹³

Stress has been shown to make chronic itch worse; therefore, stress-reduction activities, such as exercise, meditation, and yoga, might be helpful.20 For patients in whom pruritus has a psychological component, referral to a psychiatrist or psychologist might be therapeutic.

Continue to: When a patient complains...

When a patient complains of severe pruritus at first presentation, consider pharmacotherapy in conjunction with nonpharmacotherapeutic options. Several of the more effective topical therapies for pruritus^a are listed in TABLE 4.²⁰ Well-known systemic agents for this purpose are reviewed below and listed in TABLE 5.⁷

Systemic treatment

Antihistamines. A staple in the treatment of pruritus for many years, antihistamines are not effective for all causes; however, they are effective in treating paraneoplastic pruritus.²⁰ First-generation antihistamines, with their sedating effect, can be useful for patients who experience generalized pruritus at night.²⁰

Anticonvulsants. Gabapentin and pregabalin are analogs of the neurotransmitter gamma-aminobutyric acid.²⁰ This drug class is helpful in neuropathic pruritus specifically caused by impingements, such as brachioradial pruritus and notalgia paresthetica.²⁰ In addition, of all systemic therapies used to treat uremic pruritus, gabapentin has, in clinical trials, most consistently been found effective for uremic pruritus.⁶ (Note: Use renal dosing of gabapentin in patients with renal failure.)

Antidepressants. Selective serotonin reuptake inhibitors (SSRIs; eg, fluvoxamine, paroxetine, and sertraline) might cause itch to subside by increasing the serotonin level, which, in turn, works to decrease inflammatory substances that cause itch.⁷ SSRIs have been used to treat patients with psychogenic pruritus, cholestatic pruritus, and paraneoplastic pruritus.⁷

Start conservatively: Use behavior modification and nonpharmacotherapeutic options for pruritus first.

Tricyclic antidepressants (eg, amitriptyline and doxepin) lessen the itch by antagonizing histamine receptors and through anticholinergic mechanisms. Tricyclics are best used in the treatment of psychogenic and nocturnal itch.⁷

Continue to: Mirtazapine...

Mirtazapine, a tetracyclic antidepressant, works in patients with uremic pruritus, psychogenic pruritus, cholestatic pruritus, and paraneoplastic pruritus.¹

Substance P antagonist. Aprepitant, a neurokinin receptor I antagonist, is a newer agent that inhibits binding of the itch mediator substance P to the neurokinin receptor. The drug has been found helpful in patients with drug-induced, paraneoplastic, and brachioradial pruritus.⁷

Opioid-receptor agents. Naltrexone, as a mu opioid-receptor antagonist, has shown promise as a treatment for uremic pruritus and cholestatic pruritus. Nalfurafine, a kappa opioid-receptor agonist, is emerging as a possible therapy for uremic pruritus.⁷

Bile-acid sequestrants. A few small studies have shown that treatment with a bile-acid sequestrant, such as cholestyramine and ursodiol, induces moderate improvement in symptoms in patients with cholestatic pruritus.²¹

CORRESPONDENCE
Matasha Russell, MD, Department of Family and Community Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, 6431 Fannin Street, JJL 324, Houston, TX 77030; [email protected].

Pruritus, defined as a sensation that induces a desire to scratch¹ and classified as acute or chronic (lasting > 6 weeks),² is one of the most common complaints among primary care patients: Approximately 1% of ambulatory visits in the United States are linked to pruritus.³

Chronic pruritus impairs quality of life; its impact has been compared to that of chronic pain.⁴ Treatment should therefore be instituted promptly. Although this condition might appear benign, chronic pruritus can be a symptom of a serious condition, as we describe here. When persistent pruritus is refractory to treatment, systemic causes should be fully explored.

In this article, we discuss the pathogenesis and management of pruritus without skin eruption in the adult nonpregnant patient. We also present practice recommendations to help you determine whether your patient’s pruritus is indicative of a serious systemic condition.

An incomplete understanding of the pathophysiology of pruritus

The pathophysiology of pruritus is not fully understood. It is generally recognized, however, that pruritus starts in the peripheral nerves located in the dermal–epidermal junction of the skin.⁵ The sensation is then transmitted along unmyelinated slow-conducting C fibers to the dorsal horn of the spinal cord.^5,6 There are 2 types of C fibers that transmit the itch impulse⁶: A histamine-dependent type and a non-­histamine-dependent type, which might explain why pruritus can be refractory to antihistamine treatment.⁶

Once the itch impulse has moved from the spinal cord, it travels along the spinothalamic tract up to the contralateral thalamus.¹ From there, the impulse ascends to the cerebral cortex.¹ In the cortex, the impulse triggers multiple areas of the brain, such as those responsible for sensation, motor function, reward, memory, and emotion.⁷

Although this condition might appear benign, chronic pruritus can be a symptom of a serious condition.

Several chemical mediators have been found to be peripheral and central inducers of pruritus: histamine, endogenous opioids, substance P, and serotonin.² There are indications that certain receptors, such as mu-opioid receptors and kappa-opioid receptors, are key contributors to itch as well.²

A diverse etiology

The International Forum for the Study of Itch (IFSI) has established 6 main categories of causes of pruritus(TABLE 1)²:

• dermatologic
• systemic
• neurologic
• psychogenic
• mixed
• other.

Continue to: In this review...

In this review, we focus on the work-up and management of 3 of those categories: systemic, neurologic, and psychogenic causes of pruritus.

Systemic causes

Research has shown that 14% to 24% of patients who seek the care of a dermatologist for chronic itch without skin lesions have a systemic illness.⁸

Renal disease. Approximately 40% of patients with end-stage renal disease who are on hemodialysis or peritoneal dialysis have uremic pruritus.2 The itch is mostly generalized but can be pronounced on the back. For most patients, the itch is worse at night, causing a major impact on quality of life.⁶

Liver disease. In hepatic disease, there is often impairment in the secretion of bile, which can lead to cholestatic pruritus.² This condition commonly affects the hands and feet first; later, it becomes generalized.² Cholestatic pruritus can be elicited by tight-fitting clothing. Relief is not achieved by scratching.⁹ This type of itch effects 70% of patients with primary biliary cirrhosis and 15% of patients with hepatitis C infection.⁹

Hematologic disorders. Pruritus is a hallmark symptom of polycythemia rubra vera. Almost 50% of patients with this disorder report pruritus that occurs after exposure to water⁹; aquagenic pruritus can precede the formal diagnosis of polycythemia rubra vera by years.² It has been speculated that platelet aggregation in this disorder leads to release of serotonin and histamine, which, in turn, causes itch.⁹

Continue to: Endocrine disorders

Endocrine disorders. Approximately 4% to 11% of patients with thyrotoxicosis have pruritus.¹ It has been suggested that vasodilation, increased skin temperature, and a decreased itch threshold from untreated Graves disease might be inciting factors.

Malignancy. In generalized chronic pruritus without a known cause, strongly consider the likelihood of underlying malignancy^8,10; for 10% of these patients, their chronic pruritus is a paraneoplastic sign. Paraneoplastic pruritus is characterized as an itch that predates clinical onset, or occurs early in the course, of a malignancy.⁹ The condition is most strongly linked to cancers of the liver, gallbladder, biliary tract, hematologic system, and skin.¹¹

Palpate the liver, spleen, lymph nodes, and thyroid for organomegaly, which could indicate a serious systemic condition as the cause of pruritus.

Chronic pruritus affects 30% of patients with Hodgkin lymphoma.⁹ General pruritus can precede this diagnosis by months, even years.¹ In Hodgkin lymphoma patients who are in remission, a return of pruritic symptoms can be a harbinger of recurrence.⁹

Neurologic causes

A recent study found that 8% to 15% of patients referred to a dermatology clinic for chronic pruritus without skin eruption had underlying neurologic pathology.¹² Although the specific mechanisms of neuropathic itch are still poorly understood, it has been theorized that the itch emanates from neuronal damage, which can come from peripheral or central nervous system lesions.⁹

Brachioradial pruritus. There are divergent theories about the etiology of brachioradial pruritus. One hypothesis is that the condition is caused by cervical nerve-root impingement at the level of C5-C8 that leads to nerve damage²; another is that chronic exposure to sunlight causes injury to peripheral cutaneous nerves.² Brachioradial pruritus is localized to the dorsolateral forearm; it can also involve the neck, back, shoulder, upper arm, and chest, unilaterally and bilaterally. This pruritus can be intermittent and become worse upon exposure to sunlight.²

Continue to: Notalgia paresthetica

Notalgia paresthetica. This condition might also cause neuropathic pruritus as a consequence of nerve impingement. The itch of notalgia paresthesia is located on the skin, medial to the scapular border on the upper or mid-back.² It has been postulated that the itch is caused by nerve entrapment of the posterior rami of spinal nerves arising from T2-T6.⁹ However, another theory suggests that the itch is caused by damage to peripheral nerves.⁹ The itch of notalgia paresthetica can wax and wane.²

Poststroke pruritus. Brain lesions, most often caused by stroke, can cause neuropathic itch. One of the best-known syndromes related to poststroke itch is Wallenberg syndrome (ischemia from a lateral medullary infarction), which typically presents with itch, thermalgic hypoesthesia of the face, cerebellar dysfunction, nausea, and vomiting.⁷

Shingles. More than one-half of patients who develop postherpetic neuralgia as a consequence of a herpes zoster infection also develop neuropathic pruritus.⁹ It is thought that postherpetic pruritus shares a comparable pathophysiology with postherpetic neuralgia, in which neurons involved in itch stimuli become damaged.⁷

Diabetes mellitus. Pruritus from diabetes can be classified as systemic or neuropathic. Diabetes is one of the most common causes of small-fiber polyneuropathy, which can cause neuropathic pruritus.¹³

Multiple sclerosis. Central nervous system lesions that affect sensory pathways can lead to neuropathic itch in multiple sclerosis. Patients can have severe episodes of generalized pruritus. It has been hypothesized that the neuropathic itch in multiple sclerosis is induced by activation of artificial synapses in demyelinated areas.²

Continue to: Psychogenic pruritus

Chronic pruritus can be a comorbidity of psychiatric illness. A retrospective study found that pruritus occurs in 32% to 42% of psychiatric inpatients.¹⁴ Depression, anxiety, bipolar disorders, obsessive–compulsive disorders, somatoform disorders, psychosis, and substance abuse all have a strong link to psychogenic excoriation.¹⁵ Psychogenic excoriation, which can cause secondary skin lesions, occurs in psychiatric patients who excessively pick and scratch normal skin because they perceive an itch sensation or have a delusion of infestation.² Affected skin can be marked by scattered crusted lesions (FIGURE) anywhere on the body that the patient can reach—most commonly, the extremities.²

Delusion of infestation. Patients with a delusion of infestation have a strong belief that their body is infected by some kind of insect or microorganism.¹⁶ Before a diagnosis of delusion of infestation can be made, other organic causes must be excluded, including withdrawal from such substances as cocaine, amphetamines, and alcohol.¹⁶ Patients with a delusion of infestation can have, and maintain, a symptomatic response with continuing use of an atypical antipsychotic agent, including risperidone and olanzapine.¹⁷

Evaluation and diagnostic work-up

A thorough medical history, review of systems, medication review, social history, and family history are important when evaluating a patient with chronic pruritus.¹⁸ These items can be valuable in formulating a differential diagnosis, even before a physical examination.

Physical examination. The physical exam should include detailed inspection of the entire skin and hair¹⁸; such a comprehensive physical exam can determine whether the source of the itch is cutaneous.⁷ This, in turn, can help further narrow the differential diagnosis. It is crucial that the physical exam include palpation of the liver, spleen, lymph nodes, and thyroid for organomegaly,⁸ which could indicate a serious systemic condition, such as lymphoma.

The ice-pack sign—in which an ice pack applied to the pruritic area provides immediate relief—is considered pathognomonic for brachioradial pruritus.

The ice-pack sign—in which an ice pack is applied to the pruritic area, the patient experiences immediate relief of pruritus, and the itch returns soon after the ice pack is removed—is considered pathognomonic for brachioradial pruritus.¹⁹

Continue to: Chronic pruritus with abnormal findings...

Chronic pruritus with abnormal findings on the physical exam should prompt an initial work-up.¹⁸ Also consider an initial work-up for a patient with chronic pruritus whose symptom has not been relieved with conservative treatment.¹⁸

Laboratory testing. The initial laboratory work-up could include any of the following evaluations: complete blood count, measurement of thyroid-stimulating hormone, comprehensive metabolic panel (liver function, renal function, and the serum glucose level) and the erythrocyte sedimentation rate (TABLE 2).¹⁸ If warranted by the evaluation and physical exam, blood work can also include serologic studies for human immunodeficiency virus infection and ­hepatitis.¹⁷

Imaging. Chest radiography should be performed if there is suspicion of malignancy, such as lymphoma.⁷ Although brachioradial pruritus and notalgia paresthetica have been postulated to be caused by impingement of spinal nerves, obtaining spinal imaging, such as magnetic resonance imaging, as part of the initial work-up is not recommended; because spinal images might not show evidence of spinal disease, obtaining spinal imaging is not a requirement before treating brachioradial pruritus and notalgia paresthetica. Do consider spinal imaging, however, for patients in whom brachioradial pruritus or notalgia paresthetica is suspected and conservative treatment has not produced a response.

Treatment: Nondrug approaches, topicals, systemic agents

Start conservatively. Treatment of pruritus should begin with behavior modification and nonpharmacotherapeutic options (TABLE 3⁸). Educate the patient that scratching might cause secondary skin lesions; empowering them with that knowledge is sometimes enough to help break the scratching cycling—especially if the patient combines behavior modification with proper skin hydration with an emollient. To prevent secondary skin lesions through involuntary scratching, consider recommending that lesions be covered with an occlusive dressing or protective clothing.¹³

Stress has been shown to make chronic itch worse; therefore, stress-reduction activities, such as exercise, meditation, and yoga, might be helpful.20 For patients in whom pruritus has a psychological component, referral to a psychiatrist or psychologist might be therapeutic.

Continue to: When a patient complains...

When a patient complains of severe pruritus at first presentation, consider pharmacotherapy in conjunction with nonpharmacotherapeutic options. Several of the more effective topical therapies for pruritus^a are listed in TABLE 4.²⁰ Well-known systemic agents for this purpose are reviewed below and listed in TABLE 5.⁷

Systemic treatment

Antihistamines. A staple in the treatment of pruritus for many years, antihistamines are not effective for all causes; however, they are effective in treating paraneoplastic pruritus.²⁰ First-generation antihistamines, with their sedating effect, can be useful for patients who experience generalized pruritus at night.²⁰

Anticonvulsants. Gabapentin and pregabalin are analogs of the neurotransmitter gamma-aminobutyric acid.²⁰ This drug class is helpful in neuropathic pruritus specifically caused by impingements, such as brachioradial pruritus and notalgia paresthetica.²⁰ In addition, of all systemic therapies used to treat uremic pruritus, gabapentin has, in clinical trials, most consistently been found effective for uremic pruritus.⁶ (Note: Use renal dosing of gabapentin in patients with renal failure.)

Antidepressants. Selective serotonin reuptake inhibitors (SSRIs; eg, fluvoxamine, paroxetine, and sertraline) might cause itch to subside by increasing the serotonin level, which, in turn, works to decrease inflammatory substances that cause itch.⁷ SSRIs have been used to treat patients with psychogenic pruritus, cholestatic pruritus, and paraneoplastic pruritus.⁷

Start conservatively: Use behavior modification and nonpharmacotherapeutic options for pruritus first.

Tricyclic antidepressants (eg, amitriptyline and doxepin) lessen the itch by antagonizing histamine receptors and through anticholinergic mechanisms. Tricyclics are best used in the treatment of psychogenic and nocturnal itch.⁷

Continue to: Mirtazapine...

Mirtazapine, a tetracyclic antidepressant, works in patients with uremic pruritus, psychogenic pruritus, cholestatic pruritus, and paraneoplastic pruritus.¹

Substance P antagonist. Aprepitant, a neurokinin receptor I antagonist, is a newer agent that inhibits binding of the itch mediator substance P to the neurokinin receptor. The drug has been found helpful in patients with drug-induced, paraneoplastic, and brachioradial pruritus.⁷

Opioid-receptor agents. Naltrexone, as a mu opioid-receptor antagonist, has shown promise as a treatment for uremic pruritus and cholestatic pruritus. Nalfurafine, a kappa opioid-receptor agonist, is emerging as a possible therapy for uremic pruritus.⁷

Bile-acid sequestrants. A few small studies have shown that treatment with a bile-acid sequestrant, such as cholestyramine and ursodiol, induces moderate improvement in symptoms in patients with cholestatic pruritus.²¹

CORRESPONDENCE
Matasha Russell, MD, Department of Family and Community Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, 6431 Fannin Street, JJL 324, Houston, TX 77030; [email protected].

Pruritus, defined as a sensation that induces a desire to scratch¹ and classified as acute or chronic (lasting > 6 weeks),² is one of the most common complaints among primary care patients: Approximately 1% of ambulatory visits in the United States are linked to pruritus.³

Chronic pruritus impairs quality of life; its impact has been compared to that of chronic pain.⁴ Treatment should therefore be instituted promptly. Although this condition might appear benign, chronic pruritus can be a symptom of a serious condition, as we describe here. When persistent pruritus is refractory to treatment, systemic causes should be fully explored.

In this article, we discuss the pathogenesis and management of pruritus without skin eruption in the adult nonpregnant patient. We also present practice recommendations to help you determine whether your patient’s pruritus is indicative of a serious systemic condition.

An incomplete understanding of the pathophysiology of pruritus

The pathophysiology of pruritus is not fully understood. It is generally recognized, however, that pruritus starts in the peripheral nerves located in the dermal–epidermal junction of the skin.⁵ The sensation is then transmitted along unmyelinated slow-conducting C fibers to the dorsal horn of the spinal cord.^5,6 There are 2 types of C fibers that transmit the itch impulse⁶: A histamine-dependent type and a non-­histamine-dependent type, which might explain why pruritus can be refractory to antihistamine treatment.⁶

Once the itch impulse has moved from the spinal cord, it travels along the spinothalamic tract up to the contralateral thalamus.¹ From there, the impulse ascends to the cerebral cortex.¹ In the cortex, the impulse triggers multiple areas of the brain, such as those responsible for sensation, motor function, reward, memory, and emotion.⁷

Although this condition might appear benign, chronic pruritus can be a symptom of a serious condition.

Several chemical mediators have been found to be peripheral and central inducers of pruritus: histamine, endogenous opioids, substance P, and serotonin.² There are indications that certain receptors, such as mu-opioid receptors and kappa-opioid receptors, are key contributors to itch as well.²

A diverse etiology

The International Forum for the Study of Itch (IFSI) has established 6 main categories of causes of pruritus(TABLE 1)²:

• dermatologic
• systemic
• neurologic
• psychogenic
• mixed
• other.

Continue to: In this review...

In this review, we focus on the work-up and management of 3 of those categories: systemic, neurologic, and psychogenic causes of pruritus.

Systemic causes

Research has shown that 14% to 24% of patients who seek the care of a dermatologist for chronic itch without skin lesions have a systemic illness.⁸

Renal disease. Approximately 40% of patients with end-stage renal disease who are on hemodialysis or peritoneal dialysis have uremic pruritus.2 The itch is mostly generalized but can be pronounced on the back. For most patients, the itch is worse at night, causing a major impact on quality of life.⁶

Liver disease. In hepatic disease, there is often impairment in the secretion of bile, which can lead to cholestatic pruritus.² This condition commonly affects the hands and feet first; later, it becomes generalized.² Cholestatic pruritus can be elicited by tight-fitting clothing. Relief is not achieved by scratching.⁹ This type of itch effects 70% of patients with primary biliary cirrhosis and 15% of patients with hepatitis C infection.⁹

Hematologic disorders. Pruritus is a hallmark symptom of polycythemia rubra vera. Almost 50% of patients with this disorder report pruritus that occurs after exposure to water⁹; aquagenic pruritus can precede the formal diagnosis of polycythemia rubra vera by years.² It has been speculated that platelet aggregation in this disorder leads to release of serotonin and histamine, which, in turn, causes itch.⁹

Continue to: Endocrine disorders

Endocrine disorders. Approximately 4% to 11% of patients with thyrotoxicosis have pruritus.¹ It has been suggested that vasodilation, increased skin temperature, and a decreased itch threshold from untreated Graves disease might be inciting factors.

Malignancy. In generalized chronic pruritus without a known cause, strongly consider the likelihood of underlying malignancy^8,10; for 10% of these patients, their chronic pruritus is a paraneoplastic sign. Paraneoplastic pruritus is characterized as an itch that predates clinical onset, or occurs early in the course, of a malignancy.⁹ The condition is most strongly linked to cancers of the liver, gallbladder, biliary tract, hematologic system, and skin.¹¹

Palpate the liver, spleen, lymph nodes, and thyroid for organomegaly, which could indicate a serious systemic condition as the cause of pruritus.

Chronic pruritus affects 30% of patients with Hodgkin lymphoma.⁹ General pruritus can precede this diagnosis by months, even years.¹ In Hodgkin lymphoma patients who are in remission, a return of pruritic symptoms can be a harbinger of recurrence.⁹

Neurologic causes

A recent study found that 8% to 15% of patients referred to a dermatology clinic for chronic pruritus without skin eruption had underlying neurologic pathology.¹² Although the specific mechanisms of neuropathic itch are still poorly understood, it has been theorized that the itch emanates from neuronal damage, which can come from peripheral or central nervous system lesions.⁹

Brachioradial pruritus. There are divergent theories about the etiology of brachioradial pruritus. One hypothesis is that the condition is caused by cervical nerve-root impingement at the level of C5-C8 that leads to nerve damage²; another is that chronic exposure to sunlight causes injury to peripheral cutaneous nerves.² Brachioradial pruritus is localized to the dorsolateral forearm; it can also involve the neck, back, shoulder, upper arm, and chest, unilaterally and bilaterally. This pruritus can be intermittent and become worse upon exposure to sunlight.²

Continue to: Notalgia paresthetica

Notalgia paresthetica. This condition might also cause neuropathic pruritus as a consequence of nerve impingement. The itch of notalgia paresthesia is located on the skin, medial to the scapular border on the upper or mid-back.² It has been postulated that the itch is caused by nerve entrapment of the posterior rami of spinal nerves arising from T2-T6.⁹ However, another theory suggests that the itch is caused by damage to peripheral nerves.⁹ The itch of notalgia paresthetica can wax and wane.²

Poststroke pruritus. Brain lesions, most often caused by stroke, can cause neuropathic itch. One of the best-known syndromes related to poststroke itch is Wallenberg syndrome (ischemia from a lateral medullary infarction), which typically presents with itch, thermalgic hypoesthesia of the face, cerebellar dysfunction, nausea, and vomiting.⁷

Shingles. More than one-half of patients who develop postherpetic neuralgia as a consequence of a herpes zoster infection also develop neuropathic pruritus.⁹ It is thought that postherpetic pruritus shares a comparable pathophysiology with postherpetic neuralgia, in which neurons involved in itch stimuli become damaged.⁷

Diabetes mellitus. Pruritus from diabetes can be classified as systemic or neuropathic. Diabetes is one of the most common causes of small-fiber polyneuropathy, which can cause neuropathic pruritus.¹³

Multiple sclerosis. Central nervous system lesions that affect sensory pathways can lead to neuropathic itch in multiple sclerosis. Patients can have severe episodes of generalized pruritus. It has been hypothesized that the neuropathic itch in multiple sclerosis is induced by activation of artificial synapses in demyelinated areas.²

Continue to: Psychogenic pruritus

Chronic pruritus can be a comorbidity of psychiatric illness. A retrospective study found that pruritus occurs in 32% to 42% of psychiatric inpatients.¹⁴ Depression, anxiety, bipolar disorders, obsessive–compulsive disorders, somatoform disorders, psychosis, and substance abuse all have a strong link to psychogenic excoriation.¹⁵ Psychogenic excoriation, which can cause secondary skin lesions, occurs in psychiatric patients who excessively pick and scratch normal skin because they perceive an itch sensation or have a delusion of infestation.² Affected skin can be marked by scattered crusted lesions (FIGURE) anywhere on the body that the patient can reach—most commonly, the extremities.²

Delusion of infestation. Patients with a delusion of infestation have a strong belief that their body is infected by some kind of insect or microorganism.¹⁶ Before a diagnosis of delusion of infestation can be made, other organic causes must be excluded, including withdrawal from such substances as cocaine, amphetamines, and alcohol.¹⁶ Patients with a delusion of infestation can have, and maintain, a symptomatic response with continuing use of an atypical antipsychotic agent, including risperidone and olanzapine.¹⁷

Evaluation and diagnostic work-up

A thorough medical history, review of systems, medication review, social history, and family history are important when evaluating a patient with chronic pruritus.¹⁸ These items can be valuable in formulating a differential diagnosis, even before a physical examination.

Physical examination. The physical exam should include detailed inspection of the entire skin and hair¹⁸; such a comprehensive physical exam can determine whether the source of the itch is cutaneous.⁷ This, in turn, can help further narrow the differential diagnosis. It is crucial that the physical exam include palpation of the liver, spleen, lymph nodes, and thyroid for organomegaly,⁸ which could indicate a serious systemic condition, such as lymphoma.

The ice-pack sign—in which an ice pack applied to the pruritic area provides immediate relief—is considered pathognomonic for brachioradial pruritus.

The ice-pack sign—in which an ice pack is applied to the pruritic area, the patient experiences immediate relief of pruritus, and the itch returns soon after the ice pack is removed—is considered pathognomonic for brachioradial pruritus.¹⁹

Continue to: Chronic pruritus with abnormal findings...

Chronic pruritus with abnormal findings on the physical exam should prompt an initial work-up.¹⁸ Also consider an initial work-up for a patient with chronic pruritus whose symptom has not been relieved with conservative treatment.¹⁸

Laboratory testing. The initial laboratory work-up could include any of the following evaluations: complete blood count, measurement of thyroid-stimulating hormone, comprehensive metabolic panel (liver function, renal function, and the serum glucose level) and the erythrocyte sedimentation rate (TABLE 2).¹⁸ If warranted by the evaluation and physical exam, blood work can also include serologic studies for human immunodeficiency virus infection and ­hepatitis.¹⁷

Imaging. Chest radiography should be performed if there is suspicion of malignancy, such as lymphoma.⁷ Although brachioradial pruritus and notalgia paresthetica have been postulated to be caused by impingement of spinal nerves, obtaining spinal imaging, such as magnetic resonance imaging, as part of the initial work-up is not recommended; because spinal images might not show evidence of spinal disease, obtaining spinal imaging is not a requirement before treating brachioradial pruritus and notalgia paresthetica. Do consider spinal imaging, however, for patients in whom brachioradial pruritus or notalgia paresthetica is suspected and conservative treatment has not produced a response.

Treatment: Nondrug approaches, topicals, systemic agents

Start conservatively. Treatment of pruritus should begin with behavior modification and nonpharmacotherapeutic options (TABLE 3⁸). Educate the patient that scratching might cause secondary skin lesions; empowering them with that knowledge is sometimes enough to help break the scratching cycling—especially if the patient combines behavior modification with proper skin hydration with an emollient. To prevent secondary skin lesions through involuntary scratching, consider recommending that lesions be covered with an occlusive dressing or protective clothing.¹³

Stress has been shown to make chronic itch worse; therefore, stress-reduction activities, such as exercise, meditation, and yoga, might be helpful.20 For patients in whom pruritus has a psychological component, referral to a psychiatrist or psychologist might be therapeutic.

Continue to: When a patient complains...

When a patient complains of severe pruritus at first presentation, consider pharmacotherapy in conjunction with nonpharmacotherapeutic options. Several of the more effective topical therapies for pruritus^a are listed in TABLE 4.²⁰ Well-known systemic agents for this purpose are reviewed below and listed in TABLE 5.⁷

Systemic treatment

Antihistamines. A staple in the treatment of pruritus for many years, antihistamines are not effective for all causes; however, they are effective in treating paraneoplastic pruritus.²⁰ First-generation antihistamines, with their sedating effect, can be useful for patients who experience generalized pruritus at night.²⁰

Anticonvulsants. Gabapentin and pregabalin are analogs of the neurotransmitter gamma-aminobutyric acid.²⁰ This drug class is helpful in neuropathic pruritus specifically caused by impingements, such as brachioradial pruritus and notalgia paresthetica.²⁰ In addition, of all systemic therapies used to treat uremic pruritus, gabapentin has, in clinical trials, most consistently been found effective for uremic pruritus.⁶ (Note: Use renal dosing of gabapentin in patients with renal failure.)

Antidepressants. Selective serotonin reuptake inhibitors (SSRIs; eg, fluvoxamine, paroxetine, and sertraline) might cause itch to subside by increasing the serotonin level, which, in turn, works to decrease inflammatory substances that cause itch.⁷ SSRIs have been used to treat patients with psychogenic pruritus, cholestatic pruritus, and paraneoplastic pruritus.⁷

Start conservatively: Use behavior modification and nonpharmacotherapeutic options for pruritus first.

Tricyclic antidepressants (eg, amitriptyline and doxepin) lessen the itch by antagonizing histamine receptors and through anticholinergic mechanisms. Tricyclics are best used in the treatment of psychogenic and nocturnal itch.⁷

Continue to: Mirtazapine...

Mirtazapine, a tetracyclic antidepressant, works in patients with uremic pruritus, psychogenic pruritus, cholestatic pruritus, and paraneoplastic pruritus.¹

Substance P antagonist. Aprepitant, a neurokinin receptor I antagonist, is a newer agent that inhibits binding of the itch mediator substance P to the neurokinin receptor. The drug has been found helpful in patients with drug-induced, paraneoplastic, and brachioradial pruritus.⁷

Opioid-receptor agents. Naltrexone, as a mu opioid-receptor antagonist, has shown promise as a treatment for uremic pruritus and cholestatic pruritus. Nalfurafine, a kappa opioid-receptor agonist, is emerging as a possible therapy for uremic pruritus.⁷

Bile-acid sequestrants. A few small studies have shown that treatment with a bile-acid sequestrant, such as cholestyramine and ursodiol, induces moderate improvement in symptoms in patients with cholestatic pruritus.²¹

CORRESPONDENCE
Matasha Russell, MD, Department of Family and Community Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, 6431 Fannin Street, JJL 324, Houston, TX 77030; [email protected].

Capillary malformation-arteriovenous malformation syndrome

Capillary Malformation-arteriovenous malformation syndrome (CM-AVM) is a rare vascular disorder characterized by the presence of capillary malformations with or without arteriovenous malformations, as well as arteriovenous fistulas (AVFs). CM-AVM is an autosomal dominant disorder.¹ CM-AVM type 1 is caused by mutations in the RASA1 gene, and CM-AVM type 2 is caused by mutations in the EPHB⁴ gene.² Approximately 70% of patients with RASA1-associated CM-AVM syndrome and 80% of patients with EPHB4-associated CM-AVM syndrome have an affected parent, while the remainder have de novo variants.¹

In patients with CM-AVM syndrome, CMs are often present at birth and more are typically acquired over time. CMs are characteristically 1-3 cm in diameter, round or oval, dull red or red-brown macules and patches with a blanched halo.³ Some CMs may be warm to touch indicating a possible underlying AVM or AVF.⁴ This can be confirmed by Doppler ultrasound, which would demonstrate increased arterial flow.⁴ CMs are most commonly located on the face and limbs and may present in isolation, but approximately one-third of patients have associated AVMs and AVFs.^1,5 These high-flow vascular malformations may be present in skin, muscle, bone, brain, and/or spine and may be asymptomatic or lead to serious sequelae, including bleeding, congestive heart failure, and neurologic complications, such as migraine headaches, seizures, or even stroke.⁵ Symptoms from intracranial and spinal high-flow lesions usually present in early childhood and affect approximately 7% of patients.³

The diagnosis of CM-AVM should be suspected in an individual with numerous characteristic CMs and may be supported by the presence of AVMs and AVFs, family history of CM-AVM, and/or identification of RASA1 or EPHB4 mutation by molecular genetic testing.^1,3 Although there are no consensus protocols for imaging CM-AVM patients, MRI of the brain and spine is recommended at diagnosis to identify underlying high-flow lesions.¹ This may allow for early treatment before the development of symptoms.¹ Any lesions identified on screening imaging may require regular surveillance, which is best determined by discussion with the radiologist.¹ Although there are no reports of patients with negative results on screening imaging who later develop AVMs or AVFs, there should be a low threshold for repeat imaging in patients who develop new symptoms or physical exam findings.^3,4

It has previously been suggested that the CMs in CM-AVM may actually represent early or small AVMs and pulsed-dye laser (PDL) treatment was not recommended because of concern for potential progression of lesions.⁴ However, a recent study demonstrated good response to PDL in patients with CM-AVM with no evidence of worsening or recurrence of lesions with long-term follow-up.⁶ Treatment of CMs that cause cosmetic concerns may be considered following discussion of risks and benefits with a dermatologist. Management of AVMs and AVFs requires a multidisciplinary team that, depending on location and symptoms of these features, may require the expertise of specialists such as neurosurgery, surgery, orthopedics, cardiology, and/or interventional radiology.¹

Given the suspicion for CM-AVM in our patient, further workup was completed. A skin biopsy was consistent with CM. Genetic testing with the Vascular Malformations Panel, Sequencing and Deletion/Duplication revealed a pathogenic variant in the RASA1 gene and a variant of unknown clinical significance in the TEK gene. Parental genetic testing for the RASA1 mutation was negative, supporting a de novo mutation in the patient. CNS imaging showed a small developmental venous malformation in the brain that neurosurgery did not think was clinically significant. At the most recent follow-up at age 8 years, our patient had developed a few new small CMs but was otherwise well.

Dr. Leszczynska is trained in pediatrics and is the current dermatology research fellow at the University of Texas at Austin. Ms. Croce is a dermatology-trained pediatric nurse practitioner and PhD student at the University of Texas at Austin School of Nursing. Dr. Diaz is chief of pediatric dermatology at Dell Children’s Medical Center, Austin, assistant professor of pediatrics and medicine (dermatology), and dermatology residency associate program director at University of Texas at Austin . The authors have no relevant conflicts of interest to disclose. Donna Bilu Martin, MD, is the editor of this column.


References

1. Bayrak-Toydemir P, Stevenson D. Capillary Malformation-Arteriovenous Malformation Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle: University of Washington, Seattle; February 22, 2011.

2.Yu J et al. Pediatr Dermatol. 2017 Sep;34(5):e227-30.

3. Orme CM et al. Pediatr Dermatol. 2013 Jul-Aug;30(4):409-15.

4. Weitz NA et al. Pediatr Dermatol. 2015 Jan-Feb;32(1):76-84.

5. Revencu N et al. Hum Mutat. 2013 Dec;34(12):1632-41.

6. Iznardo H et al. Pediatr Dermatol. 2020 Mar;37(2):342-44.
 

Capillary malformation-arteriovenous malformation syndrome

Capillary Malformation-arteriovenous malformation syndrome (CM-AVM) is a rare vascular disorder characterized by the presence of capillary malformations with or without arteriovenous malformations, as well as arteriovenous fistulas (AVFs). CM-AVM is an autosomal dominant disorder.¹ CM-AVM type 1 is caused by mutations in the RASA1 gene, and CM-AVM type 2 is caused by mutations in the EPHB⁴ gene.² Approximately 70% of patients with RASA1-associated CM-AVM syndrome and 80% of patients with EPHB4-associated CM-AVM syndrome have an affected parent, while the remainder have de novo variants.¹

In patients with CM-AVM syndrome, CMs are often present at birth and more are typically acquired over time. CMs are characteristically 1-3 cm in diameter, round or oval, dull red or red-brown macules and patches with a blanched halo.³ Some CMs may be warm to touch indicating a possible underlying AVM or AVF.⁴ This can be confirmed by Doppler ultrasound, which would demonstrate increased arterial flow.⁴ CMs are most commonly located on the face and limbs and may present in isolation, but approximately one-third of patients have associated AVMs and AVFs.^1,5 These high-flow vascular malformations may be present in skin, muscle, bone, brain, and/or spine and may be asymptomatic or lead to serious sequelae, including bleeding, congestive heart failure, and neurologic complications, such as migraine headaches, seizures, or even stroke.⁵ Symptoms from intracranial and spinal high-flow lesions usually present in early childhood and affect approximately 7% of patients.³

The diagnosis of CM-AVM should be suspected in an individual with numerous characteristic CMs and may be supported by the presence of AVMs and AVFs, family history of CM-AVM, and/or identification of RASA1 or EPHB4 mutation by molecular genetic testing.^1,3 Although there are no consensus protocols for imaging CM-AVM patients, MRI of the brain and spine is recommended at diagnosis to identify underlying high-flow lesions.¹ This may allow for early treatment before the development of symptoms.¹ Any lesions identified on screening imaging may require regular surveillance, which is best determined by discussion with the radiologist.¹ Although there are no reports of patients with negative results on screening imaging who later develop AVMs or AVFs, there should be a low threshold for repeat imaging in patients who develop new symptoms or physical exam findings.^3,4

It has previously been suggested that the CMs in CM-AVM may actually represent early or small AVMs and pulsed-dye laser (PDL) treatment was not recommended because of concern for potential progression of lesions.⁴ However, a recent study demonstrated good response to PDL in patients with CM-AVM with no evidence of worsening or recurrence of lesions with long-term follow-up.⁶ Treatment of CMs that cause cosmetic concerns may be considered following discussion of risks and benefits with a dermatologist. Management of AVMs and AVFs requires a multidisciplinary team that, depending on location and symptoms of these features, may require the expertise of specialists such as neurosurgery, surgery, orthopedics, cardiology, and/or interventional radiology.¹

Given the suspicion for CM-AVM in our patient, further workup was completed. A skin biopsy was consistent with CM. Genetic testing with the Vascular Malformations Panel, Sequencing and Deletion/Duplication revealed a pathogenic variant in the RASA1 gene and a variant of unknown clinical significance in the TEK gene. Parental genetic testing for the RASA1 mutation was negative, supporting a de novo mutation in the patient. CNS imaging showed a small developmental venous malformation in the brain that neurosurgery did not think was clinically significant. At the most recent follow-up at age 8 years, our patient had developed a few new small CMs but was otherwise well.

Dr. Leszczynska is trained in pediatrics and is the current dermatology research fellow at the University of Texas at Austin. Ms. Croce is a dermatology-trained pediatric nurse practitioner and PhD student at the University of Texas at Austin School of Nursing. Dr. Diaz is chief of pediatric dermatology at Dell Children’s Medical Center, Austin, assistant professor of pediatrics and medicine (dermatology), and dermatology residency associate program director at University of Texas at Austin . The authors have no relevant conflicts of interest to disclose. Donna Bilu Martin, MD, is the editor of this column.


References

1. Bayrak-Toydemir P, Stevenson D. Capillary Malformation-Arteriovenous Malformation Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle: University of Washington, Seattle; February 22, 2011.

2.Yu J et al. Pediatr Dermatol. 2017 Sep;34(5):e227-30.

3. Orme CM et al. Pediatr Dermatol. 2013 Jul-Aug;30(4):409-15.

4. Weitz NA et al. Pediatr Dermatol. 2015 Jan-Feb;32(1):76-84.

5. Revencu N et al. Hum Mutat. 2013 Dec;34(12):1632-41.

6. Iznardo H et al. Pediatr Dermatol. 2020 Mar;37(2):342-44.
 

Capillary malformation-arteriovenous malformation syndrome

Capillary Malformation-arteriovenous malformation syndrome (CM-AVM) is a rare vascular disorder characterized by the presence of capillary malformations with or without arteriovenous malformations, as well as arteriovenous fistulas (AVFs). CM-AVM is an autosomal dominant disorder.¹ CM-AVM type 1 is caused by mutations in the RASA1 gene, and CM-AVM type 2 is caused by mutations in the EPHB⁴ gene.² Approximately 70% of patients with RASA1-associated CM-AVM syndrome and 80% of patients with EPHB4-associated CM-AVM syndrome have an affected parent, while the remainder have de novo variants.¹

In patients with CM-AVM syndrome, CMs are often present at birth and more are typically acquired over time. CMs are characteristically 1-3 cm in diameter, round or oval, dull red or red-brown macules and patches with a blanched halo.³ Some CMs may be warm to touch indicating a possible underlying AVM or AVF.⁴ This can be confirmed by Doppler ultrasound, which would demonstrate increased arterial flow.⁴ CMs are most commonly located on the face and limbs and may present in isolation, but approximately one-third of patients have associated AVMs and AVFs.^1,5 These high-flow vascular malformations may be present in skin, muscle, bone, brain, and/or spine and may be asymptomatic or lead to serious sequelae, including bleeding, congestive heart failure, and neurologic complications, such as migraine headaches, seizures, or even stroke.⁵ Symptoms from intracranial and spinal high-flow lesions usually present in early childhood and affect approximately 7% of patients.³

The diagnosis of CM-AVM should be suspected in an individual with numerous characteristic CMs and may be supported by the presence of AVMs and AVFs, family history of CM-AVM, and/or identification of RASA1 or EPHB4 mutation by molecular genetic testing.^1,3 Although there are no consensus protocols for imaging CM-AVM patients, MRI of the brain and spine is recommended at diagnosis to identify underlying high-flow lesions.¹ This may allow for early treatment before the development of symptoms.¹ Any lesions identified on screening imaging may require regular surveillance, which is best determined by discussion with the radiologist.¹ Although there are no reports of patients with negative results on screening imaging who later develop AVMs or AVFs, there should be a low threshold for repeat imaging in patients who develop new symptoms or physical exam findings.^3,4

It has previously been suggested that the CMs in CM-AVM may actually represent early or small AVMs and pulsed-dye laser (PDL) treatment was not recommended because of concern for potential progression of lesions.⁴ However, a recent study demonstrated good response to PDL in patients with CM-AVM with no evidence of worsening or recurrence of lesions with long-term follow-up.⁶ Treatment of CMs that cause cosmetic concerns may be considered following discussion of risks and benefits with a dermatologist. Management of AVMs and AVFs requires a multidisciplinary team that, depending on location and symptoms of these features, may require the expertise of specialists such as neurosurgery, surgery, orthopedics, cardiology, and/or interventional radiology.¹

Given the suspicion for CM-AVM in our patient, further workup was completed. A skin biopsy was consistent with CM. Genetic testing with the Vascular Malformations Panel, Sequencing and Deletion/Duplication revealed a pathogenic variant in the RASA1 gene and a variant of unknown clinical significance in the TEK gene. Parental genetic testing for the RASA1 mutation was negative, supporting a de novo mutation in the patient. CNS imaging showed a small developmental venous malformation in the brain that neurosurgery did not think was clinically significant. At the most recent follow-up at age 8 years, our patient had developed a few new small CMs but was otherwise well.

Dr. Leszczynska is trained in pediatrics and is the current dermatology research fellow at the University of Texas at Austin. Ms. Croce is a dermatology-trained pediatric nurse practitioner and PhD student at the University of Texas at Austin School of Nursing. Dr. Diaz is chief of pediatric dermatology at Dell Children’s Medical Center, Austin, assistant professor of pediatrics and medicine (dermatology), and dermatology residency associate program director at University of Texas at Austin . The authors have no relevant conflicts of interest to disclose. Donna Bilu Martin, MD, is the editor of this column.


References

1. Bayrak-Toydemir P, Stevenson D. Capillary Malformation-Arteriovenous Malformation Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle: University of Washington, Seattle; February 22, 2011.

2.Yu J et al. Pediatr Dermatol. 2017 Sep;34(5):e227-30.

3. Orme CM et al. Pediatr Dermatol. 2013 Jul-Aug;30(4):409-15.

4. Weitz NA et al. Pediatr Dermatol. 2015 Jan-Feb;32(1):76-84.

5. Revencu N et al. Hum Mutat. 2013 Dec;34(12):1632-41.

6. Iznardo H et al. Pediatr Dermatol. 2020 Mar;37(2):342-44.
 

Adding the immunomodulator mycophenolate mofetil (MMF) to therapy with pegloticase (Krystexxa) may improve outcomes in patients with refractory gout, results of the proof-of-concept RECIPE trial suggest.

In the phase 2 trial, 19 of 22 patients randomized to received pegloticase and MMF achieved the primary outcome of serum uric acid levels below 6 mg/dL at week 12, compared with 4 of 10 patients assigned to pegloticase and placebo, reported Puja Khanna MD, MPH, of the University of Michigan, Ann Arbor, and colleagues.

“The use of MMF was associated with statistically significant and clinically meaningful impact on the proportion of subjects who achieved and maintained a serum urate of less than 6 mg/dL. Short-term concomitant use of MMF with pegloticase was generally well tolerated, and the estimated rates of adverse events were comparable between the groups,” she said during the virtual annual meeting of the American College of Rheumatology.

Pegloticase is a pegylated recombinant form of porcine uricase that has been shown to be effective in the treatment of gout in patients for whom other therapies have failed.

The drug’s use is limited, however, by immunogenicity, with high antipegloticase antibody titers associated with a loss of response.

“The PEG portion of the molecule, the polyethylene glycol component, can initiate an immune response that would cause significant infusion reactions and preclude further use of the medication for our patients,” explained Suleman Bhana, MD, a rheumatologist with Crystal Run Healthcare in New York’s Hudson Valley, who was not involved in the study.

“By trying to attenuate that immune response by whatever means one can, that could reduce the risk of these infusion reactions and lead to longevity and continuing efficacy of the medication,” he said.
 

Study details

The RECIPE trial was designed to test whether concomitant immunomodulation could prolong the efficacy of pegloticase therapy by dampening immune reactions.

Investigators enrolled patients 18 years and older who met 2015 ACR/European League Against Rheumatism gout classification criteria and had chronic refractory disease, defined as having symptoms inadequately controlled with oral urate-lowering therapy or a contraindication to ULT.

A total of 42 patients from five rheumatology practices were screened, and 35 were randomized on a 3:1 basis. In the intention-to-treat analysis of the results, the investigators included 32 patients: 22 in the MMF/pegloticase group and 10 placebo-treated controls who had received at least one dose of pegloticase.

Men comprised approximately 90% of the patients in each study arm, with the mean patient age around 55 years. In both groups, patients had a median of one gout flare in the prior year, and a mean duration of gout of 13 years plus a few months.

The patients’ prior urate-lowering agents included allopurinol and febuxostat, and patients had received colchicine, NSAIDs, and corticosteroids for acute gout.

The mean serum urate levels at baseline were 8.9 mg/dL in the MMF group, and 9.8 mg/dL in the placebo group.

Patients were given either MMF 1 g twice daily or a placebo during a 2-week run-in, with the assigned medications continuing for the first 12 weeks concomitantly with pegloticase. The uricase was given intravenously at a dose of 8 mg every 2 weeks for a total of 12 infusions.

As noted before, 86% of patients in the MMF arm (19 of 22) reached the primary outcome of serum uric acid levels below 6 mg/dL by week 12, compared with 40% (4 of 10) in the placebo arm (P = .01).

Week 24 serum uric acid response, a secondary endpoint, was sustained in 68% of patients in the MMF arm, compared with 30% in the placebo arm (P = .03).

“We found no significant differences between the groups in the absolute change in serum urate from baseline to week 24, or from week 12 to 24. We also did not find any differences between the treatment arms for the PROMIS [Patient Reported Outcomes Measurement Information System] or for the Gout Impact Scale,” Dr. Khanna said.

The most commonly reported adverse events included gout flares in 13% of patients in the MMF group and 3% in the placebo group, cardiac disorders in 3% versus 2%, respectively, and gastrointestinal disorders in 9% versus 2%.

Adverse events that occurred only in the MMF group included infections (3%), musculoskeletal and connective tissue disorders (18%), and respiratory events.

Three patients in the placebo arm had infusion reactions, two of which occurred during the first infusion, and one during the second. One of the reactions was considered serious and required hospitalization, but all infusion reactions resolved and none were fatal. There were no infusion reactions in the MMF arm.

Maybe methotrexate instead?

“The efficacy data for mycophenolate in the RECIPE study are convincing, and suggest that this combination substantially increases the proportion of people who respond to pegloticase,” commented Nicola Dalbeth, MD, professor of medicine at the University of Auckland (New Zealand), who moderated the session where the RECIPE data were reported.

“Previous open-label studies of methotrexate with pegloticase [e.g., the MIRROR study] suggest that methotrexate is another effective option to increase the response to pegloticase. However, at this stage, placebo-controlled trials of methotrexate have not been reported. I think a key consideration will be safety, and which option [methotrexate vs. mycophenolate] is safer, noting that many patients with severe gout have important comorbidities, including chronic kidney disease, diabetes, and liver disease,” she said.

Dr. Bhana also noted that there are multiple factors that might determine the choice of MMF or methotrexate as an immunomodulatory partner for pegloticase.

“Some gout patients have chronic kidney disease or a variety of comorbidities – high uric acid can also cause kidney damage – and if they have a kidney illness, methotrexate may not be a safe medicine because there’s a risk of further toxicity that can lead to bone marrow suppression, which I have seen personally in patients, and in this case mycophenolate would be the preferred option,” he said.

The study was sponsored by the University of Alabama at Birmingham, with collaboration from the University of Michigan, as well as the National Institute of Arthritis and Musculoskeletal and Skin Diseases and Horizon, which makes pegloticase. Dr. Khanna disclosed grant and research support from Dyve, Selecta, and Sobi, and consulting for Sobi and Horizon. Dr. Dalbeth disclosed relationships with AstraZeneca, AbbVie, Arthrosi, Dyve, Selecta, and Janssen. Dr. Bhana disclosed nonbranded consulting work for Horizon.

SOURCE: Khanna P et al. Arthritis Rheumatol. 2020;72(suppl 10), Abstract 0952.

Adding the immunomodulator mycophenolate mofetil (MMF) to therapy with pegloticase (Krystexxa) may improve outcomes in patients with refractory gout, results of the proof-of-concept RECIPE trial suggest.

In the phase 2 trial, 19 of 22 patients randomized to received pegloticase and MMF achieved the primary outcome of serum uric acid levels below 6 mg/dL at week 12, compared with 4 of 10 patients assigned to pegloticase and placebo, reported Puja Khanna MD, MPH, of the University of Michigan, Ann Arbor, and colleagues.

“The use of MMF was associated with statistically significant and clinically meaningful impact on the proportion of subjects who achieved and maintained a serum urate of less than 6 mg/dL. Short-term concomitant use of MMF with pegloticase was generally well tolerated, and the estimated rates of adverse events were comparable between the groups,” she said during the virtual annual meeting of the American College of Rheumatology.

Pegloticase is a pegylated recombinant form of porcine uricase that has been shown to be effective in the treatment of gout in patients for whom other therapies have failed.

The drug’s use is limited, however, by immunogenicity, with high antipegloticase antibody titers associated with a loss of response.

“The PEG portion of the molecule, the polyethylene glycol component, can initiate an immune response that would cause significant infusion reactions and preclude further use of the medication for our patients,” explained Suleman Bhana, MD, a rheumatologist with Crystal Run Healthcare in New York’s Hudson Valley, who was not involved in the study.

“By trying to attenuate that immune response by whatever means one can, that could reduce the risk of these infusion reactions and lead to longevity and continuing efficacy of the medication,” he said.
 

Study details

The RECIPE trial was designed to test whether concomitant immunomodulation could prolong the efficacy of pegloticase therapy by dampening immune reactions.

Investigators enrolled patients 18 years and older who met 2015 ACR/European League Against Rheumatism gout classification criteria and had chronic refractory disease, defined as having symptoms inadequately controlled with oral urate-lowering therapy or a contraindication to ULT.

A total of 42 patients from five rheumatology practices were screened, and 35 were randomized on a 3:1 basis. In the intention-to-treat analysis of the results, the investigators included 32 patients: 22 in the MMF/pegloticase group and 10 placebo-treated controls who had received at least one dose of pegloticase.

Men comprised approximately 90% of the patients in each study arm, with the mean patient age around 55 years. In both groups, patients had a median of one gout flare in the prior year, and a mean duration of gout of 13 years plus a few months.

The patients’ prior urate-lowering agents included allopurinol and febuxostat, and patients had received colchicine, NSAIDs, and corticosteroids for acute gout.

The mean serum urate levels at baseline were 8.9 mg/dL in the MMF group, and 9.8 mg/dL in the placebo group.

Patients were given either MMF 1 g twice daily or a placebo during a 2-week run-in, with the assigned medications continuing for the first 12 weeks concomitantly with pegloticase. The uricase was given intravenously at a dose of 8 mg every 2 weeks for a total of 12 infusions.

As noted before, 86% of patients in the MMF arm (19 of 22) reached the primary outcome of serum uric acid levels below 6 mg/dL by week 12, compared with 40% (4 of 10) in the placebo arm (P = .01).

Week 24 serum uric acid response, a secondary endpoint, was sustained in 68% of patients in the MMF arm, compared with 30% in the placebo arm (P = .03).

“We found no significant differences between the groups in the absolute change in serum urate from baseline to week 24, or from week 12 to 24. We also did not find any differences between the treatment arms for the PROMIS [Patient Reported Outcomes Measurement Information System] or for the Gout Impact Scale,” Dr. Khanna said.

The most commonly reported adverse events included gout flares in 13% of patients in the MMF group and 3% in the placebo group, cardiac disorders in 3% versus 2%, respectively, and gastrointestinal disorders in 9% versus 2%.

Adverse events that occurred only in the MMF group included infections (3%), musculoskeletal and connective tissue disorders (18%), and respiratory events.

Three patients in the placebo arm had infusion reactions, two of which occurred during the first infusion, and one during the second. One of the reactions was considered serious and required hospitalization, but all infusion reactions resolved and none were fatal. There were no infusion reactions in the MMF arm.

Maybe methotrexate instead?

“The efficacy data for mycophenolate in the RECIPE study are convincing, and suggest that this combination substantially increases the proportion of people who respond to pegloticase,” commented Nicola Dalbeth, MD, professor of medicine at the University of Auckland (New Zealand), who moderated the session where the RECIPE data were reported.

“Previous open-label studies of methotrexate with pegloticase [e.g., the MIRROR study] suggest that methotrexate is another effective option to increase the response to pegloticase. However, at this stage, placebo-controlled trials of methotrexate have not been reported. I think a key consideration will be safety, and which option [methotrexate vs. mycophenolate] is safer, noting that many patients with severe gout have important comorbidities, including chronic kidney disease, diabetes, and liver disease,” she said.

Dr. Bhana also noted that there are multiple factors that might determine the choice of MMF or methotrexate as an immunomodulatory partner for pegloticase.

“Some gout patients have chronic kidney disease or a variety of comorbidities – high uric acid can also cause kidney damage – and if they have a kidney illness, methotrexate may not be a safe medicine because there’s a risk of further toxicity that can lead to bone marrow suppression, which I have seen personally in patients, and in this case mycophenolate would be the preferred option,” he said.

The study was sponsored by the University of Alabama at Birmingham, with collaboration from the University of Michigan, as well as the National Institute of Arthritis and Musculoskeletal and Skin Diseases and Horizon, which makes pegloticase. Dr. Khanna disclosed grant and research support from Dyve, Selecta, and Sobi, and consulting for Sobi and Horizon. Dr. Dalbeth disclosed relationships with AstraZeneca, AbbVie, Arthrosi, Dyve, Selecta, and Janssen. Dr. Bhana disclosed nonbranded consulting work for Horizon.

SOURCE: Khanna P et al. Arthritis Rheumatol. 2020;72(suppl 10), Abstract 0952.

Adding the immunomodulator mycophenolate mofetil (MMF) to therapy with pegloticase (Krystexxa) may improve outcomes in patients with refractory gout, results of the proof-of-concept RECIPE trial suggest.

In the phase 2 trial, 19 of 22 patients randomized to received pegloticase and MMF achieved the primary outcome of serum uric acid levels below 6 mg/dL at week 12, compared with 4 of 10 patients assigned to pegloticase and placebo, reported Puja Khanna MD, MPH, of the University of Michigan, Ann Arbor, and colleagues.

“The use of MMF was associated with statistically significant and clinically meaningful impact on the proportion of subjects who achieved and maintained a serum urate of less than 6 mg/dL. Short-term concomitant use of MMF with pegloticase was generally well tolerated, and the estimated rates of adverse events were comparable between the groups,” she said during the virtual annual meeting of the American College of Rheumatology.

Pegloticase is a pegylated recombinant form of porcine uricase that has been shown to be effective in the treatment of gout in patients for whom other therapies have failed.

The drug’s use is limited, however, by immunogenicity, with high antipegloticase antibody titers associated with a loss of response.

“The PEG portion of the molecule, the polyethylene glycol component, can initiate an immune response that would cause significant infusion reactions and preclude further use of the medication for our patients,” explained Suleman Bhana, MD, a rheumatologist with Crystal Run Healthcare in New York’s Hudson Valley, who was not involved in the study.

“By trying to attenuate that immune response by whatever means one can, that could reduce the risk of these infusion reactions and lead to longevity and continuing efficacy of the medication,” he said.
 

Study details

The RECIPE trial was designed to test whether concomitant immunomodulation could prolong the efficacy of pegloticase therapy by dampening immune reactions.

Investigators enrolled patients 18 years and older who met 2015 ACR/European League Against Rheumatism gout classification criteria and had chronic refractory disease, defined as having symptoms inadequately controlled with oral urate-lowering therapy or a contraindication to ULT.

A total of 42 patients from five rheumatology practices were screened, and 35 were randomized on a 3:1 basis. In the intention-to-treat analysis of the results, the investigators included 32 patients: 22 in the MMF/pegloticase group and 10 placebo-treated controls who had received at least one dose of pegloticase.

Men comprised approximately 90% of the patients in each study arm, with the mean patient age around 55 years. In both groups, patients had a median of one gout flare in the prior year, and a mean duration of gout of 13 years plus a few months.

The patients’ prior urate-lowering agents included allopurinol and febuxostat, and patients had received colchicine, NSAIDs, and corticosteroids for acute gout.

The mean serum urate levels at baseline were 8.9 mg/dL in the MMF group, and 9.8 mg/dL in the placebo group.

Patients were given either MMF 1 g twice daily or a placebo during a 2-week run-in, with the assigned medications continuing for the first 12 weeks concomitantly with pegloticase. The uricase was given intravenously at a dose of 8 mg every 2 weeks for a total of 12 infusions.

As noted before, 86% of patients in the MMF arm (19 of 22) reached the primary outcome of serum uric acid levels below 6 mg/dL by week 12, compared with 40% (4 of 10) in the placebo arm (P = .01).

Week 24 serum uric acid response, a secondary endpoint, was sustained in 68% of patients in the MMF arm, compared with 30% in the placebo arm (P = .03).

“We found no significant differences between the groups in the absolute change in serum urate from baseline to week 24, or from week 12 to 24. We also did not find any differences between the treatment arms for the PROMIS [Patient Reported Outcomes Measurement Information System] or for the Gout Impact Scale,” Dr. Khanna said.

The most commonly reported adverse events included gout flares in 13% of patients in the MMF group and 3% in the placebo group, cardiac disorders in 3% versus 2%, respectively, and gastrointestinal disorders in 9% versus 2%.

Adverse events that occurred only in the MMF group included infections (3%), musculoskeletal and connective tissue disorders (18%), and respiratory events.

Three patients in the placebo arm had infusion reactions, two of which occurred during the first infusion, and one during the second. One of the reactions was considered serious and required hospitalization, but all infusion reactions resolved and none were fatal. There were no infusion reactions in the MMF arm.

Maybe methotrexate instead?

“The efficacy data for mycophenolate in the RECIPE study are convincing, and suggest that this combination substantially increases the proportion of people who respond to pegloticase,” commented Nicola Dalbeth, MD, professor of medicine at the University of Auckland (New Zealand), who moderated the session where the RECIPE data were reported.

“Previous open-label studies of methotrexate with pegloticase [e.g., the MIRROR study] suggest that methotrexate is another effective option to increase the response to pegloticase. However, at this stage, placebo-controlled trials of methotrexate have not been reported. I think a key consideration will be safety, and which option [methotrexate vs. mycophenolate] is safer, noting that many patients with severe gout have important comorbidities, including chronic kidney disease, diabetes, and liver disease,” she said.

Dr. Bhana also noted that there are multiple factors that might determine the choice of MMF or methotrexate as an immunomodulatory partner for pegloticase.

“Some gout patients have chronic kidney disease or a variety of comorbidities – high uric acid can also cause kidney damage – and if they have a kidney illness, methotrexate may not be a safe medicine because there’s a risk of further toxicity that can lead to bone marrow suppression, which I have seen personally in patients, and in this case mycophenolate would be the preferred option,” he said.

The study was sponsored by the University of Alabama at Birmingham, with collaboration from the University of Michigan, as well as the National Institute of Arthritis and Musculoskeletal and Skin Diseases and Horizon, which makes pegloticase. Dr. Khanna disclosed grant and research support from Dyve, Selecta, and Sobi, and consulting for Sobi and Horizon. Dr. Dalbeth disclosed relationships with AstraZeneca, AbbVie, Arthrosi, Dyve, Selecta, and Janssen. Dr. Bhana disclosed nonbranded consulting work for Horizon.

SOURCE: Khanna P et al. Arthritis Rheumatol. 2020;72(suppl 10), Abstract 0952.

Many individuals infected with SARS-CoV-2 never become symptomatic. In a South Korean study, these infected individuals remained asymptomatic for a prolonged period while maintaining the same viral load as symptomatic patients, suggesting that they are just as infectious.¹ A narrative review found high rates of asymptomatic disease in several younger populations, including women in an obstetric ward (88%), the crew of an aircraft carrier (58%), and prisoners (96%).² However, there is no published research on the percentage of university students who are asymptomatic.

Methods 

The University of Georgia (UGA) began classes on August 20, 2020. Shortly before the beginning of classes, UGA implemented a surveillance program for asymptomatic students, faculty, and staff, testing 300 to 450 people per day. Initially, during Weeks 1 and 2 of data collection, anyone could choose to be tested. In Weeks 3 and 4, students, faculty, and staff were randomly invited to participate.

The estimated percentage of asymptomatic students infected with SARS-CoV-2 ranged from 73% to 92.5% by week and was 81.1% overall.

Over the 4-week period beginning on August 17, we calculated the percent of positive cases in surveillance testing and applied this percentage to the entire UGA student population (n = 38,920) to estimate the total number of asymptomatic COVID-19 students each week.³ Data for symptomatic cases were also reported by the university on a weekly basis. This included positive tests from the University Health Center, as well as voluntary reporting using a smartphone app from other sites.

Positive tests in symptomatic individuals were not stratified by student vs nonstudent until Week 3; students comprised 95% of positive symptomatic reports in Week 3 and 99% in Week 4, so we conservatively estimated that 95% of symptomatic cases in Weeks 1 and 2 were students. These data were used to estimate the percentage of SARS-CoV-2–positive students who were asymptomatic. 

Results

Our results are summarized in the table. The percentage of asymptomatic students testing positive in surveillance testing was 3.4% in Week 1 and rose steadily to 9% by Week 4. We estimated that there were 1303 asymptomatic cases among students in Week 1, increasing to 3487 asymptomatic positive students on campus by Week 4. The estimated percentage of asymptomatic students infected with SARS-CoV-2 ranged from 73% to 92.5% by week and was 81.1% overall.

Discussion

During the reporting period from August 17 to September 13, the 7-day moving average of new cases in Clarke County (home of UGA) increased from 30 to 83 per 100,000 persons/day (https://dph.georgia.gov/covid-19-daily-status-report). During this period, there were large increases in the number of infected students, more than 80% of whom were asymptomatic. With the assumption that anyone could be infected even if asymptomatic, these numbers highlight the importance for infection control to prevent potential spread within a community by taking universal precautions such as wearing a mask, following physical distancing guidelines, and handwashing.

Limitations. First, reporting of positive tests in symptomatic individuals is highly encouraged but not required. The large drop in symptomatic positive test reports between Weeks 3 and 4, with no change in test positivity in surveillance of asymptomatic students (8.9% vs 9%), suggests that students may have chosen to be tested elsewhere in conjunction with evaluation of their symptoms and/or not reported positive tests, possibly to avoid mandatory isolation and other restrictions on their activities. Further evidence to support no change in actual infection rates comes from testing for virus in wastewater, which also remained unchanged.⁴

Continue to: Second, each week's surveillance...

Second, each week’s surveillance population is not a true random sample, so extrapolating this estimate to the full student population could over- or undercount asymptomatic cases depending on the direction of bias (ie, healthy volunteer bias vs test avoidance by those with high-risk behaviors).

Finally, some students who were positive in surveillance testing may have been presymptomatic, rather than asymptomatic.

In conclusion, we estimate that approximately 80% of students infected with SARS-CoV-2 are asymptomatic. This is consistent with other studies in young adult populations.²

Mark H. Ebell, MD, MS
Cassie Chupp, MPH
Michelle Bentivegna, MPH
Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens
[email protected]

The authors reported no potential conflict of interest relevant to this article.

Many individuals infected with SARS-CoV-2 never become symptomatic. In a South Korean study, these infected individuals remained asymptomatic for a prolonged period while maintaining the same viral load as symptomatic patients, suggesting that they are just as infectious.¹ A narrative review found high rates of asymptomatic disease in several younger populations, including women in an obstetric ward (88%), the crew of an aircraft carrier (58%), and prisoners (96%).² However, there is no published research on the percentage of university students who are asymptomatic.

Methods 

The University of Georgia (UGA) began classes on August 20, 2020. Shortly before the beginning of classes, UGA implemented a surveillance program for asymptomatic students, faculty, and staff, testing 300 to 450 people per day. Initially, during Weeks 1 and 2 of data collection, anyone could choose to be tested. In Weeks 3 and 4, students, faculty, and staff were randomly invited to participate.

The estimated percentage of asymptomatic students infected with SARS-CoV-2 ranged from 73% to 92.5% by week and was 81.1% overall.

Over the 4-week period beginning on August 17, we calculated the percent of positive cases in surveillance testing and applied this percentage to the entire UGA student population (n = 38,920) to estimate the total number of asymptomatic COVID-19 students each week.³ Data for symptomatic cases were also reported by the university on a weekly basis. This included positive tests from the University Health Center, as well as voluntary reporting using a smartphone app from other sites.

Positive tests in symptomatic individuals were not stratified by student vs nonstudent until Week 3; students comprised 95% of positive symptomatic reports in Week 3 and 99% in Week 4, so we conservatively estimated that 95% of symptomatic cases in Weeks 1 and 2 were students. These data were used to estimate the percentage of SARS-CoV-2–positive students who were asymptomatic. 

Results

Our results are summarized in the table. The percentage of asymptomatic students testing positive in surveillance testing was 3.4% in Week 1 and rose steadily to 9% by Week 4. We estimated that there were 1303 asymptomatic cases among students in Week 1, increasing to 3487 asymptomatic positive students on campus by Week 4. The estimated percentage of asymptomatic students infected with SARS-CoV-2 ranged from 73% to 92.5% by week and was 81.1% overall.

Discussion

During the reporting period from August 17 to September 13, the 7-day moving average of new cases in Clarke County (home of UGA) increased from 30 to 83 per 100,000 persons/day (https://dph.georgia.gov/covid-19-daily-status-report). During this period, there were large increases in the number of infected students, more than 80% of whom were asymptomatic. With the assumption that anyone could be infected even if asymptomatic, these numbers highlight the importance for infection control to prevent potential spread within a community by taking universal precautions such as wearing a mask, following physical distancing guidelines, and handwashing.

Limitations. First, reporting of positive tests in symptomatic individuals is highly encouraged but not required. The large drop in symptomatic positive test reports between Weeks 3 and 4, with no change in test positivity in surveillance of asymptomatic students (8.9% vs 9%), suggests that students may have chosen to be tested elsewhere in conjunction with evaluation of their symptoms and/or not reported positive tests, possibly to avoid mandatory isolation and other restrictions on their activities. Further evidence to support no change in actual infection rates comes from testing for virus in wastewater, which also remained unchanged.⁴

Continue to: Second, each week's surveillance...

Second, each week’s surveillance population is not a true random sample, so extrapolating this estimate to the full student population could over- or undercount asymptomatic cases depending on the direction of bias (ie, healthy volunteer bias vs test avoidance by those with high-risk behaviors).

Finally, some students who were positive in surveillance testing may have been presymptomatic, rather than asymptomatic.

In conclusion, we estimate that approximately 80% of students infected with SARS-CoV-2 are asymptomatic. This is consistent with other studies in young adult populations.²

Mark H. Ebell, MD, MS
Cassie Chupp, MPH
Michelle Bentivegna, MPH
Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens
[email protected]

The authors reported no potential conflict of interest relevant to this article.

Many individuals infected with SARS-CoV-2 never become symptomatic. In a South Korean study, these infected individuals remained asymptomatic for a prolonged period while maintaining the same viral load as symptomatic patients, suggesting that they are just as infectious.¹ A narrative review found high rates of asymptomatic disease in several younger populations, including women in an obstetric ward (88%), the crew of an aircraft carrier (58%), and prisoners (96%).² However, there is no published research on the percentage of university students who are asymptomatic.

Methods 

The University of Georgia (UGA) began classes on August 20, 2020. Shortly before the beginning of classes, UGA implemented a surveillance program for asymptomatic students, faculty, and staff, testing 300 to 450 people per day. Initially, during Weeks 1 and 2 of data collection, anyone could choose to be tested. In Weeks 3 and 4, students, faculty, and staff were randomly invited to participate.

The estimated percentage of asymptomatic students infected with SARS-CoV-2 ranged from 73% to 92.5% by week and was 81.1% overall.

Over the 4-week period beginning on August 17, we calculated the percent of positive cases in surveillance testing and applied this percentage to the entire UGA student population (n = 38,920) to estimate the total number of asymptomatic COVID-19 students each week.³ Data for symptomatic cases were also reported by the university on a weekly basis. This included positive tests from the University Health Center, as well as voluntary reporting using a smartphone app from other sites.

Positive tests in symptomatic individuals were not stratified by student vs nonstudent until Week 3; students comprised 95% of positive symptomatic reports in Week 3 and 99% in Week 4, so we conservatively estimated that 95% of symptomatic cases in Weeks 1 and 2 were students. These data were used to estimate the percentage of SARS-CoV-2–positive students who were asymptomatic. 

Results

Our results are summarized in the table. The percentage of asymptomatic students testing positive in surveillance testing was 3.4% in Week 1 and rose steadily to 9% by Week 4. We estimated that there were 1303 asymptomatic cases among students in Week 1, increasing to 3487 asymptomatic positive students on campus by Week 4. The estimated percentage of asymptomatic students infected with SARS-CoV-2 ranged from 73% to 92.5% by week and was 81.1% overall.

Discussion

During the reporting period from August 17 to September 13, the 7-day moving average of new cases in Clarke County (home of UGA) increased from 30 to 83 per 100,000 persons/day (https://dph.georgia.gov/covid-19-daily-status-report). During this period, there were large increases in the number of infected students, more than 80% of whom were asymptomatic. With the assumption that anyone could be infected even if asymptomatic, these numbers highlight the importance for infection control to prevent potential spread within a community by taking universal precautions such as wearing a mask, following physical distancing guidelines, and handwashing.

Limitations. First, reporting of positive tests in symptomatic individuals is highly encouraged but not required. The large drop in symptomatic positive test reports between Weeks 3 and 4, with no change in test positivity in surveillance of asymptomatic students (8.9% vs 9%), suggests that students may have chosen to be tested elsewhere in conjunction with evaluation of their symptoms and/or not reported positive tests, possibly to avoid mandatory isolation and other restrictions on their activities. Further evidence to support no change in actual infection rates comes from testing for virus in wastewater, which also remained unchanged.⁴

Continue to: Second, each week's surveillance...

Second, each week’s surveillance population is not a true random sample, so extrapolating this estimate to the full student population could over- or undercount asymptomatic cases depending on the direction of bias (ie, healthy volunteer bias vs test avoidance by those with high-risk behaviors).

Finally, some students who were positive in surveillance testing may have been presymptomatic, rather than asymptomatic.

In conclusion, we estimate that approximately 80% of students infected with SARS-CoV-2 are asymptomatic. This is consistent with other studies in young adult populations.²

Mark H. Ebell, MD, MS
Cassie Chupp, MPH
Michelle Bentivegna, MPH
Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens
[email protected]

The authors reported no potential conflict of interest relevant to this article.

Zoonoses are no respecter of biological boundaries and are notorious for crossing genus and even higher taxonomic boundaries. SARS-CoV-2 is no exception, the current outbreak most probably having originated in bats, a common source of human-affecting zoonoses throughout history. But it is not a one-way street, and the virus has been shown to spread from infected humans to a variety of other land mammals, including our domesticated animals and kept zoo species.

A recent troubling report, however, has indicated that sea mammals may be part of a next wave of likely candidates for infection, put at risk by the current human pandemic and environmental degradation on a global scale, according to a the results of a genomic analysis of four major groups of sea mammals.

Researchers Sabateeshan Mathavarajah and colleagues from Dalhousie University, Halifax, N.S., examined the sequences of the ACE2 receptors in the various marine mammal species. The ACE2 receptor has recently been identified as the SARS-CoV-2 receptor, which allows for infection.

The researchers examined genomic databases of the marine species to determine if their ACE2 receptor sequences indicated the potential for high, medium, or low susceptibility to infection, as reported in Science of the Total Environment. Database analysis was performed for four groups: Cetacea (whales and dolphins), Pinnepidia (seals), Sirenia (sea cows), and Fissipedia (sea otters and polar bears).

The researchers defined susceptibility values based on comparable binding with the receptor and came up with the following subgroups: higher than human, high (resembles human ACE2), medium (resembles cat ACE2), and low (resembles dog ACE2). It has yet to be established if these marine mammals actually are infected with SARS-CoV-2 and what the impact of such an infection might have on animal health or humans who come in contact with infected animals.

They also cross-referenced for the level of species endangerment and with maps of potential wastewater contamination for certain areas that species came in contact with, using Alaska as the model.
 

Populations in danger

The researchers found 15 species that are already at risk globally that fall under the categories of near threatened, vulnerable, endangered, and critically endangered that were predicted to be medium to higher susceptibility to the SARS-CoV-2 virus than humans. Cross infection is of particular concern because other coronaviruses have been shown to have severe and lethal effects among many of these species.

Among the potentially impacted species were the near threatened–status Antarctic Mink whale and the stellar sea lion; the vulnerable sperm whale, northern fur seal, and Atlantic walrus; the endangered northern and southern sea otters, the North Pacific right whale, and the Amazon River dolphin; and the critically threatened Baiji and Vaquita dolphin species.
 

Pollution risks

In Alaska, as of Aug. 7th, 2020, there were 4,221 confirmed cases of COVID-19 and this number continues to rise, according to the researchers. Since there is a diversity of marine mammals in Alaska and their populations are well documented, they compared this information with available data on the wastewater treatment plants in the state. They were thus able to determine the potential geographic locations and species at high risk for transmission of SARS-CoV-2 via wastewater effluent.

Among their findings, the city of Cold Bay discharges wastewater into Cold Bay, where there are Northern sea otter populations that are predicted to be highly susceptible to the virus. Beluga whales are also predicted to have high susceptibility and they can be found in Bristol Bay near Naknek, a city which relies only on lagoon treatment prior to the discharge of wastewater effluent; the city of Dillingham discharges wastewater into the Nushagak River where beluga whales are found. In Palmer, wastewater effluent flows into the Talkeetna River, which is a tributary to the Susitna River and home to two species predicted to have high susceptibility, beluga whales and harbor seals, the authors added.

Based on these results, the researchers predicted that there was likely a significant risk to sea mammals across the globe, especially where less-adequate treatment facilities and high population densities may lead to greater wastewater contamination.

“Given the proximity of marine animals to high-risk environments where viral spill over is likely, we must act with foresight to protect marine mammal species predicted to be at risk and mitigate the environmental impact of the COVID-19 pandemic,” the researchers concluded.

The authors reported that they had no disclosures.

[email protected]

SOURCE: Mathavarajah S et al. Sci Total Environ. 2020 Oct 29. doi: 10.1016/j.scitotenv.2020.143346.

Zoonoses are no respecter of biological boundaries and are notorious for crossing genus and even higher taxonomic boundaries. SARS-CoV-2 is no exception, the current outbreak most probably having originated in bats, a common source of human-affecting zoonoses throughout history. But it is not a one-way street, and the virus has been shown to spread from infected humans to a variety of other land mammals, including our domesticated animals and kept zoo species.

A recent troubling report, however, has indicated that sea mammals may be part of a next wave of likely candidates for infection, put at risk by the current human pandemic and environmental degradation on a global scale, according to a the results of a genomic analysis of four major groups of sea mammals.

Researchers Sabateeshan Mathavarajah and colleagues from Dalhousie University, Halifax, N.S., examined the sequences of the ACE2 receptors in the various marine mammal species. The ACE2 receptor has recently been identified as the SARS-CoV-2 receptor, which allows for infection.

The researchers examined genomic databases of the marine species to determine if their ACE2 receptor sequences indicated the potential for high, medium, or low susceptibility to infection, as reported in Science of the Total Environment. Database analysis was performed for four groups: Cetacea (whales and dolphins), Pinnepidia (seals), Sirenia (sea cows), and Fissipedia (sea otters and polar bears).

The researchers defined susceptibility values based on comparable binding with the receptor and came up with the following subgroups: higher than human, high (resembles human ACE2), medium (resembles cat ACE2), and low (resembles dog ACE2). It has yet to be established if these marine mammals actually are infected with SARS-CoV-2 and what the impact of such an infection might have on animal health or humans who come in contact with infected animals.

They also cross-referenced for the level of species endangerment and with maps of potential wastewater contamination for certain areas that species came in contact with, using Alaska as the model.
 

Populations in danger

The researchers found 15 species that are already at risk globally that fall under the categories of near threatened, vulnerable, endangered, and critically endangered that were predicted to be medium to higher susceptibility to the SARS-CoV-2 virus than humans. Cross infection is of particular concern because other coronaviruses have been shown to have severe and lethal effects among many of these species.

Among the potentially impacted species were the near threatened–status Antarctic Mink whale and the stellar sea lion; the vulnerable sperm whale, northern fur seal, and Atlantic walrus; the endangered northern and southern sea otters, the North Pacific right whale, and the Amazon River dolphin; and the critically threatened Baiji and Vaquita dolphin species.
 

Pollution risks

In Alaska, as of Aug. 7th, 2020, there were 4,221 confirmed cases of COVID-19 and this number continues to rise, according to the researchers. Since there is a diversity of marine mammals in Alaska and their populations are well documented, they compared this information with available data on the wastewater treatment plants in the state. They were thus able to determine the potential geographic locations and species at high risk for transmission of SARS-CoV-2 via wastewater effluent.

Among their findings, the city of Cold Bay discharges wastewater into Cold Bay, where there are Northern sea otter populations that are predicted to be highly susceptible to the virus. Beluga whales are also predicted to have high susceptibility and they can be found in Bristol Bay near Naknek, a city which relies only on lagoon treatment prior to the discharge of wastewater effluent; the city of Dillingham discharges wastewater into the Nushagak River where beluga whales are found. In Palmer, wastewater effluent flows into the Talkeetna River, which is a tributary to the Susitna River and home to two species predicted to have high susceptibility, beluga whales and harbor seals, the authors added.

Based on these results, the researchers predicted that there was likely a significant risk to sea mammals across the globe, especially where less-adequate treatment facilities and high population densities may lead to greater wastewater contamination.

“Given the proximity of marine animals to high-risk environments where viral spill over is likely, we must act with foresight to protect marine mammal species predicted to be at risk and mitigate the environmental impact of the COVID-19 pandemic,” the researchers concluded.

The authors reported that they had no disclosures.

[email protected]

SOURCE: Mathavarajah S et al. Sci Total Environ. 2020 Oct 29. doi: 10.1016/j.scitotenv.2020.143346.

Zoonoses are no respecter of biological boundaries and are notorious for crossing genus and even higher taxonomic boundaries. SARS-CoV-2 is no exception, the current outbreak most probably having originated in bats, a common source of human-affecting zoonoses throughout history. But it is not a one-way street, and the virus has been shown to spread from infected humans to a variety of other land mammals, including our domesticated animals and kept zoo species.

A recent troubling report, however, has indicated that sea mammals may be part of a next wave of likely candidates for infection, put at risk by the current human pandemic and environmental degradation on a global scale, according to a the results of a genomic analysis of four major groups of sea mammals.

Researchers Sabateeshan Mathavarajah and colleagues from Dalhousie University, Halifax, N.S., examined the sequences of the ACE2 receptors in the various marine mammal species. The ACE2 receptor has recently been identified as the SARS-CoV-2 receptor, which allows for infection.

The researchers examined genomic databases of the marine species to determine if their ACE2 receptor sequences indicated the potential for high, medium, or low susceptibility to infection, as reported in Science of the Total Environment. Database analysis was performed for four groups: Cetacea (whales and dolphins), Pinnepidia (seals), Sirenia (sea cows), and Fissipedia (sea otters and polar bears).

The researchers defined susceptibility values based on comparable binding with the receptor and came up with the following subgroups: higher than human, high (resembles human ACE2), medium (resembles cat ACE2), and low (resembles dog ACE2). It has yet to be established if these marine mammals actually are infected with SARS-CoV-2 and what the impact of such an infection might have on animal health or humans who come in contact with infected animals.

They also cross-referenced for the level of species endangerment and with maps of potential wastewater contamination for certain areas that species came in contact with, using Alaska as the model.
 

Populations in danger

The researchers found 15 species that are already at risk globally that fall under the categories of near threatened, vulnerable, endangered, and critically endangered that were predicted to be medium to higher susceptibility to the SARS-CoV-2 virus than humans. Cross infection is of particular concern because other coronaviruses have been shown to have severe and lethal effects among many of these species.

Among the potentially impacted species were the near threatened–status Antarctic Mink whale and the stellar sea lion; the vulnerable sperm whale, northern fur seal, and Atlantic walrus; the endangered northern and southern sea otters, the North Pacific right whale, and the Amazon River dolphin; and the critically threatened Baiji and Vaquita dolphin species.
 

Pollution risks

In Alaska, as of Aug. 7th, 2020, there were 4,221 confirmed cases of COVID-19 and this number continues to rise, according to the researchers. Since there is a diversity of marine mammals in Alaska and their populations are well documented, they compared this information with available data on the wastewater treatment plants in the state. They were thus able to determine the potential geographic locations and species at high risk for transmission of SARS-CoV-2 via wastewater effluent.

Among their findings, the city of Cold Bay discharges wastewater into Cold Bay, where there are Northern sea otter populations that are predicted to be highly susceptible to the virus. Beluga whales are also predicted to have high susceptibility and they can be found in Bristol Bay near Naknek, a city which relies only on lagoon treatment prior to the discharge of wastewater effluent; the city of Dillingham discharges wastewater into the Nushagak River where beluga whales are found. In Palmer, wastewater effluent flows into the Talkeetna River, which is a tributary to the Susitna River and home to two species predicted to have high susceptibility, beluga whales and harbor seals, the authors added.

Based on these results, the researchers predicted that there was likely a significant risk to sea mammals across the globe, especially where less-adequate treatment facilities and high population densities may lead to greater wastewater contamination.

“Given the proximity of marine animals to high-risk environments where viral spill over is likely, we must act with foresight to protect marine mammal species predicted to be at risk and mitigate the environmental impact of the COVID-19 pandemic,” the researchers concluded.

The authors reported that they had no disclosures.

[email protected]

SOURCE: Mathavarajah S et al. Sci Total Environ. 2020 Oct 29. doi: 10.1016/j.scitotenv.2020.143346.

A previously healthy 12-year-old boy with normal development presented to his primary care physician (PCP) with a 1-week history of moderate ear pain. He was given a diagnosis of acute otitis media (AOM) and prescribed a 7-day course of amoxicillin. Although the child’s history was otherwise unremarkable, the mother reported that she’d had a deep venous thrombosis and pulmonary embolism a year earlier.

The boy continued to experience intermittent left ear pain 2 weeks after completing his antibiotic treatment, leading the PCP to refer him to an otolaryngologist. An examination by the otolaryngologist revealed a cloudy, bulging tympanic membrane. The patient was prescribed amoxicillin/clavulanate and ofloxacin ear drops.

Two days later, he was admitted to the emergency department (ED) due to worsening left ear pain and a new-onset left-sided headache. His left tympanic membrane was normal, with no tenderness or erythema of the mastoid. His vital signs were normal. He was afebrile and discharged home.

A week later, he returned to the ED with worsening ear pain and severe persistent headache, which was localized in the left occipital, left frontal, and retro-orbital regions. He denied light or sound sensitivity, nausea, vomiting, or increased lacrimation. He was tearful on examination due to the pain. He had no meningismus and normal fundi. A neurologic examination was nonlateralizing. Laboratory tests showed a normal complete blood count but increased C-reactive protein at 113 mg/dL (normal, < 0.3 mg/dL) and an erythrocyte sedimentation rate of 88 mm/hr (normal, 0-20 mm/hr).

Magnetic resonance imaging was ordered (FIGURES 1A and 1B), and Neurosurgery and Otolaryngology were consulted.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The contrast-enhanced cranial MRI scan ­(FIGURE 1A) revealed a case of acute mastoiditis with fluid in the left mastoid (blue arrow) and a large epidural abscess in the left posterior fossa (green arrow). The normal right mastoid was air-filled (yellow arrow). The T2-weighted MRI scan (FIGURE 1B) showed mild dilatation of the lateral ventricles (blue arrow) secondary to compression on the fourth ventricle by mass effect from the epidural abscess.

Acute mastoiditis—a ­complication of AOM—is an inflammatory process of mastoid air cells, which are contiguous to the middle ear cleft. In one large study of 61,783 inpatient children admitted with AOM, acute mastoiditis was reported as the most common complication in 1505 (2.4%) of the cases.¹ The 2000-2012 national estimated incidence rate of pediatric mastoiditis has ranged from a high of 2.7 per 100,000 population in 2006 to a low of 1.8 per 100,000 in 2012.² Clinical features of mastoiditis include localized mastoid tenderness, swelling, erythema, fluctuance, protrusion of the auricle, and ear pain.³

The clinical presentation of epidural abscess can be subtle with fever, headache, neck pain, and changes in mental status developing over several days.¹ Focal deficits and seizures are relatively uncommon. In a review of 308 children with acute mastoiditis (3 with an epidural abscess), high-grade fever and high absolute neutrophil count and C-reactive protein levels were associated with the development of complications of mastoiditis, including hearing loss, sinus venous thrombosis, intracranial abscess, and cranial nerve palsies.⁴

Venous sinus thrombosis was part of the differential

When we were caring for this patient, the differential diagnosis included a cranial extension of AOM. Venous sinus thrombosis was also considered, given the family history of a hypercoagulable state. The patient did not have any features suggesting primary headache syndromes, such as migraine, tension type, or cluster headache.

The differential for a patient complaining of ear pain also includes postauricular lymphadenopathy, mumps, periauricular cellulitis (with and without otitis externa), perichondritis of the auricle, and tumors involving the mastoid bone.⁴

Continue to: Imaging and treatment

Imaging of temporal bone is not recommended to make a diagnosis of mastoiditis in children with characteristic clinical findings. When imaging is needed, contrast-enhanced computed tomography (CT) is best to help visualize changes in temporal bone. If intracranial complications are suspected, cranial MRI with contrast or cranial CT with contrast can be ordered (depending on availability).⁵

Conservative management with intravenous antimicrobial therapy and middle ear drainage with myringotomy is indicated for a child with uncomplicated acute or subacute mastoiditis. For patients with suppurative extracranial or intracranial complications, aggressive surgical management is needed.⁵

Treatment for this patient included craniotomy, evacuation of the epidural abscess, and mastoidectomy. A culture obtained from the abscess showed Streptococcus intermedius. He was treated with broad-spectrum antibiotics, including ceftriaxone, vancomycin, and metronidazole. Within a week of surgery, he was discharged from the hospital and continued antibiotic treatment for 6 weeks via a peripherally inserted central catheter line.

A previously healthy 12-year-old boy with normal development presented to his primary care physician (PCP) with a 1-week history of moderate ear pain. He was given a diagnosis of acute otitis media (AOM) and prescribed a 7-day course of amoxicillin. Although the child’s history was otherwise unremarkable, the mother reported that she’d had a deep venous thrombosis and pulmonary embolism a year earlier.

The boy continued to experience intermittent left ear pain 2 weeks after completing his antibiotic treatment, leading the PCP to refer him to an otolaryngologist. An examination by the otolaryngologist revealed a cloudy, bulging tympanic membrane. The patient was prescribed amoxicillin/clavulanate and ofloxacin ear drops.

Two days later, he was admitted to the emergency department (ED) due to worsening left ear pain and a new-onset left-sided headache. His left tympanic membrane was normal, with no tenderness or erythema of the mastoid. His vital signs were normal. He was afebrile and discharged home.

A week later, he returned to the ED with worsening ear pain and severe persistent headache, which was localized in the left occipital, left frontal, and retro-orbital regions. He denied light or sound sensitivity, nausea, vomiting, or increased lacrimation. He was tearful on examination due to the pain. He had no meningismus and normal fundi. A neurologic examination was nonlateralizing. Laboratory tests showed a normal complete blood count but increased C-reactive protein at 113 mg/dL (normal, < 0.3 mg/dL) and an erythrocyte sedimentation rate of 88 mm/hr (normal, 0-20 mm/hr).

Magnetic resonance imaging was ordered (FIGURES 1A and 1B), and Neurosurgery and Otolaryngology were consulted.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The contrast-enhanced cranial MRI scan ­(FIGURE 1A) revealed a case of acute mastoiditis with fluid in the left mastoid (blue arrow) and a large epidural abscess in the left posterior fossa (green arrow). The normal right mastoid was air-filled (yellow arrow). The T2-weighted MRI scan (FIGURE 1B) showed mild dilatation of the lateral ventricles (blue arrow) secondary to compression on the fourth ventricle by mass effect from the epidural abscess.

Acute mastoiditis—a ­complication of AOM—is an inflammatory process of mastoid air cells, which are contiguous to the middle ear cleft. In one large study of 61,783 inpatient children admitted with AOM, acute mastoiditis was reported as the most common complication in 1505 (2.4%) of the cases.¹ The 2000-2012 national estimated incidence rate of pediatric mastoiditis has ranged from a high of 2.7 per 100,000 population in 2006 to a low of 1.8 per 100,000 in 2012.² Clinical features of mastoiditis include localized mastoid tenderness, swelling, erythema, fluctuance, protrusion of the auricle, and ear pain.³

The clinical presentation of epidural abscess can be subtle with fever, headache, neck pain, and changes in mental status developing over several days.¹ Focal deficits and seizures are relatively uncommon. In a review of 308 children with acute mastoiditis (3 with an epidural abscess), high-grade fever and high absolute neutrophil count and C-reactive protein levels were associated with the development of complications of mastoiditis, including hearing loss, sinus venous thrombosis, intracranial abscess, and cranial nerve palsies.⁴

Venous sinus thrombosis was part of the differential

When we were caring for this patient, the differential diagnosis included a cranial extension of AOM. Venous sinus thrombosis was also considered, given the family history of a hypercoagulable state. The patient did not have any features suggesting primary headache syndromes, such as migraine, tension type, or cluster headache.

The differential for a patient complaining of ear pain also includes postauricular lymphadenopathy, mumps, periauricular cellulitis (with and without otitis externa), perichondritis of the auricle, and tumors involving the mastoid bone.⁴

Continue to: Imaging and treatment

Imaging of temporal bone is not recommended to make a diagnosis of mastoiditis in children with characteristic clinical findings. When imaging is needed, contrast-enhanced computed tomography (CT) is best to help visualize changes in temporal bone. If intracranial complications are suspected, cranial MRI with contrast or cranial CT with contrast can be ordered (depending on availability).⁵

Conservative management with intravenous antimicrobial therapy and middle ear drainage with myringotomy is indicated for a child with uncomplicated acute or subacute mastoiditis. For patients with suppurative extracranial or intracranial complications, aggressive surgical management is needed.⁵

Treatment for this patient included craniotomy, evacuation of the epidural abscess, and mastoidectomy. A culture obtained from the abscess showed Streptococcus intermedius. He was treated with broad-spectrum antibiotics, including ceftriaxone, vancomycin, and metronidazole. Within a week of surgery, he was discharged from the hospital and continued antibiotic treatment for 6 weeks via a peripherally inserted central catheter line.

A previously healthy 12-year-old boy with normal development presented to his primary care physician (PCP) with a 1-week history of moderate ear pain. He was given a diagnosis of acute otitis media (AOM) and prescribed a 7-day course of amoxicillin. Although the child’s history was otherwise unremarkable, the mother reported that she’d had a deep venous thrombosis and pulmonary embolism a year earlier.

The boy continued to experience intermittent left ear pain 2 weeks after completing his antibiotic treatment, leading the PCP to refer him to an otolaryngologist. An examination by the otolaryngologist revealed a cloudy, bulging tympanic membrane. The patient was prescribed amoxicillin/clavulanate and ofloxacin ear drops.

Two days later, he was admitted to the emergency department (ED) due to worsening left ear pain and a new-onset left-sided headache. His left tympanic membrane was normal, with no tenderness or erythema of the mastoid. His vital signs were normal. He was afebrile and discharged home.

A week later, he returned to the ED with worsening ear pain and severe persistent headache, which was localized in the left occipital, left frontal, and retro-orbital regions. He denied light or sound sensitivity, nausea, vomiting, or increased lacrimation. He was tearful on examination due to the pain. He had no meningismus and normal fundi. A neurologic examination was nonlateralizing. Laboratory tests showed a normal complete blood count but increased C-reactive protein at 113 mg/dL (normal, < 0.3 mg/dL) and an erythrocyte sedimentation rate of 88 mm/hr (normal, 0-20 mm/hr).

Magnetic resonance imaging was ordered (FIGURES 1A and 1B), and Neurosurgery and Otolaryngology were consulted.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The contrast-enhanced cranial MRI scan ­(FIGURE 1A) revealed a case of acute mastoiditis with fluid in the left mastoid (blue arrow) and a large epidural abscess in the left posterior fossa (green arrow). The normal right mastoid was air-filled (yellow arrow). The T2-weighted MRI scan (FIGURE 1B) showed mild dilatation of the lateral ventricles (blue arrow) secondary to compression on the fourth ventricle by mass effect from the epidural abscess.

Acute mastoiditis—a ­complication of AOM—is an inflammatory process of mastoid air cells, which are contiguous to the middle ear cleft. In one large study of 61,783 inpatient children admitted with AOM, acute mastoiditis was reported as the most common complication in 1505 (2.4%) of the cases.¹ The 2000-2012 national estimated incidence rate of pediatric mastoiditis has ranged from a high of 2.7 per 100,000 population in 2006 to a low of 1.8 per 100,000 in 2012.² Clinical features of mastoiditis include localized mastoid tenderness, swelling, erythema, fluctuance, protrusion of the auricle, and ear pain.³

The clinical presentation of epidural abscess can be subtle with fever, headache, neck pain, and changes in mental status developing over several days.¹ Focal deficits and seizures are relatively uncommon. In a review of 308 children with acute mastoiditis (3 with an epidural abscess), high-grade fever and high absolute neutrophil count and C-reactive protein levels were associated with the development of complications of mastoiditis, including hearing loss, sinus venous thrombosis, intracranial abscess, and cranial nerve palsies.⁴

Venous sinus thrombosis was part of the differential

When we were caring for this patient, the differential diagnosis included a cranial extension of AOM. Venous sinus thrombosis was also considered, given the family history of a hypercoagulable state. The patient did not have any features suggesting primary headache syndromes, such as migraine, tension type, or cluster headache.

The differential for a patient complaining of ear pain also includes postauricular lymphadenopathy, mumps, periauricular cellulitis (with and without otitis externa), perichondritis of the auricle, and tumors involving the mastoid bone.⁴

Continue to: Imaging and treatment

Imaging of temporal bone is not recommended to make a diagnosis of mastoiditis in children with characteristic clinical findings. When imaging is needed, contrast-enhanced computed tomography (CT) is best to help visualize changes in temporal bone. If intracranial complications are suspected, cranial MRI with contrast or cranial CT with contrast can be ordered (depending on availability).⁵

Conservative management with intravenous antimicrobial therapy and middle ear drainage with myringotomy is indicated for a child with uncomplicated acute or subacute mastoiditis. For patients with suppurative extracranial or intracranial complications, aggressive surgical management is needed.⁵

Treatment for this patient included craniotomy, evacuation of the epidural abscess, and mastoidectomy. A culture obtained from the abscess showed Streptococcus intermedius. He was treated with broad-spectrum antibiotics, including ceftriaxone, vancomycin, and metronidazole. Within a week of surgery, he was discharged from the hospital and continued antibiotic treatment for 6 weeks via a peripherally inserted central catheter line.

Five common therapies and practices related to children’s heart health may be unnecessary, and physicians and parents should be careful about using them, the American Academy of Pediatrics explained in guidance released Nov. 2.

The AAP Section on Cardiology and Cardiac Surgery developed the recommendations as part of the Choosing Wisely campaign after reviewing evidence pertaining to practices common during pediatric visits, such as routinely ordering an electrocardiogram (ECG) as part of a sports exam.

The guidance lets physicians know what is not necessary or not indicated, with noted exceptions, Christopher S. Snyder, MD, chair of the section, said in an interview.

In all cases, family history is key, said Dr. Snyder, who is also chief of the division of pediatric cardiology at University Hospitals Cleveland Medical Center. That means taking the time necessary to ask about aunts, uncles, and all first-degree relatives, not just asking the single question of whether a patient has a family history of cardiac problems.

The following are the targeted practices and the AAP’s guidance on each.
 

ECG for sports participation

A screening ECG should not be ordered as part of a routine sports entry examination in otherwise healthy patients who have no symptoms and no personal or family history of cardiac disease, the committee says.

Some medical societies argue that all children who participate in sports should have an ECG, but, Dr. Snyder said, “Currently there are no data that support that, especially in the United States.”

ECGs often yield false positive findings, he noted: “About 10% of them will say the child is a little abnormal.”

That can be a particular problem in places with few or no pediatric cardiologists because kids can become sidelined from sports without access to experts who could clear them.

“In the U.S.,” he said, “we believe that the preparticipation physical exam and screening, which is routine for all high school athletes for sure and most athletes who compete in sports, is currently good enough.”

However, he warned, patients with a family history of heart disease need to see a pediatric cardiologist and “those patients need an ECG.”

The test is not perfect, though, he noted: “You could get your screening, go home, get a fever, COVID, something like that, and come back and have myocarditis and drop dead.”
 

ECG before ADHD therapy

Similarly, a screening ECG is not routinely needed before initiating therapy for ADHD in asymptomatic, otherwise healthy children who have no personal or family history of cardiac disease, according to the new guidance.

Dr. Snyder said that it has become routine for children to undergo an ECG before ADHD therapy, but evidence doesn’t support the practice, and with the rise in the number of ADHD diagnoses, the tests have increasingly become a burden.

Twenty years ago, the prevalence of ADHD was 3%-4%, Dr. Snyder said. It is now almost threefold higher.

The AAP committee points out that, when ECG abnormalities are identified, they rarely lead to a change in ADHD therapy. Additionally, the typical stimulants used to treat ADHD “have never shown any major effect on the heart,” Dr. Snyder said.

“Black box warnings have been put on these medications, but nothing has been found in the very routine stimulants in normal, routine doses to warrant an ECG,” he said.
 

Echocardiogram for syncope

The committee says routine use of echocardiograms for children with syncope is unnecessary unless a child has a concerning history or ECG abnormalities.

Most patient who have true syncope or are passing out or fainting are diagnosed through thorough family history, Dr. Snyder said.

“The vast majority of those need an ECG to rule out one other cause that can do this and a physical exam. If those things are normal, there really is no indication to do an echocardiogram,” he said.

“If the patient passes out while they’re running, they pass out doing strenuous exercise, or they pass out for 10-15 minutes as opposed to 20 seconds – those are the ones that need a thorough cardiac workup. But routine passing out, waking up in seconds, those do not.”
 

Echocardiogram for chest pain

Children with chest pain do not need an echocardiogram unless an ECG is abnormal or the patient has a concerning history, according to the new recommendations.

Too often, Dr. Snyder said, providers treat kids as they would adults.

“Often it comes down to what you learn in medical school,” Dr. Snyder said. “In medical school, we have 6 weeks of cardiology and we had 1 hour of pediatric cardiology.”

That younger patients will clog their arteries with fatty foods and high lipids “is really exceptionally rare,” Dr. Snyder said.

Chest pain “rarely, if ever” means heart attack in younger children, he added.

A thorough history and complete physical exam are critical, “without jumping immediately to an echocardiogram, which 99.9% of the time is going to be normal,” he said.
 

Troponins for chest pain

In addition, a typical workup for pediatric chest pain need not include evaluating troponins unless there is a concerning history or ECG abnormalities.

Snyder notes that kids with chest pain are often brought to emergency departments that are not pediatric specific, and thus clinicians turn to the standard treatment for adults with chest pain: ECG and troponin.

“The reason we in pediatric cardiology don’t love this is that troponins tend not to be specific just for heart in kids,” Dr. Snyder said. “If someone has anginal chest pain – shortness of breath, chest pain doing anything and everything, [chest pain that] occurs when they’re exercising, feels like an elephant standing on their chest – then we do encourage troponins on those patients.”

The guidance discourages ordering troponins without careful consideration of the patient’s age and condition, he said.

This list was developed by faculty in Pediatric Cardiology at University Hospitals in Cleveland. It was revised and approved by the AAP Section on Cardiology and Cardiac Surgery and the AAP Executive Committee.
 

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

Five common therapies and practices related to children’s heart health may be unnecessary, and physicians and parents should be careful about using them, the American Academy of Pediatrics explained in guidance released Nov. 2.

The AAP Section on Cardiology and Cardiac Surgery developed the recommendations as part of the Choosing Wisely campaign after reviewing evidence pertaining to practices common during pediatric visits, such as routinely ordering an electrocardiogram (ECG) as part of a sports exam.

The guidance lets physicians know what is not necessary or not indicated, with noted exceptions, Christopher S. Snyder, MD, chair of the section, said in an interview.

In all cases, family history is key, said Dr. Snyder, who is also chief of the division of pediatric cardiology at University Hospitals Cleveland Medical Center. That means taking the time necessary to ask about aunts, uncles, and all first-degree relatives, not just asking the single question of whether a patient has a family history of cardiac problems.

The following are the targeted practices and the AAP’s guidance on each.
 

ECG for sports participation

A screening ECG should not be ordered as part of a routine sports entry examination in otherwise healthy patients who have no symptoms and no personal or family history of cardiac disease, the committee says.

Some medical societies argue that all children who participate in sports should have an ECG, but, Dr. Snyder said, “Currently there are no data that support that, especially in the United States.”

ECGs often yield false positive findings, he noted: “About 10% of them will say the child is a little abnormal.”

That can be a particular problem in places with few or no pediatric cardiologists because kids can become sidelined from sports without access to experts who could clear them.

“In the U.S.,” he said, “we believe that the preparticipation physical exam and screening, which is routine for all high school athletes for sure and most athletes who compete in sports, is currently good enough.”

However, he warned, patients with a family history of heart disease need to see a pediatric cardiologist and “those patients need an ECG.”

The test is not perfect, though, he noted: “You could get your screening, go home, get a fever, COVID, something like that, and come back and have myocarditis and drop dead.”
 

ECG before ADHD therapy

Similarly, a screening ECG is not routinely needed before initiating therapy for ADHD in asymptomatic, otherwise healthy children who have no personal or family history of cardiac disease, according to the new guidance.

Dr. Snyder said that it has become routine for children to undergo an ECG before ADHD therapy, but evidence doesn’t support the practice, and with the rise in the number of ADHD diagnoses, the tests have increasingly become a burden.

Twenty years ago, the prevalence of ADHD was 3%-4%, Dr. Snyder said. It is now almost threefold higher.

The AAP committee points out that, when ECG abnormalities are identified, they rarely lead to a change in ADHD therapy. Additionally, the typical stimulants used to treat ADHD “have never shown any major effect on the heart,” Dr. Snyder said.

“Black box warnings have been put on these medications, but nothing has been found in the very routine stimulants in normal, routine doses to warrant an ECG,” he said.
 

Echocardiogram for syncope

The committee says routine use of echocardiograms for children with syncope is unnecessary unless a child has a concerning history or ECG abnormalities.

Most patient who have true syncope or are passing out or fainting are diagnosed through thorough family history, Dr. Snyder said.

“The vast majority of those need an ECG to rule out one other cause that can do this and a physical exam. If those things are normal, there really is no indication to do an echocardiogram,” he said.

“If the patient passes out while they’re running, they pass out doing strenuous exercise, or they pass out for 10-15 minutes as opposed to 20 seconds – those are the ones that need a thorough cardiac workup. But routine passing out, waking up in seconds, those do not.”
 

Echocardiogram for chest pain

Children with chest pain do not need an echocardiogram unless an ECG is abnormal or the patient has a concerning history, according to the new recommendations.

Too often, Dr. Snyder said, providers treat kids as they would adults.

“Often it comes down to what you learn in medical school,” Dr. Snyder said. “In medical school, we have 6 weeks of cardiology and we had 1 hour of pediatric cardiology.”

That younger patients will clog their arteries with fatty foods and high lipids “is really exceptionally rare,” Dr. Snyder said.

Chest pain “rarely, if ever” means heart attack in younger children, he added.

A thorough history and complete physical exam are critical, “without jumping immediately to an echocardiogram, which 99.9% of the time is going to be normal,” he said.
 

Troponins for chest pain

In addition, a typical workup for pediatric chest pain need not include evaluating troponins unless there is a concerning history or ECG abnormalities.

Snyder notes that kids with chest pain are often brought to emergency departments that are not pediatric specific, and thus clinicians turn to the standard treatment for adults with chest pain: ECG and troponin.

“The reason we in pediatric cardiology don’t love this is that troponins tend not to be specific just for heart in kids,” Dr. Snyder said. “If someone has anginal chest pain – shortness of breath, chest pain doing anything and everything, [chest pain that] occurs when they’re exercising, feels like an elephant standing on their chest – then we do encourage troponins on those patients.”

The guidance discourages ordering troponins without careful consideration of the patient’s age and condition, he said.

This list was developed by faculty in Pediatric Cardiology at University Hospitals in Cleveland. It was revised and approved by the AAP Section on Cardiology and Cardiac Surgery and the AAP Executive Committee.
 

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

Five common therapies and practices related to children’s heart health may be unnecessary, and physicians and parents should be careful about using them, the American Academy of Pediatrics explained in guidance released Nov. 2.

The AAP Section on Cardiology and Cardiac Surgery developed the recommendations as part of the Choosing Wisely campaign after reviewing evidence pertaining to practices common during pediatric visits, such as routinely ordering an electrocardiogram (ECG) as part of a sports exam.

The guidance lets physicians know what is not necessary or not indicated, with noted exceptions, Christopher S. Snyder, MD, chair of the section, said in an interview.

In all cases, family history is key, said Dr. Snyder, who is also chief of the division of pediatric cardiology at University Hospitals Cleveland Medical Center. That means taking the time necessary to ask about aunts, uncles, and all first-degree relatives, not just asking the single question of whether a patient has a family history of cardiac problems.

The following are the targeted practices and the AAP’s guidance on each.
 

ECG for sports participation

A screening ECG should not be ordered as part of a routine sports entry examination in otherwise healthy patients who have no symptoms and no personal or family history of cardiac disease, the committee says.

Some medical societies argue that all children who participate in sports should have an ECG, but, Dr. Snyder said, “Currently there are no data that support that, especially in the United States.”

ECGs often yield false positive findings, he noted: “About 10% of them will say the child is a little abnormal.”

That can be a particular problem in places with few or no pediatric cardiologists because kids can become sidelined from sports without access to experts who could clear them.

“In the U.S.,” he said, “we believe that the preparticipation physical exam and screening, which is routine for all high school athletes for sure and most athletes who compete in sports, is currently good enough.”

However, he warned, patients with a family history of heart disease need to see a pediatric cardiologist and “those patients need an ECG.”

The test is not perfect, though, he noted: “You could get your screening, go home, get a fever, COVID, something like that, and come back and have myocarditis and drop dead.”
 

ECG before ADHD therapy

Similarly, a screening ECG is not routinely needed before initiating therapy for ADHD in asymptomatic, otherwise healthy children who have no personal or family history of cardiac disease, according to the new guidance.

Dr. Snyder said that it has become routine for children to undergo an ECG before ADHD therapy, but evidence doesn’t support the practice, and with the rise in the number of ADHD diagnoses, the tests have increasingly become a burden.

Twenty years ago, the prevalence of ADHD was 3%-4%, Dr. Snyder said. It is now almost threefold higher.

The AAP committee points out that, when ECG abnormalities are identified, they rarely lead to a change in ADHD therapy. Additionally, the typical stimulants used to treat ADHD “have never shown any major effect on the heart,” Dr. Snyder said.

“Black box warnings have been put on these medications, but nothing has been found in the very routine stimulants in normal, routine doses to warrant an ECG,” he said.
 

Echocardiogram for syncope

The committee says routine use of echocardiograms for children with syncope is unnecessary unless a child has a concerning history or ECG abnormalities.

Most patient who have true syncope or are passing out or fainting are diagnosed through thorough family history, Dr. Snyder said.

“The vast majority of those need an ECG to rule out one other cause that can do this and a physical exam. If those things are normal, there really is no indication to do an echocardiogram,” he said.

“If the patient passes out while they’re running, they pass out doing strenuous exercise, or they pass out for 10-15 minutes as opposed to 20 seconds – those are the ones that need a thorough cardiac workup. But routine passing out, waking up in seconds, those do not.”
 

Echocardiogram for chest pain

Children with chest pain do not need an echocardiogram unless an ECG is abnormal or the patient has a concerning history, according to the new recommendations.

Too often, Dr. Snyder said, providers treat kids as they would adults.

“Often it comes down to what you learn in medical school,” Dr. Snyder said. “In medical school, we have 6 weeks of cardiology and we had 1 hour of pediatric cardiology.”

That younger patients will clog their arteries with fatty foods and high lipids “is really exceptionally rare,” Dr. Snyder said.

Chest pain “rarely, if ever” means heart attack in younger children, he added.

A thorough history and complete physical exam are critical, “without jumping immediately to an echocardiogram, which 99.9% of the time is going to be normal,” he said.
 

Troponins for chest pain

In addition, a typical workup for pediatric chest pain need not include evaluating troponins unless there is a concerning history or ECG abnormalities.

Snyder notes that kids with chest pain are often brought to emergency departments that are not pediatric specific, and thus clinicians turn to the standard treatment for adults with chest pain: ECG and troponin.

“The reason we in pediatric cardiology don’t love this is that troponins tend not to be specific just for heart in kids,” Dr. Snyder said. “If someone has anginal chest pain – shortness of breath, chest pain doing anything and everything, [chest pain that] occurs when they’re exercising, feels like an elephant standing on their chest – then we do encourage troponins on those patients.”

The guidance discourages ordering troponins without careful consideration of the patient’s age and condition, he said.

This list was developed by faculty in Pediatric Cardiology at University Hospitals in Cleveland. It was revised and approved by the AAP Section on Cardiology and Cardiac Surgery and the AAP Executive Committee.
 

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

Many screening tools are available in the public domain to assess a variety of symptoms related to impaired mental health. These tools can be used to quickly evaluate for mood, suicidal ideation or behavior, anxiety, sleep, substance use, pain, trauma, memory, and cognition (TABLE). Individuals with poor mental health incur high health care costs. Those suffering from anxiety and posttraumatic stress have more outpatient and emergency department visits and hospitalizations than patients without these disorders,^1,2 although use of mental health care services has been related to a decrease in the overutilization of health care services in general.³

Here we review several screening tools that can help you to identify symptoms of mental illnesses and thus, provide prompt early intervention, including referrals to psychological and psychiatric services.

Mood disorders

Most patients with mood disorders are treated in primary care settings.⁴ Quickly measuring patients’ mood symptoms can expedite treatment for those who need it. Many primary care clinics use the 9-item Patient Health Questionnaire (PHQ-9) to screen for depression.⁵ The US Preventive Services Task Force (USPSTF) has recommended screening for depression with adequate systems to ensure accurate diagnoses, effective treatment, and follow-up. Although the USPSTF did not specially endorse screening for bipolar disorder, it followed that recommendation with the qualifying statement, “positive screening results [for depression] should lead to additional assessment that considers severity of depression and comorbid psychological problems, alternate diagnoses, and medical conditions.”⁶ Thus, following a positive screen result for depression, consider using a screening tool for mood disorders to provide diagnostic clarification.

The Mood Disorder Questionnaire (MDQ) is a validated 15-item, self-­administered questionnaire that takes only 5 minutes to use in screening adult patients for bipolar I disorder.⁷ The MDQ assesses specific behaviors related to bipolar disorder, symptom co-occurrence, and functional impairment. The MDQ has low sensitivity (58%) but good specificity (93%) in a primary care setting.⁸ However, the MDQ is not a diagnostic instrument. A positive screen result should prompt a more thorough clinical evaluation, if necessary, by a professional trained in psychiatric disorders.

We recommend completing the MDQ prior to prescribing antidepressants. You can also monitor a patient’s response to treatment with serial MDQ testing. The MDQ is useful, too, when a patient has unclear mood symptoms that may have features overlapping with bipolar disorder. Furthermore, we recommend screening for bipolar disorder with every patient who reports symptoms of depression, given that some pharmacologic treatments (predominately selective serotonin reuptake inhibitors) can induce mania in patients who actually have unrecognized bipolar disorder.⁹

Suicide

Suicide is the 10th leading cause of death among the general population. All demographic groups are impacted by suicide; however, the most vulnerable are men ages 45 to 64 years.¹⁰ Given the imminent risk to individuals who experience suicidal ideation, properly assessing and targeting suicidal risk is paramount.

The Columbia Suicide Severity Rating Scale (C-SSRS) can be completed in an interview format or as a patient self-report. Versions of the C-SSRS are available for children, adolescents, and adults. It can be used in practice with any patient who may be at risk for suicide. Specifically, consider using the ­C-SSRS when a patient scores 1 or greater on the ­PHQ-9 or when risk is revealed with another brief screening tool that includes suicidal ideation.

Continue to: The C-SSRS covers...

The C-SSRS covers 10 categories related to suicidal ideation and behavior that the clinician explores with questions requiring only Yes/No responses. The C-SSRS demonstrates moderate-to-strong internal consistency and reliability, and it has shown a high degree of sensitivity (95%) and specificity (95%) for suicidal ideation.¹¹

Anxiety and physiologic arousal

Generalized anxiety disorder (GAD) is one of the most common anxiety disorders, with an estimated prevalence of 2.8% to 8.5% among primary care patients.¹² Brief, validated screening tools such as the Generalized Anxiety Disorder–7 item (GAD-7) scale can be effective in identifying anxiety and other related disorders in primary care settings.

The GAD-7 comprises 7 items inquiring about symptoms experienced in the past 2 weeks. Scores range from 0 to 21, with cutoffs of 5, 10, and 15 indicating mild, moderate, and severe anxiety, respectively. This questionnaire is appropriate for use with adults and has strong specificity, internal consistency, and test-retest reliability.¹² Specificity and sensitivity of the GAD-7 are maximized at a cutoff score of 10 or greater, both exceeding 80%.¹² The GAD-7 can be used when patients report symptoms of anxiety or when one needs to screen for anxiety with new patients or more clearly understand symptoms among patients who have complex mental health concerns.

Screen for bipolar disorder when symptoms of depression are reported.

The Screen for Child Anxiety Related Disorders (SCARED) is a 41-item self-report measure of anxiety for children ages 8 to 18. The SCARED questionnaire yields an overall anxiety score, as well as subscales for panic disorder or significant somatic symptoms, generalized anxiety disorder, separation anxiety, social anxiety disorder, and significant school avoidance.¹³ There is also a 5-item version of the SCARED, which can be useful for brief screening in fast-paced settings when no anxiety disorder is suspected, or for children who may have anxiety but exhibit reduced verbal capacity. The SCARED has been found to have moderate sensitivity (81.8%) and specificity (52%) for diagnosing anxiety disorders in a community sample, with an optimal cutoff point of 22 on the total scale.¹⁴

Sleep

Sleep concerns are common, with the prevalence of insomnia among adults in the United States estimated to be 19.2%.¹⁵ The importance of assessing these concerns cannot be overstated, and primary care providers are the ones patients consult most often.¹⁶ The gold standard in assessing sleep disorders is a structured clinical interview, polysomnography, sleep diary, and actigraphy (home-based monitoring of movement through a device, often worn on the wrist).^17,18 However, this work-up is expensive, time-intensive, and impractical in integrated care settings; thus the need for a brief, self-report screening tool to guide further assessment and intervention.

Continue to: The Insomnia Severity Index...

The Insomnia Severity Index (ISI) assesses patients’ perceptions of their insomnia. The ISI was developed to aid both in the clinical evaluation of patients with insomnia and to measure treatment outcomes. Administration of the ISI takes approximately 5 minutes, and scoring takes less than 1 minute.

The ISI is composed of 7 items that measure the severity of sleep onset and sleep maintenance difficulties, satisfaction with current sleep, impact on daily functioning, impairment observable to others, and degree of distress caused by the sleep problems. Each item is scored on a 0 to 4 Likert-type scale, and the individual items are summed for a total score of 0 to 28, with higher scores suggesting more severe insomnia. Evidence-based guidelines recommend cognitive behavioral therapy for insomnia (CBT-I) as the first-line treatment for adults with primary insomnia.¹⁹

Several validation studies have found the ISI to be a reliable measure of perceived insomnia severity, and one that is sensitive to changes in patients’ perceptions of treatment outcomes.^20,21 An additional validation study confirmed that in primary care settings, a cutoff score of 14 should be used to indicate the likely presence of clinical insomnia²² and to guide further assessment and intervention.

The percentage of insomniac patients correctly identified with the ISI was 82.2%, with moderate sensitivity (82.4%) and specificity (82.1%).²² A positive predictive value of 70% was found, meaning that an insomnia disorder is probable when the ISI total score is 14 or higher; conversely, the negative predictive value was 90.2%.

Substance use and pain

The evaluation of alcohol and drug use is an integral part of assessing risky health behaviors. The 10-item Alcohol Use Disorder Identification Test (AUDIT) is a self-report tool developed by the World Health Organization.^23,24 Validated in medical settings, scores of 8 or higher suggest problematic drinking.^25,26 The AUDIT has demonstrated high specificity (94%) and moderate sensitivity (81%) in primary care settings.²⁷ The AUDIT-C (items 1, 2, and 3 of the AUDIT) has also demonstrated comparable sensitivity, although slightly lower specificity, than the full AUDIT, suggesting that this 3-question screen can also be used in primary care settings.²⁷

Continue to: Opioid medications...

Opioid medications, frequently prescribed for chronic pain, present serious risks for many patients. The Screener and Opioid Assessment for Patients with Pain–Revised (SOAPP-R) is a 24-item self-reporting scale that can be completed in approximately 10 minutes.²⁸ A score of 18 or higher has identified 81% of patients at high risk for opioid misuse in a clinical setting, with moderate specificity (68%). Although other factors should be considered when assessing risk of opioid misuse, the SOAPP-R is a helpful and quick addition to an opioid risk assessment.

The CRAFFT Screening Tool for Adolescent Substance Use is administered by the clinician for youths ages 14 to 21. The first 3 questions ask about use of alcohol, marijuana, or other substances during the past 12 months. What follows are questions related to the young person’s specific experiences with substances in relation to Cars, Relaxation, being Alone, Forgetting, Family/Friends, and Trouble (CRAFFT). The CRAFFT has shown moderate sensitivity (76%) and good specificity (94%) for identifying any problem with substance use.²⁹ These measures may be administered to clarify or confirm substance use patterns (ie, duration, frequency), or to determine the severity of problems related to substance use (ie, social or legal problems).

Trauma and PTSD

Approximately 7.7 million adults per year will experience posttraumatic stress disorder (PTSD) symptoms, although PTSD can affect individuals of any age.³⁰ Given the impact that trauma can have, assess for PTSD in patients who have a history of trauma or who otherwise seem to be at risk. The Posttraumatic Stress Disorder Checklist (PCL-5) is a 20-item self-report questionnaire that screens for symptoms directly from the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for PTSD. One limitation is that the questionnaire is only validated for adults ages 18 years or older. Completion of the PCL-5 takes 5 to 10 minutes. The PCL-5 has strong internal consistency reliability (94%) and test-retest reliability (82%).³¹ With a cutoff score of 33 or higher, the sensitivity and specificity have been shown to be moderately high (74.5% and 70.6%, respectively).³²

The SCARED questionnaire for children yields an overall anxiety score, as well as subscales for such features as panic disorder, separation anxiety, and significant school avoidance.

The Child and Adolescent Trauma Screen (CATS) is used to assess for potentially traumatic events and PTSD symptoms in children and adolescents. These symptoms are based on the DSM-5, and therefore the CATS can act as a useful diagnostic aid. The CATS is also available in Spanish, with both caregiver-report (for children ages 3-6 years or 7-17 years) and self-report (for ages 7-17 years) versions. Practical use of the PCL-5 and the CATS involves screening for PTSD symptoms, supporting a provisional diagnosis of PTSD, and monitoring PTSD symptom changes during and after ­treatment.

Memory and cognition

Cognitive screening is a first step in evaluating possible dementia and other neuropsychological disorders. The importance of brief cognitive screening in primary care cannot be understated, especially for an aging patient population. Although the Mini Mental Status Exam (MMSE) has been widely used among health care providers and researchers, we recommend the Montreal Cognitive Assessment (MoCA).

Continue to: The MoCA is a simple...

The MoCA is a simple, standalone cognitive screening tool validated for adults ages 55 to 85 years.³³ The MoCA addresses many important cognitive domains, fits on one page, and can be administered by a trained provider in 10 minutes. Research also suggests that it has strong test-retest reliability and positive and negative predictive values for mild cognitive impairment and Alzheimer dementia, and it has been found to be more sensitive than the MMSE.³⁴ We additionally recommend the MoCA as it measures several cognitive skills that are not addressed on the MMSE, including verbal fluency and abstraction.³⁴ Scores below 25 are suggestive of cognitive impairment and should lead to a referral for neuropsychological testing.

The MoCA’s sensitivity for detecting cognitive impairment is high (94%), and specificity is low (42%).³⁵ To ensure consistency and accuracy in administering the MoCA, certification is now required via an online training program through www.mocatest.org.

Adapting these screening tools to practice

These tools are not meant to be used at every appointment. Every practice is different, and each clinic or physician can tailor the use of these screening tools to the needs of the patient population, as concerns arise, or in collaboration with other providers. Additionally, these screening tools can be used in both integrated care and in private practice, to prompt a more thorough assessment or to aid in—and inform—treatment. Although some physicians choose to administer certain screening tools at each clinic visit, knowing about the availability of other tools can be useful in ­assessing various issues.

The FIGURE can be used to aid in the clinical decision-making process.

CORRESPONDENCE
Rebecca Sewell, PsyD, Bon Secours Mercy Health, 2213 Cherry Street, Toledo, OH 4360; [email protected].

Many screening tools are available in the public domain to assess a variety of symptoms related to impaired mental health. These tools can be used to quickly evaluate for mood, suicidal ideation or behavior, anxiety, sleep, substance use, pain, trauma, memory, and cognition (TABLE). Individuals with poor mental health incur high health care costs. Those suffering from anxiety and posttraumatic stress have more outpatient and emergency department visits and hospitalizations than patients without these disorders,^1,2 although use of mental health care services has been related to a decrease in the overutilization of health care services in general.³

Here we review several screening tools that can help you to identify symptoms of mental illnesses and thus, provide prompt early intervention, including referrals to psychological and psychiatric services.

Mood disorders

Most patients with mood disorders are treated in primary care settings.⁴ Quickly measuring patients’ mood symptoms can expedite treatment for those who need it. Many primary care clinics use the 9-item Patient Health Questionnaire (PHQ-9) to screen for depression.⁵ The US Preventive Services Task Force (USPSTF) has recommended screening for depression with adequate systems to ensure accurate diagnoses, effective treatment, and follow-up. Although the USPSTF did not specially endorse screening for bipolar disorder, it followed that recommendation with the qualifying statement, “positive screening results [for depression] should lead to additional assessment that considers severity of depression and comorbid psychological problems, alternate diagnoses, and medical conditions.”⁶ Thus, following a positive screen result for depression, consider using a screening tool for mood disorders to provide diagnostic clarification.

The Mood Disorder Questionnaire (MDQ) is a validated 15-item, self-­administered questionnaire that takes only 5 minutes to use in screening adult patients for bipolar I disorder.⁷ The MDQ assesses specific behaviors related to bipolar disorder, symptom co-occurrence, and functional impairment. The MDQ has low sensitivity (58%) but good specificity (93%) in a primary care setting.⁸ However, the MDQ is not a diagnostic instrument. A positive screen result should prompt a more thorough clinical evaluation, if necessary, by a professional trained in psychiatric disorders.

We recommend completing the MDQ prior to prescribing antidepressants. You can also monitor a patient’s response to treatment with serial MDQ testing. The MDQ is useful, too, when a patient has unclear mood symptoms that may have features overlapping with bipolar disorder. Furthermore, we recommend screening for bipolar disorder with every patient who reports symptoms of depression, given that some pharmacologic treatments (predominately selective serotonin reuptake inhibitors) can induce mania in patients who actually have unrecognized bipolar disorder.⁹

Suicide

Suicide is the 10th leading cause of death among the general population. All demographic groups are impacted by suicide; however, the most vulnerable are men ages 45 to 64 years.¹⁰ Given the imminent risk to individuals who experience suicidal ideation, properly assessing and targeting suicidal risk is paramount.

The Columbia Suicide Severity Rating Scale (C-SSRS) can be completed in an interview format or as a patient self-report. Versions of the C-SSRS are available for children, adolescents, and adults. It can be used in practice with any patient who may be at risk for suicide. Specifically, consider using the ­C-SSRS when a patient scores 1 or greater on the ­PHQ-9 or when risk is revealed with another brief screening tool that includes suicidal ideation.

Continue to: The C-SSRS covers...

The C-SSRS covers 10 categories related to suicidal ideation and behavior that the clinician explores with questions requiring only Yes/No responses. The C-SSRS demonstrates moderate-to-strong internal consistency and reliability, and it has shown a high degree of sensitivity (95%) and specificity (95%) for suicidal ideation.¹¹

Anxiety and physiologic arousal

Generalized anxiety disorder (GAD) is one of the most common anxiety disorders, with an estimated prevalence of 2.8% to 8.5% among primary care patients.¹² Brief, validated screening tools such as the Generalized Anxiety Disorder–7 item (GAD-7) scale can be effective in identifying anxiety and other related disorders in primary care settings.

The GAD-7 comprises 7 items inquiring about symptoms experienced in the past 2 weeks. Scores range from 0 to 21, with cutoffs of 5, 10, and 15 indicating mild, moderate, and severe anxiety, respectively. This questionnaire is appropriate for use with adults and has strong specificity, internal consistency, and test-retest reliability.¹² Specificity and sensitivity of the GAD-7 are maximized at a cutoff score of 10 or greater, both exceeding 80%.¹² The GAD-7 can be used when patients report symptoms of anxiety or when one needs to screen for anxiety with new patients or more clearly understand symptoms among patients who have complex mental health concerns.

Screen for bipolar disorder when symptoms of depression are reported.

The Screen for Child Anxiety Related Disorders (SCARED) is a 41-item self-report measure of anxiety for children ages 8 to 18. The SCARED questionnaire yields an overall anxiety score, as well as subscales for panic disorder or significant somatic symptoms, generalized anxiety disorder, separation anxiety, social anxiety disorder, and significant school avoidance.¹³ There is also a 5-item version of the SCARED, which can be useful for brief screening in fast-paced settings when no anxiety disorder is suspected, or for children who may have anxiety but exhibit reduced verbal capacity. The SCARED has been found to have moderate sensitivity (81.8%) and specificity (52%) for diagnosing anxiety disorders in a community sample, with an optimal cutoff point of 22 on the total scale.¹⁴

Sleep

Sleep concerns are common, with the prevalence of insomnia among adults in the United States estimated to be 19.2%.¹⁵ The importance of assessing these concerns cannot be overstated, and primary care providers are the ones patients consult most often.¹⁶ The gold standard in assessing sleep disorders is a structured clinical interview, polysomnography, sleep diary, and actigraphy (home-based monitoring of movement through a device, often worn on the wrist).^17,18 However, this work-up is expensive, time-intensive, and impractical in integrated care settings; thus the need for a brief, self-report screening tool to guide further assessment and intervention.

Continue to: The Insomnia Severity Index...

The Insomnia Severity Index (ISI) assesses patients’ perceptions of their insomnia. The ISI was developed to aid both in the clinical evaluation of patients with insomnia and to measure treatment outcomes. Administration of the ISI takes approximately 5 minutes, and scoring takes less than 1 minute.

The ISI is composed of 7 items that measure the severity of sleep onset and sleep maintenance difficulties, satisfaction with current sleep, impact on daily functioning, impairment observable to others, and degree of distress caused by the sleep problems. Each item is scored on a 0 to 4 Likert-type scale, and the individual items are summed for a total score of 0 to 28, with higher scores suggesting more severe insomnia. Evidence-based guidelines recommend cognitive behavioral therapy for insomnia (CBT-I) as the first-line treatment for adults with primary insomnia.¹⁹

Several validation studies have found the ISI to be a reliable measure of perceived insomnia severity, and one that is sensitive to changes in patients’ perceptions of treatment outcomes.^20,21 An additional validation study confirmed that in primary care settings, a cutoff score of 14 should be used to indicate the likely presence of clinical insomnia²² and to guide further assessment and intervention.

The percentage of insomniac patients correctly identified with the ISI was 82.2%, with moderate sensitivity (82.4%) and specificity (82.1%).²² A positive predictive value of 70% was found, meaning that an insomnia disorder is probable when the ISI total score is 14 or higher; conversely, the negative predictive value was 90.2%.

Substance use and pain

The evaluation of alcohol and drug use is an integral part of assessing risky health behaviors. The 10-item Alcohol Use Disorder Identification Test (AUDIT) is a self-report tool developed by the World Health Organization.^23,24 Validated in medical settings, scores of 8 or higher suggest problematic drinking.^25,26 The AUDIT has demonstrated high specificity (94%) and moderate sensitivity (81%) in primary care settings.²⁷ The AUDIT-C (items 1, 2, and 3 of the AUDIT) has also demonstrated comparable sensitivity, although slightly lower specificity, than the full AUDIT, suggesting that this 3-question screen can also be used in primary care settings.²⁷

Continue to: Opioid medications...

Opioid medications, frequently prescribed for chronic pain, present serious risks for many patients. The Screener and Opioid Assessment for Patients with Pain–Revised (SOAPP-R) is a 24-item self-reporting scale that can be completed in approximately 10 minutes.²⁸ A score of 18 or higher has identified 81% of patients at high risk for opioid misuse in a clinical setting, with moderate specificity (68%). Although other factors should be considered when assessing risk of opioid misuse, the SOAPP-R is a helpful and quick addition to an opioid risk assessment.

The CRAFFT Screening Tool for Adolescent Substance Use is administered by the clinician for youths ages 14 to 21. The first 3 questions ask about use of alcohol, marijuana, or other substances during the past 12 months. What follows are questions related to the young person’s specific experiences with substances in relation to Cars, Relaxation, being Alone, Forgetting, Family/Friends, and Trouble (CRAFFT). The CRAFFT has shown moderate sensitivity (76%) and good specificity (94%) for identifying any problem with substance use.²⁹ These measures may be administered to clarify or confirm substance use patterns (ie, duration, frequency), or to determine the severity of problems related to substance use (ie, social or legal problems).

Trauma and PTSD

Approximately 7.7 million adults per year will experience posttraumatic stress disorder (PTSD) symptoms, although PTSD can affect individuals of any age.³⁰ Given the impact that trauma can have, assess for PTSD in patients who have a history of trauma or who otherwise seem to be at risk. The Posttraumatic Stress Disorder Checklist (PCL-5) is a 20-item self-report questionnaire that screens for symptoms directly from the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for PTSD. One limitation is that the questionnaire is only validated for adults ages 18 years or older. Completion of the PCL-5 takes 5 to 10 minutes. The PCL-5 has strong internal consistency reliability (94%) and test-retest reliability (82%).³¹ With a cutoff score of 33 or higher, the sensitivity and specificity have been shown to be moderately high (74.5% and 70.6%, respectively).³²

The SCARED questionnaire for children yields an overall anxiety score, as well as subscales for such features as panic disorder, separation anxiety, and significant school avoidance.

The Child and Adolescent Trauma Screen (CATS) is used to assess for potentially traumatic events and PTSD symptoms in children and adolescents. These symptoms are based on the DSM-5, and therefore the CATS can act as a useful diagnostic aid. The CATS is also available in Spanish, with both caregiver-report (for children ages 3-6 years or 7-17 years) and self-report (for ages 7-17 years) versions. Practical use of the PCL-5 and the CATS involves screening for PTSD symptoms, supporting a provisional diagnosis of PTSD, and monitoring PTSD symptom changes during and after ­treatment.

Memory and cognition

Cognitive screening is a first step in evaluating possible dementia and other neuropsychological disorders. The importance of brief cognitive screening in primary care cannot be understated, especially for an aging patient population. Although the Mini Mental Status Exam (MMSE) has been widely used among health care providers and researchers, we recommend the Montreal Cognitive Assessment (MoCA).

Continue to: The MoCA is a simple...

The MoCA is a simple, standalone cognitive screening tool validated for adults ages 55 to 85 years.³³ The MoCA addresses many important cognitive domains, fits on one page, and can be administered by a trained provider in 10 minutes. Research also suggests that it has strong test-retest reliability and positive and negative predictive values for mild cognitive impairment and Alzheimer dementia, and it has been found to be more sensitive than the MMSE.³⁴ We additionally recommend the MoCA as it measures several cognitive skills that are not addressed on the MMSE, including verbal fluency and abstraction.³⁴ Scores below 25 are suggestive of cognitive impairment and should lead to a referral for neuropsychological testing.

The MoCA’s sensitivity for detecting cognitive impairment is high (94%), and specificity is low (42%).³⁵ To ensure consistency and accuracy in administering the MoCA, certification is now required via an online training program through www.mocatest.org.

Adapting these screening tools to practice

These tools are not meant to be used at every appointment. Every practice is different, and each clinic or physician can tailor the use of these screening tools to the needs of the patient population, as concerns arise, or in collaboration with other providers. Additionally, these screening tools can be used in both integrated care and in private practice, to prompt a more thorough assessment or to aid in—and inform—treatment. Although some physicians choose to administer certain screening tools at each clinic visit, knowing about the availability of other tools can be useful in ­assessing various issues.

The FIGURE can be used to aid in the clinical decision-making process.

CORRESPONDENCE
Rebecca Sewell, PsyD, Bon Secours Mercy Health, 2213 Cherry Street, Toledo, OH 4360; [email protected].

Many screening tools are available in the public domain to assess a variety of symptoms related to impaired mental health. These tools can be used to quickly evaluate for mood, suicidal ideation or behavior, anxiety, sleep, substance use, pain, trauma, memory, and cognition (TABLE). Individuals with poor mental health incur high health care costs. Those suffering from anxiety and posttraumatic stress have more outpatient and emergency department visits and hospitalizations than patients without these disorders,^1,2 although use of mental health care services has been related to a decrease in the overutilization of health care services in general.³

Here we review several screening tools that can help you to identify symptoms of mental illnesses and thus, provide prompt early intervention, including referrals to psychological and psychiatric services.

Mood disorders

Most patients with mood disorders are treated in primary care settings.⁴ Quickly measuring patients’ mood symptoms can expedite treatment for those who need it. Many primary care clinics use the 9-item Patient Health Questionnaire (PHQ-9) to screen for depression.⁵ The US Preventive Services Task Force (USPSTF) has recommended screening for depression with adequate systems to ensure accurate diagnoses, effective treatment, and follow-up. Although the USPSTF did not specially endorse screening for bipolar disorder, it followed that recommendation with the qualifying statement, “positive screening results [for depression] should lead to additional assessment that considers severity of depression and comorbid psychological problems, alternate diagnoses, and medical conditions.”⁶ Thus, following a positive screen result for depression, consider using a screening tool for mood disorders to provide diagnostic clarification.

The Mood Disorder Questionnaire (MDQ) is a validated 15-item, self-­administered questionnaire that takes only 5 minutes to use in screening adult patients for bipolar I disorder.⁷ The MDQ assesses specific behaviors related to bipolar disorder, symptom co-occurrence, and functional impairment. The MDQ has low sensitivity (58%) but good specificity (93%) in a primary care setting.⁸ However, the MDQ is not a diagnostic instrument. A positive screen result should prompt a more thorough clinical evaluation, if necessary, by a professional trained in psychiatric disorders.

We recommend completing the MDQ prior to prescribing antidepressants. You can also monitor a patient’s response to treatment with serial MDQ testing. The MDQ is useful, too, when a patient has unclear mood symptoms that may have features overlapping with bipolar disorder. Furthermore, we recommend screening for bipolar disorder with every patient who reports symptoms of depression, given that some pharmacologic treatments (predominately selective serotonin reuptake inhibitors) can induce mania in patients who actually have unrecognized bipolar disorder.⁹

Suicide

Suicide is the 10th leading cause of death among the general population. All demographic groups are impacted by suicide; however, the most vulnerable are men ages 45 to 64 years.¹⁰ Given the imminent risk to individuals who experience suicidal ideation, properly assessing and targeting suicidal risk is paramount.

The Columbia Suicide Severity Rating Scale (C-SSRS) can be completed in an interview format or as a patient self-report. Versions of the C-SSRS are available for children, adolescents, and adults. It can be used in practice with any patient who may be at risk for suicide. Specifically, consider using the ­C-SSRS when a patient scores 1 or greater on the ­PHQ-9 or when risk is revealed with another brief screening tool that includes suicidal ideation.

Continue to: The C-SSRS covers...

The C-SSRS covers 10 categories related to suicidal ideation and behavior that the clinician explores with questions requiring only Yes/No responses. The C-SSRS demonstrates moderate-to-strong internal consistency and reliability, and it has shown a high degree of sensitivity (95%) and specificity (95%) for suicidal ideation.¹¹

Anxiety and physiologic arousal

Generalized anxiety disorder (GAD) is one of the most common anxiety disorders, with an estimated prevalence of 2.8% to 8.5% among primary care patients.¹² Brief, validated screening tools such as the Generalized Anxiety Disorder–7 item (GAD-7) scale can be effective in identifying anxiety and other related disorders in primary care settings.

The GAD-7 comprises 7 items inquiring about symptoms experienced in the past 2 weeks. Scores range from 0 to 21, with cutoffs of 5, 10, and 15 indicating mild, moderate, and severe anxiety, respectively. This questionnaire is appropriate for use with adults and has strong specificity, internal consistency, and test-retest reliability.¹² Specificity and sensitivity of the GAD-7 are maximized at a cutoff score of 10 or greater, both exceeding 80%.¹² The GAD-7 can be used when patients report symptoms of anxiety or when one needs to screen for anxiety with new patients or more clearly understand symptoms among patients who have complex mental health concerns.

Screen for bipolar disorder when symptoms of depression are reported.

The Screen for Child Anxiety Related Disorders (SCARED) is a 41-item self-report measure of anxiety for children ages 8 to 18. The SCARED questionnaire yields an overall anxiety score, as well as subscales for panic disorder or significant somatic symptoms, generalized anxiety disorder, separation anxiety, social anxiety disorder, and significant school avoidance.¹³ There is also a 5-item version of the SCARED, which can be useful for brief screening in fast-paced settings when no anxiety disorder is suspected, or for children who may have anxiety but exhibit reduced verbal capacity. The SCARED has been found to have moderate sensitivity (81.8%) and specificity (52%) for diagnosing anxiety disorders in a community sample, with an optimal cutoff point of 22 on the total scale.¹⁴

Sleep

Sleep concerns are common, with the prevalence of insomnia among adults in the United States estimated to be 19.2%.¹⁵ The importance of assessing these concerns cannot be overstated, and primary care providers are the ones patients consult most often.¹⁶ The gold standard in assessing sleep disorders is a structured clinical interview, polysomnography, sleep diary, and actigraphy (home-based monitoring of movement through a device, often worn on the wrist).^17,18 However, this work-up is expensive, time-intensive, and impractical in integrated care settings; thus the need for a brief, self-report screening tool to guide further assessment and intervention.

Continue to: The Insomnia Severity Index...

The Insomnia Severity Index (ISI) assesses patients’ perceptions of their insomnia. The ISI was developed to aid both in the clinical evaluation of patients with insomnia and to measure treatment outcomes. Administration of the ISI takes approximately 5 minutes, and scoring takes less than 1 minute.

The ISI is composed of 7 items that measure the severity of sleep onset and sleep maintenance difficulties, satisfaction with current sleep, impact on daily functioning, impairment observable to others, and degree of distress caused by the sleep problems. Each item is scored on a 0 to 4 Likert-type scale, and the individual items are summed for a total score of 0 to 28, with higher scores suggesting more severe insomnia. Evidence-based guidelines recommend cognitive behavioral therapy for insomnia (CBT-I) as the first-line treatment for adults with primary insomnia.¹⁹

Several validation studies have found the ISI to be a reliable measure of perceived insomnia severity, and one that is sensitive to changes in patients’ perceptions of treatment outcomes.^20,21 An additional validation study confirmed that in primary care settings, a cutoff score of 14 should be used to indicate the likely presence of clinical insomnia²² and to guide further assessment and intervention.

The percentage of insomniac patients correctly identified with the ISI was 82.2%, with moderate sensitivity (82.4%) and specificity (82.1%).²² A positive predictive value of 70% was found, meaning that an insomnia disorder is probable when the ISI total score is 14 or higher; conversely, the negative predictive value was 90.2%.

Substance use and pain

The evaluation of alcohol and drug use is an integral part of assessing risky health behaviors. The 10-item Alcohol Use Disorder Identification Test (AUDIT) is a self-report tool developed by the World Health Organization.^23,24 Validated in medical settings, scores of 8 or higher suggest problematic drinking.^25,26 The AUDIT has demonstrated high specificity (94%) and moderate sensitivity (81%) in primary care settings.²⁷ The AUDIT-C (items 1, 2, and 3 of the AUDIT) has also demonstrated comparable sensitivity, although slightly lower specificity, than the full AUDIT, suggesting that this 3-question screen can also be used in primary care settings.²⁷

Continue to: Opioid medications...

Opioid medications, frequently prescribed for chronic pain, present serious risks for many patients. The Screener and Opioid Assessment for Patients with Pain–Revised (SOAPP-R) is a 24-item self-reporting scale that can be completed in approximately 10 minutes.²⁸ A score of 18 or higher has identified 81% of patients at high risk for opioid misuse in a clinical setting, with moderate specificity (68%). Although other factors should be considered when assessing risk of opioid misuse, the SOAPP-R is a helpful and quick addition to an opioid risk assessment.

The CRAFFT Screening Tool for Adolescent Substance Use is administered by the clinician for youths ages 14 to 21. The first 3 questions ask about use of alcohol, marijuana, or other substances during the past 12 months. What follows are questions related to the young person’s specific experiences with substances in relation to Cars, Relaxation, being Alone, Forgetting, Family/Friends, and Trouble (CRAFFT). The CRAFFT has shown moderate sensitivity (76%) and good specificity (94%) for identifying any problem with substance use.²⁹ These measures may be administered to clarify or confirm substance use patterns (ie, duration, frequency), or to determine the severity of problems related to substance use (ie, social or legal problems).

Trauma and PTSD

Approximately 7.7 million adults per year will experience posttraumatic stress disorder (PTSD) symptoms, although PTSD can affect individuals of any age.³⁰ Given the impact that trauma can have, assess for PTSD in patients who have a history of trauma or who otherwise seem to be at risk. The Posttraumatic Stress Disorder Checklist (PCL-5) is a 20-item self-report questionnaire that screens for symptoms directly from the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for PTSD. One limitation is that the questionnaire is only validated for adults ages 18 years or older. Completion of the PCL-5 takes 5 to 10 minutes. The PCL-5 has strong internal consistency reliability (94%) and test-retest reliability (82%).³¹ With a cutoff score of 33 or higher, the sensitivity and specificity have been shown to be moderately high (74.5% and 70.6%, respectively).³²

The SCARED questionnaire for children yields an overall anxiety score, as well as subscales for such features as panic disorder, separation anxiety, and significant school avoidance.

The Child and Adolescent Trauma Screen (CATS) is used to assess for potentially traumatic events and PTSD symptoms in children and adolescents. These symptoms are based on the DSM-5, and therefore the CATS can act as a useful diagnostic aid. The CATS is also available in Spanish, with both caregiver-report (for children ages 3-6 years or 7-17 years) and self-report (for ages 7-17 years) versions. Practical use of the PCL-5 and the CATS involves screening for PTSD symptoms, supporting a provisional diagnosis of PTSD, and monitoring PTSD symptom changes during and after ­treatment.

Memory and cognition

Cognitive screening is a first step in evaluating possible dementia and other neuropsychological disorders. The importance of brief cognitive screening in primary care cannot be understated, especially for an aging patient population. Although the Mini Mental Status Exam (MMSE) has been widely used among health care providers and researchers, we recommend the Montreal Cognitive Assessment (MoCA).

Continue to: The MoCA is a simple...

The MoCA is a simple, standalone cognitive screening tool validated for adults ages 55 to 85 years.³³ The MoCA addresses many important cognitive domains, fits on one page, and can be administered by a trained provider in 10 minutes. Research also suggests that it has strong test-retest reliability and positive and negative predictive values for mild cognitive impairment and Alzheimer dementia, and it has been found to be more sensitive than the MMSE.³⁴ We additionally recommend the MoCA as it measures several cognitive skills that are not addressed on the MMSE, including verbal fluency and abstraction.³⁴ Scores below 25 are suggestive of cognitive impairment and should lead to a referral for neuropsychological testing.

The MoCA’s sensitivity for detecting cognitive impairment is high (94%), and specificity is low (42%).³⁵ To ensure consistency and accuracy in administering the MoCA, certification is now required via an online training program through www.mocatest.org.

Adapting these screening tools to practice

These tools are not meant to be used at every appointment. Every practice is different, and each clinic or physician can tailor the use of these screening tools to the needs of the patient population, as concerns arise, or in collaboration with other providers. Additionally, these screening tools can be used in both integrated care and in private practice, to prompt a more thorough assessment or to aid in—and inform—treatment. Although some physicians choose to administer certain screening tools at each clinic visit, knowing about the availability of other tools can be useful in ­assessing various issues.

The FIGURE can be used to aid in the clinical decision-making process.

CORRESPONDENCE
Rebecca Sewell, PsyD, Bon Secours Mercy Health, 2213 Cherry Street, Toledo, OH 4360; [email protected].