The use of statins by patients with rheumatoid arthritis appears to provide an overall net benefit on cardiovascular disease outcomes that outweighs the risk of type 2 diabetes mellitus (T2DM) seen with the drugs in the general population, according to evidence from a cohort study of more than 16,000 people in the United Kingdom that was presented at the virtual annual meeting of the American College of Rheumatology.

“Our study emphasizes that RA patients should be assessed for statin initiation to improve CVD risk,” lead study author Gulsen Ozen, MD, a third-year resident at the University of Nebraska, Omaha, said in an interview. Because the risk of T2DM with statin use is no worse in patients with RA than in the general population, statin initiation “is actually a great opportunity to address the risk factors for T2DM such as activity and exercise, obesity and weight loss, and [use of glucocorticoids], which have other important health effects,” she said.

“Also, importantly, even if [patients] develop T2DM, statins still work on CVD and mortality outcomes as in patients without diabetes,” Dr. Ozen added. “Given all, the benefits of statins way outweigh the hazards.”

Dr. Ozen said this was the first large cohort study to evaluate CVD mortality and T2DM risks with statins in patients with RA, a claim with which rheumatologist Elena Myasoedova, MD, PhD, of the Mayo Clinic in Rochester, Minn., concurred.

Dr. Myasoedova, professor of rheumatology and epidemiology at Mayo, said in an interview that the study was “methodologically rigorous” using time-conditional propensity score (TCPS) matching and a prevalent new-user design, “thus addressing the immortal time bias” found in the design of studies in which patients enter a cohort but do not start a treatment before developing the outcome of interest and are assigned to the untreated group or when the period of delay from when patients enter the cohort to when they are treated is excluded from the analysis. An earlier study from the same authors did not use TCPS matching, she said.

“The study findings suggest that patients with RA can benefit from statin use in terms of CVD outcomes and mortality but physicians should use vigilance regarding increased T2DM risk and discuss this possibility with patients,” Dr. Myasoedova said. “Identifying patients who are at higher risk of developing T2DM after statin initiation would be important to personalize the approach to statin therapy.”
 

Study details

The study accessed records from the U.K. Clinical Practice Research Datalink and linked Hospital Episode Statistics and Office of National Statistics databases. It analyzed adult patients with RA who were diagnosed during 1989-2018 in two cohorts: One for CVD and all-cause mortality, consisting of 1,768 statin initiators and 3,528 TCPS-matched nonusers; and a T2DM cohort with 3,608 statin initiators and 7,208 TCPS-matched nonusers.

In the entire cohort, statin use was associated with a 32% reduction in CV events (composite endpoint of the nonfatal or fatal MI, stroke, hospitalized heart failure, or CVD mortality), a 54% reduction in all-cause mortality, and a 33% increase in risk for T2DM, Dr. Ozen said. Results were similar in both sexes, although CV event reduction with statins in men did not reach statistical significance, likely because of a smaller sample size, she said.

Patients with and without a history of CVD had a similar reduction in CV events and all-cause mortality, and risk for T2DM increased with statins, but the latter reached statistical significance only in patients without a history of CVD, Dr. Ozen said.

Patients with RA who are at risk for T2DM and who are taking statins require blood glucose monitoring, which is typically done in patients with RA on disease-modifying antirheumatic drugs, and hemoglobin A1c testing when glucose levels are impaired, she said. “Any concerns for T2DM would be also communicated by the primary care providers of the patients to initiate further assessment and management,” she said.

But Dr. Ozen noted that confusion exists among primary care physicians and rheumatologists about who’s responsible for prescribing statins in these patients. “I would like to remind you that instead of assigning this role to a certain specialty, just good communication could improve this care gap of statin underutilization in RA,” she said. “Also, for rheumatologists, given that all-cause mortality reduction with statins was as high as CV event reduction, statins may be reducing other causes of mortality through improving disease activity.”

Bristol-Myers Squibb provided funding for the study. Dr. Ozen and Dr. Myasoedova have no relevant disclosures.

The use of statins by patients with rheumatoid arthritis appears to provide an overall net benefit on cardiovascular disease outcomes that outweighs the risk of type 2 diabetes mellitus (T2DM) seen with the drugs in the general population, according to evidence from a cohort study of more than 16,000 people in the United Kingdom that was presented at the virtual annual meeting of the American College of Rheumatology.

“Our study emphasizes that RA patients should be assessed for statin initiation to improve CVD risk,” lead study author Gulsen Ozen, MD, a third-year resident at the University of Nebraska, Omaha, said in an interview. Because the risk of T2DM with statin use is no worse in patients with RA than in the general population, statin initiation “is actually a great opportunity to address the risk factors for T2DM such as activity and exercise, obesity and weight loss, and [use of glucocorticoids], which have other important health effects,” she said.

“Also, importantly, even if [patients] develop T2DM, statins still work on CVD and mortality outcomes as in patients without diabetes,” Dr. Ozen added. “Given all, the benefits of statins way outweigh the hazards.”

Dr. Ozen said this was the first large cohort study to evaluate CVD mortality and T2DM risks with statins in patients with RA, a claim with which rheumatologist Elena Myasoedova, MD, PhD, of the Mayo Clinic in Rochester, Minn., concurred.

Dr. Myasoedova, professor of rheumatology and epidemiology at Mayo, said in an interview that the study was “methodologically rigorous” using time-conditional propensity score (TCPS) matching and a prevalent new-user design, “thus addressing the immortal time bias” found in the design of studies in which patients enter a cohort but do not start a treatment before developing the outcome of interest and are assigned to the untreated group or when the period of delay from when patients enter the cohort to when they are treated is excluded from the analysis. An earlier study from the same authors did not use TCPS matching, she said.

“The study findings suggest that patients with RA can benefit from statin use in terms of CVD outcomes and mortality but physicians should use vigilance regarding increased T2DM risk and discuss this possibility with patients,” Dr. Myasoedova said. “Identifying patients who are at higher risk of developing T2DM after statin initiation would be important to personalize the approach to statin therapy.”
 

Study details

The study accessed records from the U.K. Clinical Practice Research Datalink and linked Hospital Episode Statistics and Office of National Statistics databases. It analyzed adult patients with RA who were diagnosed during 1989-2018 in two cohorts: One for CVD and all-cause mortality, consisting of 1,768 statin initiators and 3,528 TCPS-matched nonusers; and a T2DM cohort with 3,608 statin initiators and 7,208 TCPS-matched nonusers.

In the entire cohort, statin use was associated with a 32% reduction in CV events (composite endpoint of the nonfatal or fatal MI, stroke, hospitalized heart failure, or CVD mortality), a 54% reduction in all-cause mortality, and a 33% increase in risk for T2DM, Dr. Ozen said. Results were similar in both sexes, although CV event reduction with statins in men did not reach statistical significance, likely because of a smaller sample size, she said.

Patients with and without a history of CVD had a similar reduction in CV events and all-cause mortality, and risk for T2DM increased with statins, but the latter reached statistical significance only in patients without a history of CVD, Dr. Ozen said.

Patients with RA who are at risk for T2DM and who are taking statins require blood glucose monitoring, which is typically done in patients with RA on disease-modifying antirheumatic drugs, and hemoglobin A1c testing when glucose levels are impaired, she said. “Any concerns for T2DM would be also communicated by the primary care providers of the patients to initiate further assessment and management,” she said.

But Dr. Ozen noted that confusion exists among primary care physicians and rheumatologists about who’s responsible for prescribing statins in these patients. “I would like to remind you that instead of assigning this role to a certain specialty, just good communication could improve this care gap of statin underutilization in RA,” she said. “Also, for rheumatologists, given that all-cause mortality reduction with statins was as high as CV event reduction, statins may be reducing other causes of mortality through improving disease activity.”

Bristol-Myers Squibb provided funding for the study. Dr. Ozen and Dr. Myasoedova have no relevant disclosures.

The use of statins by patients with rheumatoid arthritis appears to provide an overall net benefit on cardiovascular disease outcomes that outweighs the risk of type 2 diabetes mellitus (T2DM) seen with the drugs in the general population, according to evidence from a cohort study of more than 16,000 people in the United Kingdom that was presented at the virtual annual meeting of the American College of Rheumatology.

“Our study emphasizes that RA patients should be assessed for statin initiation to improve CVD risk,” lead study author Gulsen Ozen, MD, a third-year resident at the University of Nebraska, Omaha, said in an interview. Because the risk of T2DM with statin use is no worse in patients with RA than in the general population, statin initiation “is actually a great opportunity to address the risk factors for T2DM such as activity and exercise, obesity and weight loss, and [use of glucocorticoids], which have other important health effects,” she said.

“Also, importantly, even if [patients] develop T2DM, statins still work on CVD and mortality outcomes as in patients without diabetes,” Dr. Ozen added. “Given all, the benefits of statins way outweigh the hazards.”

Dr. Ozen said this was the first large cohort study to evaluate CVD mortality and T2DM risks with statins in patients with RA, a claim with which rheumatologist Elena Myasoedova, MD, PhD, of the Mayo Clinic in Rochester, Minn., concurred.

Dr. Myasoedova, professor of rheumatology and epidemiology at Mayo, said in an interview that the study was “methodologically rigorous” using time-conditional propensity score (TCPS) matching and a prevalent new-user design, “thus addressing the immortal time bias” found in the design of studies in which patients enter a cohort but do not start a treatment before developing the outcome of interest and are assigned to the untreated group or when the period of delay from when patients enter the cohort to when they are treated is excluded from the analysis. An earlier study from the same authors did not use TCPS matching, she said.

“The study findings suggest that patients with RA can benefit from statin use in terms of CVD outcomes and mortality but physicians should use vigilance regarding increased T2DM risk and discuss this possibility with patients,” Dr. Myasoedova said. “Identifying patients who are at higher risk of developing T2DM after statin initiation would be important to personalize the approach to statin therapy.”
 

Study details

The study accessed records from the U.K. Clinical Practice Research Datalink and linked Hospital Episode Statistics and Office of National Statistics databases. It analyzed adult patients with RA who were diagnosed during 1989-2018 in two cohorts: One for CVD and all-cause mortality, consisting of 1,768 statin initiators and 3,528 TCPS-matched nonusers; and a T2DM cohort with 3,608 statin initiators and 7,208 TCPS-matched nonusers.

In the entire cohort, statin use was associated with a 32% reduction in CV events (composite endpoint of the nonfatal or fatal MI, stroke, hospitalized heart failure, or CVD mortality), a 54% reduction in all-cause mortality, and a 33% increase in risk for T2DM, Dr. Ozen said. Results were similar in both sexes, although CV event reduction with statins in men did not reach statistical significance, likely because of a smaller sample size, she said.

Patients with and without a history of CVD had a similar reduction in CV events and all-cause mortality, and risk for T2DM increased with statins, but the latter reached statistical significance only in patients without a history of CVD, Dr. Ozen said.

Patients with RA who are at risk for T2DM and who are taking statins require blood glucose monitoring, which is typically done in patients with RA on disease-modifying antirheumatic drugs, and hemoglobin A1c testing when glucose levels are impaired, she said. “Any concerns for T2DM would be also communicated by the primary care providers of the patients to initiate further assessment and management,” she said.

But Dr. Ozen noted that confusion exists among primary care physicians and rheumatologists about who’s responsible for prescribing statins in these patients. “I would like to remind you that instead of assigning this role to a certain specialty, just good communication could improve this care gap of statin underutilization in RA,” she said. “Also, for rheumatologists, given that all-cause mortality reduction with statins was as high as CV event reduction, statins may be reducing other causes of mortality through improving disease activity.”

Bristol-Myers Squibb provided funding for the study. Dr. Ozen and Dr. Myasoedova have no relevant disclosures.

As children aged 5-11 years began to receive the first officially approved doses of COVID-19 vaccine, new pediatric cases increased after 8 consecutive weeks of declines, according to the American Academy of Pediatrics and the Children’s Hospital Association.

Reported cases of COVID-19 in children totaled over 107,000 for the week of Oct. 29 to Nov. 4 after coming in at just under 101,000 the previous week. Weekly cases peaked at almost 252,000 in early September and then dropped for 8 straight weeks before this latest rise, the AAP and the CHA said in their weekly COVID report, which is based on data reported by 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

The end of that 8-week drop, unfortunately, allowed another streak to continue: New cases have been above 100,000 for 13 consecutive weeks, the AAP and CHA noted.

The cumulative COVID count in children as of Nov. 4 was 6.5 million, the AAP/CHA said, although that figure does not fully cover Alabama, Nebraska, and Texas, which stopped public reporting over the summer. The Centers for Disease Control and Prevention, with input from all states and territories, puts the total through Nov. 8 at almost 5.7 million cases in children under 18 years of age, while most states define a child as someone aged 0-19 years.

As for the newest group of vaccinees, the CDC said that “updated vaccination data for 5-11 year-olds will be added to COVID Data Tracker later this week,” meaning the week of Nov. 7-13. Currently available data, however, show that almost 157,000 children under age 12 initiated vaccination in the 14 days ending Nov. 8, which was more than those aged 12-15 and 16-17 years combined (127,000).

Among those older groups, the CDC reports that 57.1% of 12- to 15-year-olds have received at least one dose and 47.9% are fully vaccinated, while 64.0% of those aged 16-17 have gotten at least one dose and 55.2% are fully vaccinated. Altogether, about 13.9 million children under age 18 have gotten at least one dose and almost 11.6 million are fully vaccinated, according to the CDC.

[email protected]

As children aged 5-11 years began to receive the first officially approved doses of COVID-19 vaccine, new pediatric cases increased after 8 consecutive weeks of declines, according to the American Academy of Pediatrics and the Children’s Hospital Association.

Reported cases of COVID-19 in children totaled over 107,000 for the week of Oct. 29 to Nov. 4 after coming in at just under 101,000 the previous week. Weekly cases peaked at almost 252,000 in early September and then dropped for 8 straight weeks before this latest rise, the AAP and the CHA said in their weekly COVID report, which is based on data reported by 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

The end of that 8-week drop, unfortunately, allowed another streak to continue: New cases have been above 100,000 for 13 consecutive weeks, the AAP and CHA noted.

The cumulative COVID count in children as of Nov. 4 was 6.5 million, the AAP/CHA said, although that figure does not fully cover Alabama, Nebraska, and Texas, which stopped public reporting over the summer. The Centers for Disease Control and Prevention, with input from all states and territories, puts the total through Nov. 8 at almost 5.7 million cases in children under 18 years of age, while most states define a child as someone aged 0-19 years.

As for the newest group of vaccinees, the CDC said that “updated vaccination data for 5-11 year-olds will be added to COVID Data Tracker later this week,” meaning the week of Nov. 7-13. Currently available data, however, show that almost 157,000 children under age 12 initiated vaccination in the 14 days ending Nov. 8, which was more than those aged 12-15 and 16-17 years combined (127,000).

Among those older groups, the CDC reports that 57.1% of 12- to 15-year-olds have received at least one dose and 47.9% are fully vaccinated, while 64.0% of those aged 16-17 have gotten at least one dose and 55.2% are fully vaccinated. Altogether, about 13.9 million children under age 18 have gotten at least one dose and almost 11.6 million are fully vaccinated, according to the CDC.

[email protected]

As children aged 5-11 years began to receive the first officially approved doses of COVID-19 vaccine, new pediatric cases increased after 8 consecutive weeks of declines, according to the American Academy of Pediatrics and the Children’s Hospital Association.

Reported cases of COVID-19 in children totaled over 107,000 for the week of Oct. 29 to Nov. 4 after coming in at just under 101,000 the previous week. Weekly cases peaked at almost 252,000 in early September and then dropped for 8 straight weeks before this latest rise, the AAP and the CHA said in their weekly COVID report, which is based on data reported by 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

The end of that 8-week drop, unfortunately, allowed another streak to continue: New cases have been above 100,000 for 13 consecutive weeks, the AAP and CHA noted.

The cumulative COVID count in children as of Nov. 4 was 6.5 million, the AAP/CHA said, although that figure does not fully cover Alabama, Nebraska, and Texas, which stopped public reporting over the summer. The Centers for Disease Control and Prevention, with input from all states and territories, puts the total through Nov. 8 at almost 5.7 million cases in children under 18 years of age, while most states define a child as someone aged 0-19 years.

As for the newest group of vaccinees, the CDC said that “updated vaccination data for 5-11 year-olds will be added to COVID Data Tracker later this week,” meaning the week of Nov. 7-13. Currently available data, however, show that almost 157,000 children under age 12 initiated vaccination in the 14 days ending Nov. 8, which was more than those aged 12-15 and 16-17 years combined (127,000).

Among those older groups, the CDC reports that 57.1% of 12- to 15-year-olds have received at least one dose and 47.9% are fully vaccinated, while 64.0% of those aged 16-17 have gotten at least one dose and 55.2% are fully vaccinated. Altogether, about 13.9 million children under age 18 have gotten at least one dose and almost 11.6 million are fully vaccinated, according to the CDC.

[email protected]

Just months after the MASTER DAPT trial showed that abbreviated dual-antiplatelet therapy (DAPT) lowers the risk of bleeding after stent placement in patients at high bleeding risk, a new analysis showed the favorable benefit-to-risk ratio was about the same in the subgroup who also had an acute or recent myocardial infarction.

In the new prespecified MASTER DAPT analysis, the data show that the subgroup with both an increased bleeding risk and an increased risk of ischemic events benefited much like the entire study population from a shorter DAPT duration, reported Pieter C. Smits, MD, PhD, at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando.

“There was no signal towards increased ischemic risk in the abbreviated DAPT population presenting with recent acute MI,” said Dr. Smits, emphasizing the consistency of results in this “bi-risk” subgroup with objective criteria for increased risks of bleeding and ischemic events.

MASTER DAPT main results published

The main results of the MASTER DAPT trial were presented at the 2021 annual meeting of the European Society of Cardiology and published recently in the New England Journal of Medicine. The trial randomized 4,434 patients who met one or more criteria for high bleeding risk. These included age of at least 75 years, documented anemia, a clinical indication for oral anticoagulants, and previous bleeding episodes requiring hospitalization.

In the trial, all patients were maintained on DAPT for 1 month after implantation of a biodegradable-polymer, sirolimus-eluting coronary stent (Ultimaster, Terumo). At the end of the month, those randomized to abbreviated DAPT started immediately on single-agent antiplatelet therapy, while those in the standard DAPT group remained on DAPT for at least 2 additional months.

Over 1 year of follow-up, the bleeding event rate was lower in the abbreviated DAPT group (6.5% vs. 9.4%; P < .0001 for superiority). The slight increase in major ischemic events among those in the abbreviated DAPT group (6.1% vs. 5.9%) was not significantly different (P = .001 for noninferiority).

When compared on the basis of net adverse clinical events (NACE), which comprised all-case death, MI, stroke, or Bleeding Academic Research Consortium (BARC) level 3 or 5 bleeding, there was a slight advantage for abbreviated DAPT (7.5% vs. 7.7%). This did not reach significance, but it was similar (P < .001 for noninferiority), favoring the abbreviated course of DAPT because of the bleeding advantage.

Recent MI vs. no MI

In the new analysis, patients in both the abbreviated and standard DAPT group were stratified into those with no major cardiovascular event within the past 12 months and those with an acute MI or acute coronary syndrome within this time. There were somewhat more patients without a history of MI within the previous 12 months in both the abbreviated DAPT (1,381 vs. 914 patients) and standard DAPT (1,418 vs. 866) groups.

In those without a recent MI, NACE rates were nearly identical over 1-year follow-up for those who received abbreviated versus standard DAPT. In both, slightly more than 6% had a NACE event, producing a hazard ratio of 1.03 for abbreviated versus standard DAPT (P = 0.85).

For those with a recent MI, event rates began to separate within 30 days. By 1 year, NACE rates exceeded 10% in those on standard DAPT, but remained below 9% for those on abbreviated DAPT. The lower hazard ratio in the abbreviated DAPT group (HR, 0.83; P = .22) did not reach statistical significance, but it did echo the larger MASTER DAPT conclusion.

“An abbreviated DAPT strategy significantly reduced clinically relevant bleeding risk in these bi-risk patients without increasing risk of ischemic events,” reported Dr. Smits, director of interventional cardiology at Maasstad Hospital, Rotterdam, the Netherlands.
 

No difference in NACE components

In fact, when the components of NACE were evaluated individually in the subgroup of patients with prior MI, both stroke (HR, 0.47; P = .16) and all-cause death (HR, 0.78; P = .28), although not significant, numerically favored abbreviated DAPT.

There was no difference between abbreviated and standard DAPT for risk of MI at 1 year (HR, 1.03; P = .92).

As in the overall MASTER DAPT results, bleeding risk (BARC 2, 3, or 5 bleeding) was significantly reduced in the substudy among those with a recent prior MI (P = .013) or those with no MI in the prior 12 months (P = .01).

In MASTER DAPT, which was an open-label study that randomized participants in 30 countries, all patients received one type of drug-eluting stent. While Dr. Smits conceded that it is not clear whether the conclusions about abbreviated DAPT can be extrapolated to other stents, he noted that recent long-term outcomes for modern drug-eluting coronary stents have been similar, suggesting these results might be more broadly applicable.

According to Dr. Smit, the consistency of this subgroup analysis with the previously published MASTER DAPT study is mutually reinforcing for a role of abbreviated DAPT in patients at high bleeding risk. Other experts agreed.

“One of the concerns that people have had is exactly what has been addressed here in this subgroup analysis. These are the patients that are not only bleeding-risk high but ischemic-risk high. The question was whether the benefit of reducing bleeding risk is offset by increasing stent thrombosis or other ischemic event outcomes, and the answer from the analysis is really clearly no,” said Philippe Gabriel Steg, MD, chief, department of cardiology, Hôpital Bichat, Paris, at the meeting, sponsored by the Cardiovascular Research Foundation.

Dr. Smits reports financial relationships with Abiomed, Abbott Vascular, Daiichi-Sankyo, Microport, Opsense, and Terumo Medical. Dr. Steg reports financial relationships with Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Idorsia, Merck, Novartis, Regeneron, and Sanofi-Aventis.

Just months after the MASTER DAPT trial showed that abbreviated dual-antiplatelet therapy (DAPT) lowers the risk of bleeding after stent placement in patients at high bleeding risk, a new analysis showed the favorable benefit-to-risk ratio was about the same in the subgroup who also had an acute or recent myocardial infarction.

In the new prespecified MASTER DAPT analysis, the data show that the subgroup with both an increased bleeding risk and an increased risk of ischemic events benefited much like the entire study population from a shorter DAPT duration, reported Pieter C. Smits, MD, PhD, at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando.

“There was no signal towards increased ischemic risk in the abbreviated DAPT population presenting with recent acute MI,” said Dr. Smits, emphasizing the consistency of results in this “bi-risk” subgroup with objective criteria for increased risks of bleeding and ischemic events.

MASTER DAPT main results published

The main results of the MASTER DAPT trial were presented at the 2021 annual meeting of the European Society of Cardiology and published recently in the New England Journal of Medicine. The trial randomized 4,434 patients who met one or more criteria for high bleeding risk. These included age of at least 75 years, documented anemia, a clinical indication for oral anticoagulants, and previous bleeding episodes requiring hospitalization.

In the trial, all patients were maintained on DAPT for 1 month after implantation of a biodegradable-polymer, sirolimus-eluting coronary stent (Ultimaster, Terumo). At the end of the month, those randomized to abbreviated DAPT started immediately on single-agent antiplatelet therapy, while those in the standard DAPT group remained on DAPT for at least 2 additional months.

Over 1 year of follow-up, the bleeding event rate was lower in the abbreviated DAPT group (6.5% vs. 9.4%; P < .0001 for superiority). The slight increase in major ischemic events among those in the abbreviated DAPT group (6.1% vs. 5.9%) was not significantly different (P = .001 for noninferiority).

When compared on the basis of net adverse clinical events (NACE), which comprised all-case death, MI, stroke, or Bleeding Academic Research Consortium (BARC) level 3 or 5 bleeding, there was a slight advantage for abbreviated DAPT (7.5% vs. 7.7%). This did not reach significance, but it was similar (P < .001 for noninferiority), favoring the abbreviated course of DAPT because of the bleeding advantage.

Recent MI vs. no MI

In the new analysis, patients in both the abbreviated and standard DAPT group were stratified into those with no major cardiovascular event within the past 12 months and those with an acute MI or acute coronary syndrome within this time. There were somewhat more patients without a history of MI within the previous 12 months in both the abbreviated DAPT (1,381 vs. 914 patients) and standard DAPT (1,418 vs. 866) groups.

In those without a recent MI, NACE rates were nearly identical over 1-year follow-up for those who received abbreviated versus standard DAPT. In both, slightly more than 6% had a NACE event, producing a hazard ratio of 1.03 for abbreviated versus standard DAPT (P = 0.85).

For those with a recent MI, event rates began to separate within 30 days. By 1 year, NACE rates exceeded 10% in those on standard DAPT, but remained below 9% for those on abbreviated DAPT. The lower hazard ratio in the abbreviated DAPT group (HR, 0.83; P = .22) did not reach statistical significance, but it did echo the larger MASTER DAPT conclusion.

“An abbreviated DAPT strategy significantly reduced clinically relevant bleeding risk in these bi-risk patients without increasing risk of ischemic events,” reported Dr. Smits, director of interventional cardiology at Maasstad Hospital, Rotterdam, the Netherlands.
 

No difference in NACE components

In fact, when the components of NACE were evaluated individually in the subgroup of patients with prior MI, both stroke (HR, 0.47; P = .16) and all-cause death (HR, 0.78; P = .28), although not significant, numerically favored abbreviated DAPT.

There was no difference between abbreviated and standard DAPT for risk of MI at 1 year (HR, 1.03; P = .92).

As in the overall MASTER DAPT results, bleeding risk (BARC 2, 3, or 5 bleeding) was significantly reduced in the substudy among those with a recent prior MI (P = .013) or those with no MI in the prior 12 months (P = .01).

In MASTER DAPT, which was an open-label study that randomized participants in 30 countries, all patients received one type of drug-eluting stent. While Dr. Smits conceded that it is not clear whether the conclusions about abbreviated DAPT can be extrapolated to other stents, he noted that recent long-term outcomes for modern drug-eluting coronary stents have been similar, suggesting these results might be more broadly applicable.

According to Dr. Smit, the consistency of this subgroup analysis with the previously published MASTER DAPT study is mutually reinforcing for a role of abbreviated DAPT in patients at high bleeding risk. Other experts agreed.

“One of the concerns that people have had is exactly what has been addressed here in this subgroup analysis. These are the patients that are not only bleeding-risk high but ischemic-risk high. The question was whether the benefit of reducing bleeding risk is offset by increasing stent thrombosis or other ischemic event outcomes, and the answer from the analysis is really clearly no,” said Philippe Gabriel Steg, MD, chief, department of cardiology, Hôpital Bichat, Paris, at the meeting, sponsored by the Cardiovascular Research Foundation.

Dr. Smits reports financial relationships with Abiomed, Abbott Vascular, Daiichi-Sankyo, Microport, Opsense, and Terumo Medical. Dr. Steg reports financial relationships with Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Idorsia, Merck, Novartis, Regeneron, and Sanofi-Aventis.

Just months after the MASTER DAPT trial showed that abbreviated dual-antiplatelet therapy (DAPT) lowers the risk of bleeding after stent placement in patients at high bleeding risk, a new analysis showed the favorable benefit-to-risk ratio was about the same in the subgroup who also had an acute or recent myocardial infarction.

In the new prespecified MASTER DAPT analysis, the data show that the subgroup with both an increased bleeding risk and an increased risk of ischemic events benefited much like the entire study population from a shorter DAPT duration, reported Pieter C. Smits, MD, PhD, at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando.

“There was no signal towards increased ischemic risk in the abbreviated DAPT population presenting with recent acute MI,” said Dr. Smits, emphasizing the consistency of results in this “bi-risk” subgroup with objective criteria for increased risks of bleeding and ischemic events.

MASTER DAPT main results published

The main results of the MASTER DAPT trial were presented at the 2021 annual meeting of the European Society of Cardiology and published recently in the New England Journal of Medicine. The trial randomized 4,434 patients who met one or more criteria for high bleeding risk. These included age of at least 75 years, documented anemia, a clinical indication for oral anticoagulants, and previous bleeding episodes requiring hospitalization.

In the trial, all patients were maintained on DAPT for 1 month after implantation of a biodegradable-polymer, sirolimus-eluting coronary stent (Ultimaster, Terumo). At the end of the month, those randomized to abbreviated DAPT started immediately on single-agent antiplatelet therapy, while those in the standard DAPT group remained on DAPT for at least 2 additional months.

Over 1 year of follow-up, the bleeding event rate was lower in the abbreviated DAPT group (6.5% vs. 9.4%; P < .0001 for superiority). The slight increase in major ischemic events among those in the abbreviated DAPT group (6.1% vs. 5.9%) was not significantly different (P = .001 for noninferiority).

When compared on the basis of net adverse clinical events (NACE), which comprised all-case death, MI, stroke, or Bleeding Academic Research Consortium (BARC) level 3 or 5 bleeding, there was a slight advantage for abbreviated DAPT (7.5% vs. 7.7%). This did not reach significance, but it was similar (P < .001 for noninferiority), favoring the abbreviated course of DAPT because of the bleeding advantage.

Recent MI vs. no MI

In the new analysis, patients in both the abbreviated and standard DAPT group were stratified into those with no major cardiovascular event within the past 12 months and those with an acute MI or acute coronary syndrome within this time. There were somewhat more patients without a history of MI within the previous 12 months in both the abbreviated DAPT (1,381 vs. 914 patients) and standard DAPT (1,418 vs. 866) groups.

In those without a recent MI, NACE rates were nearly identical over 1-year follow-up for those who received abbreviated versus standard DAPT. In both, slightly more than 6% had a NACE event, producing a hazard ratio of 1.03 for abbreviated versus standard DAPT (P = 0.85).

For those with a recent MI, event rates began to separate within 30 days. By 1 year, NACE rates exceeded 10% in those on standard DAPT, but remained below 9% for those on abbreviated DAPT. The lower hazard ratio in the abbreviated DAPT group (HR, 0.83; P = .22) did not reach statistical significance, but it did echo the larger MASTER DAPT conclusion.

“An abbreviated DAPT strategy significantly reduced clinically relevant bleeding risk in these bi-risk patients without increasing risk of ischemic events,” reported Dr. Smits, director of interventional cardiology at Maasstad Hospital, Rotterdam, the Netherlands.
 

No difference in NACE components

In fact, when the components of NACE were evaluated individually in the subgroup of patients with prior MI, both stroke (HR, 0.47; P = .16) and all-cause death (HR, 0.78; P = .28), although not significant, numerically favored abbreviated DAPT.

There was no difference between abbreviated and standard DAPT for risk of MI at 1 year (HR, 1.03; P = .92).

As in the overall MASTER DAPT results, bleeding risk (BARC 2, 3, or 5 bleeding) was significantly reduced in the substudy among those with a recent prior MI (P = .013) or those with no MI in the prior 12 months (P = .01).

In MASTER DAPT, which was an open-label study that randomized participants in 30 countries, all patients received one type of drug-eluting stent. While Dr. Smits conceded that it is not clear whether the conclusions about abbreviated DAPT can be extrapolated to other stents, he noted that recent long-term outcomes for modern drug-eluting coronary stents have been similar, suggesting these results might be more broadly applicable.

According to Dr. Smit, the consistency of this subgroup analysis with the previously published MASTER DAPT study is mutually reinforcing for a role of abbreviated DAPT in patients at high bleeding risk. Other experts agreed.

“One of the concerns that people have had is exactly what has been addressed here in this subgroup analysis. These are the patients that are not only bleeding-risk high but ischemic-risk high. The question was whether the benefit of reducing bleeding risk is offset by increasing stent thrombosis or other ischemic event outcomes, and the answer from the analysis is really clearly no,” said Philippe Gabriel Steg, MD, chief, department of cardiology, Hôpital Bichat, Paris, at the meeting, sponsored by the Cardiovascular Research Foundation.

Dr. Smits reports financial relationships with Abiomed, Abbott Vascular, Daiichi-Sankyo, Microport, Opsense, and Terumo Medical. Dr. Steg reports financial relationships with Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Idorsia, Merck, Novartis, Regeneron, and Sanofi-Aventis.

An electronic nose (eNose) that measures volatile organic compounds (VOCs) emitted from the lungs successfully distinguished sarcoidosis from interstitial lung disease (ILD) and healthy controls, according to a report in the journal CHEST.

The approach has the potential to generate clinical data that can’t be achieved through other noninvasive means, such as the serum biomarker soluble interleukin-2 receptor (sIL-2R). sIL-2R is often used to track disease activity, but it isn’t specific for diagnosing sarcoidosis, and it isn’t available worldwide.

Sarcoidosis is a granulomatous inflammatory disease with no known cause and can affect most organs, but an estimated 89%-99% of cases affect the lungs. There is no simple noninvasive diagnostic test, leaving physicians to rely on clinical features, biopsies to obtain tissue pathology, and the ruling out of other granulomatous diagnoses.

The challenge is more difficult because sarcoidosis is a heterogeneous disease, with great variation in the number of organs affected, severity, rate of progression, and response to therapy.

Previous researchers have used VOCs in an attempt to diagnose diseases, since the compounds reflect pathophysiological processes. Gas chromatography/mass spectrometry (GCMS) is one method to identify the individual VOCs, but the process is time consuming and complex. Some nevertheless showed potential in sarcoidosis, but failed to reproduce their performance in validation cohorts.

In the new study, a cross-sectional analysis showed that exhaled breath analysis using an eNose had excellent sensitivity and specificity for distinguishing sarcoidosis from ILD and healthy controls, and identified sarcoidosis regardless of pulmonary involvement, pulmonary fibrosis, multiple organ involvement, immunosuppressive treatment, or whether or not pathology supported the diagnosis.

The eNose technology produces a “breath-print” after combining information from a broad range of VOCs. The information originates from an array of metal-oxide semiconductor sensors with partial specificity that artificial intelligence processes to discern patterns. Overall, the system functions similarly to the mammalian olfactory system. The artificial intelligence instead views it as a “breath-print” that it can compare against previously learned patterns.

“It is a quite easy, simple, and quick procedure, which is noninvasive. We can collect a lot of data from the VOCs in the exhaled breath because there are several sensors that cross-react. We can create breath profiles and group patients to see if profiles differ. Ultimately, we can use the profiles to diagnose or detect disease in the earlier stage and more accurately,” said Iris van der Sar, MD. Dr. van der Sar is the lead author on the study and a PhD candidate at Erasmus Medical Center in Rotterdam.

The study requires further prospective validation, but the technology could have important clinical benefits, said senior author and principal investigator Marlies Wijsenbeek, MD, PhD, pulmonologist and head of the Interstitial Lung Disease Center at Erasmus Medical Center. “If we in future can avoid a biopsy, that would be most attractive,” said Dr. Wijsenbeek.

“We hope to come to a point-of-care device that can be used to facilitate early diagnosis at low burden for the patient and health care system,” said Karen Moor, MD, PhD, and post-doc on this project. The researchers also hope to determine if the eNose can help evaluate a patient’s response to therapy.

Studies of eNose technology in other chronic diseases have shown promising results, but not all results have been validated yet in independent or external cohorts.

The current study included 569 outpatients, 252 with sarcoidosis and 317 with ILD, along with 48 healthy controls. The researchers constructed a training set using 168 patients with sarcoidosis and 32 healthy controls, and a validation set using 84 patients with sarcoidosis and 16 healthy controls. The eNose differentiated between patients and controls in both groups, with an area under the curve of 1.00 for each regardless of pulmonary involvement or treatment.

It also distinguished those with sarcoidosis and pulmonary involvement from those with ILD, with an AUC of 0.90 (95% confidence interval, 0.87-0.94) in the training set, and an AUC of 0.87 (95% CI, 0.82-0.93) in the validation set.

It differentiated between pulmonary sarcoidosis and hypersensitivity pneumonitis in the training set (AUC 0.95; 95% CI, 0.90-0.99) and the validation set (AUC, 0.88; 95% CI, 0.75-1.00).

The study received no funding. Dr. Wijsenbeek, Dr. van der Sar, and Dr. Moor have no relevant financial disclosures.

An electronic nose (eNose) that measures volatile organic compounds (VOCs) emitted from the lungs successfully distinguished sarcoidosis from interstitial lung disease (ILD) and healthy controls, according to a report in the journal CHEST.

The approach has the potential to generate clinical data that can’t be achieved through other noninvasive means, such as the serum biomarker soluble interleukin-2 receptor (sIL-2R). sIL-2R is often used to track disease activity, but it isn’t specific for diagnosing sarcoidosis, and it isn’t available worldwide.

Sarcoidosis is a granulomatous inflammatory disease with no known cause and can affect most organs, but an estimated 89%-99% of cases affect the lungs. There is no simple noninvasive diagnostic test, leaving physicians to rely on clinical features, biopsies to obtain tissue pathology, and the ruling out of other granulomatous diagnoses.

The challenge is more difficult because sarcoidosis is a heterogeneous disease, with great variation in the number of organs affected, severity, rate of progression, and response to therapy.

Previous researchers have used VOCs in an attempt to diagnose diseases, since the compounds reflect pathophysiological processes. Gas chromatography/mass spectrometry (GCMS) is one method to identify the individual VOCs, but the process is time consuming and complex. Some nevertheless showed potential in sarcoidosis, but failed to reproduce their performance in validation cohorts.

In the new study, a cross-sectional analysis showed that exhaled breath analysis using an eNose had excellent sensitivity and specificity for distinguishing sarcoidosis from ILD and healthy controls, and identified sarcoidosis regardless of pulmonary involvement, pulmonary fibrosis, multiple organ involvement, immunosuppressive treatment, or whether or not pathology supported the diagnosis.

The eNose technology produces a “breath-print” after combining information from a broad range of VOCs. The information originates from an array of metal-oxide semiconductor sensors with partial specificity that artificial intelligence processes to discern patterns. Overall, the system functions similarly to the mammalian olfactory system. The artificial intelligence instead views it as a “breath-print” that it can compare against previously learned patterns.

“It is a quite easy, simple, and quick procedure, which is noninvasive. We can collect a lot of data from the VOCs in the exhaled breath because there are several sensors that cross-react. We can create breath profiles and group patients to see if profiles differ. Ultimately, we can use the profiles to diagnose or detect disease in the earlier stage and more accurately,” said Iris van der Sar, MD. Dr. van der Sar is the lead author on the study and a PhD candidate at Erasmus Medical Center in Rotterdam.

The study requires further prospective validation, but the technology could have important clinical benefits, said senior author and principal investigator Marlies Wijsenbeek, MD, PhD, pulmonologist and head of the Interstitial Lung Disease Center at Erasmus Medical Center. “If we in future can avoid a biopsy, that would be most attractive,” said Dr. Wijsenbeek.

“We hope to come to a point-of-care device that can be used to facilitate early diagnosis at low burden for the patient and health care system,” said Karen Moor, MD, PhD, and post-doc on this project. The researchers also hope to determine if the eNose can help evaluate a patient’s response to therapy.

Studies of eNose technology in other chronic diseases have shown promising results, but not all results have been validated yet in independent or external cohorts.

The current study included 569 outpatients, 252 with sarcoidosis and 317 with ILD, along with 48 healthy controls. The researchers constructed a training set using 168 patients with sarcoidosis and 32 healthy controls, and a validation set using 84 patients with sarcoidosis and 16 healthy controls. The eNose differentiated between patients and controls in both groups, with an area under the curve of 1.00 for each regardless of pulmonary involvement or treatment.

It also distinguished those with sarcoidosis and pulmonary involvement from those with ILD, with an AUC of 0.90 (95% confidence interval, 0.87-0.94) in the training set, and an AUC of 0.87 (95% CI, 0.82-0.93) in the validation set.

It differentiated between pulmonary sarcoidosis and hypersensitivity pneumonitis in the training set (AUC 0.95; 95% CI, 0.90-0.99) and the validation set (AUC, 0.88; 95% CI, 0.75-1.00).

The study received no funding. Dr. Wijsenbeek, Dr. van der Sar, and Dr. Moor have no relevant financial disclosures.

An electronic nose (eNose) that measures volatile organic compounds (VOCs) emitted from the lungs successfully distinguished sarcoidosis from interstitial lung disease (ILD) and healthy controls, according to a report in the journal CHEST.

The approach has the potential to generate clinical data that can’t be achieved through other noninvasive means, such as the serum biomarker soluble interleukin-2 receptor (sIL-2R). sIL-2R is often used to track disease activity, but it isn’t specific for diagnosing sarcoidosis, and it isn’t available worldwide.

Sarcoidosis is a granulomatous inflammatory disease with no known cause and can affect most organs, but an estimated 89%-99% of cases affect the lungs. There is no simple noninvasive diagnostic test, leaving physicians to rely on clinical features, biopsies to obtain tissue pathology, and the ruling out of other granulomatous diagnoses.

The challenge is more difficult because sarcoidosis is a heterogeneous disease, with great variation in the number of organs affected, severity, rate of progression, and response to therapy.

Previous researchers have used VOCs in an attempt to diagnose diseases, since the compounds reflect pathophysiological processes. Gas chromatography/mass spectrometry (GCMS) is one method to identify the individual VOCs, but the process is time consuming and complex. Some nevertheless showed potential in sarcoidosis, but failed to reproduce their performance in validation cohorts.

In the new study, a cross-sectional analysis showed that exhaled breath analysis using an eNose had excellent sensitivity and specificity for distinguishing sarcoidosis from ILD and healthy controls, and identified sarcoidosis regardless of pulmonary involvement, pulmonary fibrosis, multiple organ involvement, immunosuppressive treatment, or whether or not pathology supported the diagnosis.

The eNose technology produces a “breath-print” after combining information from a broad range of VOCs. The information originates from an array of metal-oxide semiconductor sensors with partial specificity that artificial intelligence processes to discern patterns. Overall, the system functions similarly to the mammalian olfactory system. The artificial intelligence instead views it as a “breath-print” that it can compare against previously learned patterns.

“It is a quite easy, simple, and quick procedure, which is noninvasive. We can collect a lot of data from the VOCs in the exhaled breath because there are several sensors that cross-react. We can create breath profiles and group patients to see if profiles differ. Ultimately, we can use the profiles to diagnose or detect disease in the earlier stage and more accurately,” said Iris van der Sar, MD. Dr. van der Sar is the lead author on the study and a PhD candidate at Erasmus Medical Center in Rotterdam.

The study requires further prospective validation, but the technology could have important clinical benefits, said senior author and principal investigator Marlies Wijsenbeek, MD, PhD, pulmonologist and head of the Interstitial Lung Disease Center at Erasmus Medical Center. “If we in future can avoid a biopsy, that would be most attractive,” said Dr. Wijsenbeek.

“We hope to come to a point-of-care device that can be used to facilitate early diagnosis at low burden for the patient and health care system,” said Karen Moor, MD, PhD, and post-doc on this project. The researchers also hope to determine if the eNose can help evaluate a patient’s response to therapy.

Studies of eNose technology in other chronic diseases have shown promising results, but not all results have been validated yet in independent or external cohorts.

The current study included 569 outpatients, 252 with sarcoidosis and 317 with ILD, along with 48 healthy controls. The researchers constructed a training set using 168 patients with sarcoidosis and 32 healthy controls, and a validation set using 84 patients with sarcoidosis and 16 healthy controls. The eNose differentiated between patients and controls in both groups, with an area under the curve of 1.00 for each regardless of pulmonary involvement or treatment.

It also distinguished those with sarcoidosis and pulmonary involvement from those with ILD, with an AUC of 0.90 (95% confidence interval, 0.87-0.94) in the training set, and an AUC of 0.87 (95% CI, 0.82-0.93) in the validation set.

It differentiated between pulmonary sarcoidosis and hypersensitivity pneumonitis in the training set (AUC 0.95; 95% CI, 0.90-0.99) and the validation set (AUC, 0.88; 95% CI, 0.75-1.00).

The study received no funding. Dr. Wijsenbeek, Dr. van der Sar, and Dr. Moor have no relevant financial disclosures.

Early trials are under way to test medicinal mushrooms and Chinese herbs to treat COVID-19 patients with mild to moderate symptoms.

The U.S. Food and Drug Administration (FDA) approved the MACH-19 trials (the acronym for Mushrooms and Chinese Herbs for COVID-19) after researchers applied for approval in April.

The first two phase 1 randomized, double-blind, placebo-controlled trials have begun at UCLA and the University of California San Diego to treat COVID-19 patients quarantining at home with mild to moderate symptoms. A third trial is investigating the use of medicinal mushrooms as an adjuvant to COVID-19 vaccines.

The researchers have also launched a fourth trial testing the mushrooms against placebo as an adjunct to a COVID booster shot. It looks at the effect in people who have comorbidities that would reduce their vaccine response. An article in JAMA  described the trials.

The two mushroom varieties being tested — turkey tail and agarikon — are available as over-the-counter supplements, according to the report. They are a separate class from hallucinogenic or “magic” mushrooms being tested for other uses in medicine.

“They are not even as psychoactive as a cup of tea,” Gordon Saxe, MD, PhD, MPH, principal investigator for the MACH-19 trials, told this news organization.

For each of the MACH-19 treatment trials, researchers plan to recruit 66 people who are quarantined at home with mild to moderate COVID-19 symptoms. Participants will be randomly assigned either to receive the mushroom combination, the Chinese herbs, or a placebo for 2 weeks, according to the JAMA paper.

D. Craig Hopp, PhD, deputy director of the division of extramural research at the National Center for Complementary and Integrative Health (NCCIH), told JAMA in an interview that he was “mildly concerned” about using mushrooms to treat people with active SARS-CoV-2 infection.

“We know that a cytokine storm poses the greatest risk of COVID mortality, not the virus itself,” Dr. Hopp said. “The danger is that an immune-stimulating agent like mushrooms might supercharge an individual’s immune response, leading to a cytokine storm.”

Stephen Wilson, PhD, an immunologist who consulted on the trials when he was chief operating officer of the La Jolla Institute for Immunology, says in the JAMA article that a cytokine storm is unlikely for these patients because the mushroom components “don’t mimic inflammatory cytokines.” Dr. Wilson is now chief innovations officer at Statera Biopharma.

“We think the mushrooms increase the number of immunologic opportunities to better see and respond to a specific threat. In the doses used, the mushrooms perturb the immune system in a good way but fall far short of driving hyper or sustained inflammation,” Dr. Wilson said.

Dr. Saxe said the FDA process was extensive and rigorous and FDA investigators also asked about potential cytokine storms before approving the trials. Cytokine storm is not an issue with a healthy response, Dr. Saxe pointed out. It’s a response that’s not balanced or modulated.

“Mushrooms are immunomodulatory,” he said. “In some ways they very specifically enhance immunity. In other ways they calm down overimmunity.” Dr. Saxe noted that they did a sentinel study for the storm potential “and we didn’t see any evidence for it.”

“Not a crazy concept”

Dr. Saxe pointed out that one of the mushrooms in the combo they use — agarikon — was used to treat pulmonary infections 2,300 years ago.

“Hippocrates, the father of western medicine, used mushrooms,” he said. “Penicillin comes from fungi. It’s not a crazy concept. Most people who oppose this or are skeptics — to some extent, it’s a lack of information.”

Dr. Saxe explained that there are receptors on human cells that bind specific mushroom polysaccharides.

“There’s a hand-in-glove fit there,” Dr. Saxe said, and that’s one way mushrooms can modulate immune cell behavior, which could have an effect against SARS-CoV-2.

Daniel Kuritzkes, MD, chief of the division of infectious diseases at Brigham and Women’s Hospital in Boston, who was not part of the study, told this news organization that he wasn’t surprised the FDA approved moving forward with the trials.

“As long as you can demonstrate that there is a rationale for doing the trial and that you have some safety data or a plan to collect safety data, they are fairly liberal about doing early-phase studies. It would be a much different issue, I think, if they were proposing to do a study for actual licensing or approval of a drug,” Dr. Kuritzkes said.

As yet unanswered, he noted, is which component of the mushrooms or herbs is having the effect. It will be a challenge, he said, to know from one batch of the compound to the next that you have the same amount of material and that it’s going to have the same potency among lots.

Another challenge is how the mushrooms and herbs might interact with other therapies, Dr. Kuritzkes said.

He gave the example of St. John’s Wort, which has been problematic in HIV treatment.

“If someone is on certain HIV medicines and they also are taking St. John’s Wort, they basically are causing the liver to eat up the HIV drug and they don’t get adequate levels of the drug,” he said.

Though there are many challenges ahead, Dr. Kuritzkes acknowledged, but added that “this is a great starting point.”

He, too, pointed out that many traditional medicines were discovered from plants.

“The most famous of these is quinine, which came from cinchona bark that was used to treat malaria.” Dr. Kuritzkes said. Digitalis, often used to treat heart failure, comes from the fox glove plant, he added.

He said it’s important to remember that “people shouldn’t be seeking experimental therapies in place of proven therapies, they should be thinking of them in addition to proven therapies.»

A co-author reports an investment in the dietary supplement company Mycomedica Life Sciences, for which he also serves as an unpaid scientific adviser. Another co-author is a medical consultant for Evergreen Herbs and Medical Supplies. Dr. Hopp, Dr. Saxe, and Dr. Wilson have disclosed no relevant financial relationships. Dr. Kuritzkes consults for Merck, Gilead, and GlaxoSmithKline.

Early trials are under way to test medicinal mushrooms and Chinese herbs to treat COVID-19 patients with mild to moderate symptoms.

The U.S. Food and Drug Administration (FDA) approved the MACH-19 trials (the acronym for Mushrooms and Chinese Herbs for COVID-19) after researchers applied for approval in April.

The first two phase 1 randomized, double-blind, placebo-controlled trials have begun at UCLA and the University of California San Diego to treat COVID-19 patients quarantining at home with mild to moderate symptoms. A third trial is investigating the use of medicinal mushrooms as an adjuvant to COVID-19 vaccines.

The researchers have also launched a fourth trial testing the mushrooms against placebo as an adjunct to a COVID booster shot. It looks at the effect in people who have comorbidities that would reduce their vaccine response. An article in JAMA  described the trials.

The two mushroom varieties being tested — turkey tail and agarikon — are available as over-the-counter supplements, according to the report. They are a separate class from hallucinogenic or “magic” mushrooms being tested for other uses in medicine.

“They are not even as psychoactive as a cup of tea,” Gordon Saxe, MD, PhD, MPH, principal investigator for the MACH-19 trials, told this news organization.

For each of the MACH-19 treatment trials, researchers plan to recruit 66 people who are quarantined at home with mild to moderate COVID-19 symptoms. Participants will be randomly assigned either to receive the mushroom combination, the Chinese herbs, or a placebo for 2 weeks, according to the JAMA paper.

D. Craig Hopp, PhD, deputy director of the division of extramural research at the National Center for Complementary and Integrative Health (NCCIH), told JAMA in an interview that he was “mildly concerned” about using mushrooms to treat people with active SARS-CoV-2 infection.

“We know that a cytokine storm poses the greatest risk of COVID mortality, not the virus itself,” Dr. Hopp said. “The danger is that an immune-stimulating agent like mushrooms might supercharge an individual’s immune response, leading to a cytokine storm.”

Stephen Wilson, PhD, an immunologist who consulted on the trials when he was chief operating officer of the La Jolla Institute for Immunology, says in the JAMA article that a cytokine storm is unlikely for these patients because the mushroom components “don’t mimic inflammatory cytokines.” Dr. Wilson is now chief innovations officer at Statera Biopharma.

“We think the mushrooms increase the number of immunologic opportunities to better see and respond to a specific threat. In the doses used, the mushrooms perturb the immune system in a good way but fall far short of driving hyper or sustained inflammation,” Dr. Wilson said.

Dr. Saxe said the FDA process was extensive and rigorous and FDA investigators also asked about potential cytokine storms before approving the trials. Cytokine storm is not an issue with a healthy response, Dr. Saxe pointed out. It’s a response that’s not balanced or modulated.

“Mushrooms are immunomodulatory,” he said. “In some ways they very specifically enhance immunity. In other ways they calm down overimmunity.” Dr. Saxe noted that they did a sentinel study for the storm potential “and we didn’t see any evidence for it.”

“Not a crazy concept”

Dr. Saxe pointed out that one of the mushrooms in the combo they use — agarikon — was used to treat pulmonary infections 2,300 years ago.

“Hippocrates, the father of western medicine, used mushrooms,” he said. “Penicillin comes from fungi. It’s not a crazy concept. Most people who oppose this or are skeptics — to some extent, it’s a lack of information.”

Dr. Saxe explained that there are receptors on human cells that bind specific mushroom polysaccharides.

“There’s a hand-in-glove fit there,” Dr. Saxe said, and that’s one way mushrooms can modulate immune cell behavior, which could have an effect against SARS-CoV-2.

Daniel Kuritzkes, MD, chief of the division of infectious diseases at Brigham and Women’s Hospital in Boston, who was not part of the study, told this news organization that he wasn’t surprised the FDA approved moving forward with the trials.

“As long as you can demonstrate that there is a rationale for doing the trial and that you have some safety data or a plan to collect safety data, they are fairly liberal about doing early-phase studies. It would be a much different issue, I think, if they were proposing to do a study for actual licensing or approval of a drug,” Dr. Kuritzkes said.

As yet unanswered, he noted, is which component of the mushrooms or herbs is having the effect. It will be a challenge, he said, to know from one batch of the compound to the next that you have the same amount of material and that it’s going to have the same potency among lots.

Another challenge is how the mushrooms and herbs might interact with other therapies, Dr. Kuritzkes said.

He gave the example of St. John’s Wort, which has been problematic in HIV treatment.

“If someone is on certain HIV medicines and they also are taking St. John’s Wort, they basically are causing the liver to eat up the HIV drug and they don’t get adequate levels of the drug,” he said.

Though there are many challenges ahead, Dr. Kuritzkes acknowledged, but added that “this is a great starting point.”

He, too, pointed out that many traditional medicines were discovered from plants.

“The most famous of these is quinine, which came from cinchona bark that was used to treat malaria.” Dr. Kuritzkes said. Digitalis, often used to treat heart failure, comes from the fox glove plant, he added.

He said it’s important to remember that “people shouldn’t be seeking experimental therapies in place of proven therapies, they should be thinking of them in addition to proven therapies.»

A co-author reports an investment in the dietary supplement company Mycomedica Life Sciences, for which he also serves as an unpaid scientific adviser. Another co-author is a medical consultant for Evergreen Herbs and Medical Supplies. Dr. Hopp, Dr. Saxe, and Dr. Wilson have disclosed no relevant financial relationships. Dr. Kuritzkes consults for Merck, Gilead, and GlaxoSmithKline.

Early trials are under way to test medicinal mushrooms and Chinese herbs to treat COVID-19 patients with mild to moderate symptoms.

The U.S. Food and Drug Administration (FDA) approved the MACH-19 trials (the acronym for Mushrooms and Chinese Herbs for COVID-19) after researchers applied for approval in April.

The first two phase 1 randomized, double-blind, placebo-controlled trials have begun at UCLA and the University of California San Diego to treat COVID-19 patients quarantining at home with mild to moderate symptoms. A third trial is investigating the use of medicinal mushrooms as an adjuvant to COVID-19 vaccines.

The researchers have also launched a fourth trial testing the mushrooms against placebo as an adjunct to a COVID booster shot. It looks at the effect in people who have comorbidities that would reduce their vaccine response. An article in JAMA  described the trials.

The two mushroom varieties being tested — turkey tail and agarikon — are available as over-the-counter supplements, according to the report. They are a separate class from hallucinogenic or “magic” mushrooms being tested for other uses in medicine.

“They are not even as psychoactive as a cup of tea,” Gordon Saxe, MD, PhD, MPH, principal investigator for the MACH-19 trials, told this news organization.

For each of the MACH-19 treatment trials, researchers plan to recruit 66 people who are quarantined at home with mild to moderate COVID-19 symptoms. Participants will be randomly assigned either to receive the mushroom combination, the Chinese herbs, or a placebo for 2 weeks, according to the JAMA paper.

D. Craig Hopp, PhD, deputy director of the division of extramural research at the National Center for Complementary and Integrative Health (NCCIH), told JAMA in an interview that he was “mildly concerned” about using mushrooms to treat people with active SARS-CoV-2 infection.

“We know that a cytokine storm poses the greatest risk of COVID mortality, not the virus itself,” Dr. Hopp said. “The danger is that an immune-stimulating agent like mushrooms might supercharge an individual’s immune response, leading to a cytokine storm.”

Stephen Wilson, PhD, an immunologist who consulted on the trials when he was chief operating officer of the La Jolla Institute for Immunology, says in the JAMA article that a cytokine storm is unlikely for these patients because the mushroom components “don’t mimic inflammatory cytokines.” Dr. Wilson is now chief innovations officer at Statera Biopharma.

“We think the mushrooms increase the number of immunologic opportunities to better see and respond to a specific threat. In the doses used, the mushrooms perturb the immune system in a good way but fall far short of driving hyper or sustained inflammation,” Dr. Wilson said.

Dr. Saxe said the FDA process was extensive and rigorous and FDA investigators also asked about potential cytokine storms before approving the trials. Cytokine storm is not an issue with a healthy response, Dr. Saxe pointed out. It’s a response that’s not balanced or modulated.

“Mushrooms are immunomodulatory,” he said. “In some ways they very specifically enhance immunity. In other ways they calm down overimmunity.” Dr. Saxe noted that they did a sentinel study for the storm potential “and we didn’t see any evidence for it.”

“Not a crazy concept”

Dr. Saxe pointed out that one of the mushrooms in the combo they use — agarikon — was used to treat pulmonary infections 2,300 years ago.

“Hippocrates, the father of western medicine, used mushrooms,” he said. “Penicillin comes from fungi. It’s not a crazy concept. Most people who oppose this or are skeptics — to some extent, it’s a lack of information.”

Dr. Saxe explained that there are receptors on human cells that bind specific mushroom polysaccharides.

“There’s a hand-in-glove fit there,” Dr. Saxe said, and that’s one way mushrooms can modulate immune cell behavior, which could have an effect against SARS-CoV-2.

Daniel Kuritzkes, MD, chief of the division of infectious diseases at Brigham and Women’s Hospital in Boston, who was not part of the study, told this news organization that he wasn’t surprised the FDA approved moving forward with the trials.

“As long as you can demonstrate that there is a rationale for doing the trial and that you have some safety data or a plan to collect safety data, they are fairly liberal about doing early-phase studies. It would be a much different issue, I think, if they were proposing to do a study for actual licensing or approval of a drug,” Dr. Kuritzkes said.

As yet unanswered, he noted, is which component of the mushrooms or herbs is having the effect. It will be a challenge, he said, to know from one batch of the compound to the next that you have the same amount of material and that it’s going to have the same potency among lots.

Another challenge is how the mushrooms and herbs might interact with other therapies, Dr. Kuritzkes said.

He gave the example of St. John’s Wort, which has been problematic in HIV treatment.

“If someone is on certain HIV medicines and they also are taking St. John’s Wort, they basically are causing the liver to eat up the HIV drug and they don’t get adequate levels of the drug,” he said.

Though there are many challenges ahead, Dr. Kuritzkes acknowledged, but added that “this is a great starting point.”

He, too, pointed out that many traditional medicines were discovered from plants.

“The most famous of these is quinine, which came from cinchona bark that was used to treat malaria.” Dr. Kuritzkes said. Digitalis, often used to treat heart failure, comes from the fox glove plant, he added.

He said it’s important to remember that “people shouldn’t be seeking experimental therapies in place of proven therapies, they should be thinking of them in addition to proven therapies.»

A co-author reports an investment in the dietary supplement company Mycomedica Life Sciences, for which he also serves as an unpaid scientific adviser. Another co-author is a medical consultant for Evergreen Herbs and Medical Supplies. Dr. Hopp, Dr. Saxe, and Dr. Wilson have disclosed no relevant financial relationships. Dr. Kuritzkes consults for Merck, Gilead, and GlaxoSmithKline.

THE CASE

A 72-year-old man was admitted to our Dallas hospital with a 4-day history of fevers and new-onset urinary frequency. He did not report any joint pain, sick contacts, or recent travel or recall any skin findings (rashes, insect bites). Past medical history was significant for hypertension, hyperlipidemia, diabetes, benign prostatic hyperplasia, recurrent urinary tract infections, and lumbar radiculopathy.

Initial signs and symptoms were suggestive of sepsis: a temperature of 102.7 °F, tachycardia, and a suspected genitourinary infection. This was supported by initial labs concerning for end-organ damage: elevated creatinine of 1.58 mg/dL (reference range, 0.67-1.17 mg/dL), elevated international normalized ratio (INR) of 1.6 (reference range, 0.9-1.1), hemoglobin of 12.8 g/dL (reference range, 13.5 - 17.5 g/dL), and platelet count of 99 ×10⁹/L (reference range, 160-383 ×10⁹/L).

Over the next several days, the patient’s condition worsened, and he experienced a decline in mental status, despite initiation of broad-spectrum antibiotics and fluid resuscitation. Although lumbar puncture was warranted, neither Neurology nor Interventional Radiology were willing to risk the procedure given the patient’s worsening hemoglobin (8.3 g/dL) and platelet count (51 ×10⁹/L).

Preliminary work-up included a urinalysis negative for leukocytes, nitrites, and ­bacteria—despite a urine culture that showed gram-positive cocci. His chest x-ray was unremarkable, and computed tomography of his brain showed generalized atrophy without acute changes. The work-up was expanded to fungal cultures and immunochemical assays. Empiric treatment with micafungin and acyclovir was started without improvement.

Further conversation with family revealed that the patient liked to spend time outdoors and he’d had a similar episode in which he’d been diagnosed with an unknown disease from an insect bite. Pertinent negative tests included: HIV, syphilis, rapid heterophile antibody, influenza, respiratory virus panel, blood culture, fungal culture, antineutrophil cytoplasmic antibodies, histoplasmosis, brucellosis, malaria, Epstein-Barr virus, cytomegalovirus, and parvovirus. Coxiella burnetii and West Nile virus immunoglobulin (Ig) G were positive, suggesting a prior exposure.

THE DIAGNOSIS

Given these new findings and reported outdoor activities, Infectious Diseases recommended we start our patient on doxycycline for possible rickettsia infection. On Day 8, doxycycline 200 mg IV once daily was started. (The IV form was initiated due to the patient’s altered mentation.) The patient started to show improvement, and on Day 14, an immunofluorescence antibody (IFA) assay revealed Rickettsia typhi IgM titers 1:512 (< 1:64) and IgG titers 1:256 (< 1:64), consistent with a diagnosis of murine (endemic) typhus.

DISCUSSION

Murine typhus is an acute febrile disease caused by R typhi, an obligate, intracellular gram-negative organism.¹ Worldwide, transmission to humans occurs mainly from infected rat fleas harbored by rodents. In the United States, it’s been suggested that opossums serve as an important reservoir in peri-domestic settings, with cat fleas as vectors.^2-4 The disease is endemic to southern California and south Texas.⁴

Continue to: Incidence of murine typhus

Incidence of murine typhus has declined in the United States since 1945 with the use of the insecticide dichlorodiphenyltrichloroethane (DDT). However, a recent rise in murine typhus cases—likely due to ecological changes—makes timely diagnosis and treatment essential.⁵ An epidemiologic study of 1762 confirmed cases in Texas from 2003 to 2013 found an increase in the number of cases and an expansion of the geographic areas impacted.³ Thus, in the work-up of acute fever of unknown origin, it is not unreasonable to include murine typhus in the differential.

Serologic testing with IFA is the preferred diagnostic method; however, a definitive diagnosis is not needed before treatment can be started.

Murine typhus can be difficult to diagnose due to nonspecific clinical manifestation.^3,4 A 2016 systematic review of 2074 patients reported common symptoms of fever, headache, malaise, chills, and myalgia.⁶ The most common laboratory abnormalities in adults were elevated aminotransferases, lactate dehydrogenase, hypoalbuminemia, and thrombocytopenia.⁶ A 4-fold increase in typhus group IgM or IgG-specific antibody titer by IFA is supportive of diagnosis.⁴ 

The differential diagnosis included urosepsis, prostatitis, syphilis, HIV, and meningitis. However, lack of response to broad-spectrum antibiotics and antifungals made a diagnosis of urologic infection unlikely. A negative sexually transmitted infection screen ruled out syphilis and HIV. An incidental, elevated INR and delirium prevented us from obtaining a lumbar puncture to test for meningitis.

Treatment may begin without a definitive diagnosis

Serologic testing with IFA is the preferred diagnostic method; however, a definitive diagnosis is not needed before treatment can be initiated. Doxycycline is the first-line therapy for all rickettsioses. Adults are advised to take doxycycline 200 mg orally once, followed by 100 mg twice daily until the patient improves, has been afebrile for 48 hours, and has received treatment for at least 7 days.⁷ Oral chloramphenicol is considered a second-line treatment; however it is not available in the United States and is associated with adverse hematologic effects.⁷

Our patient responded remarkably well to the doxycycline. After a 14-day course was completed, he was discharged to a skilled nursing facility for physical rehabilitation.

Continue to: THE TAKEAWAY

 

 

THE TAKEAWAY

Rickettsia diseases, such as murine typhus, should be considered in the differential if a patient presents with a worsening clinical picture of unresolved delirium; fever despite use of broad-spectrum antibiotics, antifungals, and antivirals; and a history of potential outdoor exposure. Sources include opossums or cats when flea contact is likely. Rickettsia diseases belong in the differential when there is a history of travel to tropical areas, as well. All suspected cases should be reported to the local health department.

CORRESPONDENCE
Tenzin Tsewang MD, 5200 Harry Hines Boulevard, Dallas, TX 75235; [email protected]

THE CASE

A 72-year-old man was admitted to our Dallas hospital with a 4-day history of fevers and new-onset urinary frequency. He did not report any joint pain, sick contacts, or recent travel or recall any skin findings (rashes, insect bites). Past medical history was significant for hypertension, hyperlipidemia, diabetes, benign prostatic hyperplasia, recurrent urinary tract infections, and lumbar radiculopathy.

Initial signs and symptoms were suggestive of sepsis: a temperature of 102.7 °F, tachycardia, and a suspected genitourinary infection. This was supported by initial labs concerning for end-organ damage: elevated creatinine of 1.58 mg/dL (reference range, 0.67-1.17 mg/dL), elevated international normalized ratio (INR) of 1.6 (reference range, 0.9-1.1), hemoglobin of 12.8 g/dL (reference range, 13.5 - 17.5 g/dL), and platelet count of 99 ×10⁹/L (reference range, 160-383 ×10⁹/L).

Over the next several days, the patient’s condition worsened, and he experienced a decline in mental status, despite initiation of broad-spectrum antibiotics and fluid resuscitation. Although lumbar puncture was warranted, neither Neurology nor Interventional Radiology were willing to risk the procedure given the patient’s worsening hemoglobin (8.3 g/dL) and platelet count (51 ×10⁹/L).

Preliminary work-up included a urinalysis negative for leukocytes, nitrites, and ­bacteria—despite a urine culture that showed gram-positive cocci. His chest x-ray was unremarkable, and computed tomography of his brain showed generalized atrophy without acute changes. The work-up was expanded to fungal cultures and immunochemical assays. Empiric treatment with micafungin and acyclovir was started without improvement.

Further conversation with family revealed that the patient liked to spend time outdoors and he’d had a similar episode in which he’d been diagnosed with an unknown disease from an insect bite. Pertinent negative tests included: HIV, syphilis, rapid heterophile antibody, influenza, respiratory virus panel, blood culture, fungal culture, antineutrophil cytoplasmic antibodies, histoplasmosis, brucellosis, malaria, Epstein-Barr virus, cytomegalovirus, and parvovirus. Coxiella burnetii and West Nile virus immunoglobulin (Ig) G were positive, suggesting a prior exposure.

THE DIAGNOSIS

Given these new findings and reported outdoor activities, Infectious Diseases recommended we start our patient on doxycycline for possible rickettsia infection. On Day 8, doxycycline 200 mg IV once daily was started. (The IV form was initiated due to the patient’s altered mentation.) The patient started to show improvement, and on Day 14, an immunofluorescence antibody (IFA) assay revealed Rickettsia typhi IgM titers 1:512 (< 1:64) and IgG titers 1:256 (< 1:64), consistent with a diagnosis of murine (endemic) typhus.

DISCUSSION

Murine typhus is an acute febrile disease caused by R typhi, an obligate, intracellular gram-negative organism.¹ Worldwide, transmission to humans occurs mainly from infected rat fleas harbored by rodents. In the United States, it’s been suggested that opossums serve as an important reservoir in peri-domestic settings, with cat fleas as vectors.^2-4 The disease is endemic to southern California and south Texas.⁴

Continue to: Incidence of murine typhus

Incidence of murine typhus has declined in the United States since 1945 with the use of the insecticide dichlorodiphenyltrichloroethane (DDT). However, a recent rise in murine typhus cases—likely due to ecological changes—makes timely diagnosis and treatment essential.⁵ An epidemiologic study of 1762 confirmed cases in Texas from 2003 to 2013 found an increase in the number of cases and an expansion of the geographic areas impacted.³ Thus, in the work-up of acute fever of unknown origin, it is not unreasonable to include murine typhus in the differential.

Serologic testing with IFA is the preferred diagnostic method; however, a definitive diagnosis is not needed before treatment can be started.

Murine typhus can be difficult to diagnose due to nonspecific clinical manifestation.^3,4 A 2016 systematic review of 2074 patients reported common symptoms of fever, headache, malaise, chills, and myalgia.⁶ The most common laboratory abnormalities in adults were elevated aminotransferases, lactate dehydrogenase, hypoalbuminemia, and thrombocytopenia.⁶ A 4-fold increase in typhus group IgM or IgG-specific antibody titer by IFA is supportive of diagnosis.⁴ 

The differential diagnosis included urosepsis, prostatitis, syphilis, HIV, and meningitis. However, lack of response to broad-spectrum antibiotics and antifungals made a diagnosis of urologic infection unlikely. A negative sexually transmitted infection screen ruled out syphilis and HIV. An incidental, elevated INR and delirium prevented us from obtaining a lumbar puncture to test for meningitis.

Treatment may begin without a definitive diagnosis

Serologic testing with IFA is the preferred diagnostic method; however, a definitive diagnosis is not needed before treatment can be initiated. Doxycycline is the first-line therapy for all rickettsioses. Adults are advised to take doxycycline 200 mg orally once, followed by 100 mg twice daily until the patient improves, has been afebrile for 48 hours, and has received treatment for at least 7 days.⁷ Oral chloramphenicol is considered a second-line treatment; however it is not available in the United States and is associated with adverse hematologic effects.⁷

Our patient responded remarkably well to the doxycycline. After a 14-day course was completed, he was discharged to a skilled nursing facility for physical rehabilitation.

Continue to: THE TAKEAWAY

 

 

THE TAKEAWAY

Rickettsia diseases, such as murine typhus, should be considered in the differential if a patient presents with a worsening clinical picture of unresolved delirium; fever despite use of broad-spectrum antibiotics, antifungals, and antivirals; and a history of potential outdoor exposure. Sources include opossums or cats when flea contact is likely. Rickettsia diseases belong in the differential when there is a history of travel to tropical areas, as well. All suspected cases should be reported to the local health department.

CORRESPONDENCE
Tenzin Tsewang MD, 5200 Harry Hines Boulevard, Dallas, TX 75235; [email protected]

THE CASE

A 72-year-old man was admitted to our Dallas hospital with a 4-day history of fevers and new-onset urinary frequency. He did not report any joint pain, sick contacts, or recent travel or recall any skin findings (rashes, insect bites). Past medical history was significant for hypertension, hyperlipidemia, diabetes, benign prostatic hyperplasia, recurrent urinary tract infections, and lumbar radiculopathy.

Initial signs and symptoms were suggestive of sepsis: a temperature of 102.7 °F, tachycardia, and a suspected genitourinary infection. This was supported by initial labs concerning for end-organ damage: elevated creatinine of 1.58 mg/dL (reference range, 0.67-1.17 mg/dL), elevated international normalized ratio (INR) of 1.6 (reference range, 0.9-1.1), hemoglobin of 12.8 g/dL (reference range, 13.5 - 17.5 g/dL), and platelet count of 99 ×10⁹/L (reference range, 160-383 ×10⁹/L).

Over the next several days, the patient’s condition worsened, and he experienced a decline in mental status, despite initiation of broad-spectrum antibiotics and fluid resuscitation. Although lumbar puncture was warranted, neither Neurology nor Interventional Radiology were willing to risk the procedure given the patient’s worsening hemoglobin (8.3 g/dL) and platelet count (51 ×10⁹/L).

Preliminary work-up included a urinalysis negative for leukocytes, nitrites, and ­bacteria—despite a urine culture that showed gram-positive cocci. His chest x-ray was unremarkable, and computed tomography of his brain showed generalized atrophy without acute changes. The work-up was expanded to fungal cultures and immunochemical assays. Empiric treatment with micafungin and acyclovir was started without improvement.

Further conversation with family revealed that the patient liked to spend time outdoors and he’d had a similar episode in which he’d been diagnosed with an unknown disease from an insect bite. Pertinent negative tests included: HIV, syphilis, rapid heterophile antibody, influenza, respiratory virus panel, blood culture, fungal culture, antineutrophil cytoplasmic antibodies, histoplasmosis, brucellosis, malaria, Epstein-Barr virus, cytomegalovirus, and parvovirus. Coxiella burnetii and West Nile virus immunoglobulin (Ig) G were positive, suggesting a prior exposure.

THE DIAGNOSIS

Given these new findings and reported outdoor activities, Infectious Diseases recommended we start our patient on doxycycline for possible rickettsia infection. On Day 8, doxycycline 200 mg IV once daily was started. (The IV form was initiated due to the patient’s altered mentation.) The patient started to show improvement, and on Day 14, an immunofluorescence antibody (IFA) assay revealed Rickettsia typhi IgM titers 1:512 (< 1:64) and IgG titers 1:256 (< 1:64), consistent with a diagnosis of murine (endemic) typhus.

DISCUSSION

Murine typhus is an acute febrile disease caused by R typhi, an obligate, intracellular gram-negative organism.¹ Worldwide, transmission to humans occurs mainly from infected rat fleas harbored by rodents. In the United States, it’s been suggested that opossums serve as an important reservoir in peri-domestic settings, with cat fleas as vectors.^2-4 The disease is endemic to southern California and south Texas.⁴

Continue to: Incidence of murine typhus

Incidence of murine typhus has declined in the United States since 1945 with the use of the insecticide dichlorodiphenyltrichloroethane (DDT). However, a recent rise in murine typhus cases—likely due to ecological changes—makes timely diagnosis and treatment essential.⁵ An epidemiologic study of 1762 confirmed cases in Texas from 2003 to 2013 found an increase in the number of cases and an expansion of the geographic areas impacted.³ Thus, in the work-up of acute fever of unknown origin, it is not unreasonable to include murine typhus in the differential.

Serologic testing with IFA is the preferred diagnostic method; however, a definitive diagnosis is not needed before treatment can be started.

Murine typhus can be difficult to diagnose due to nonspecific clinical manifestation.^3,4 A 2016 systematic review of 2074 patients reported common symptoms of fever, headache, malaise, chills, and myalgia.⁶ The most common laboratory abnormalities in adults were elevated aminotransferases, lactate dehydrogenase, hypoalbuminemia, and thrombocytopenia.⁶ A 4-fold increase in typhus group IgM or IgG-specific antibody titer by IFA is supportive of diagnosis.⁴ 

The differential diagnosis included urosepsis, prostatitis, syphilis, HIV, and meningitis. However, lack of response to broad-spectrum antibiotics and antifungals made a diagnosis of urologic infection unlikely. A negative sexually transmitted infection screen ruled out syphilis and HIV. An incidental, elevated INR and delirium prevented us from obtaining a lumbar puncture to test for meningitis.

Treatment may begin without a definitive diagnosis

Serologic testing with IFA is the preferred diagnostic method; however, a definitive diagnosis is not needed before treatment can be initiated. Doxycycline is the first-line therapy for all rickettsioses. Adults are advised to take doxycycline 200 mg orally once, followed by 100 mg twice daily until the patient improves, has been afebrile for 48 hours, and has received treatment for at least 7 days.⁷ Oral chloramphenicol is considered a second-line treatment; however it is not available in the United States and is associated with adverse hematologic effects.⁷

Our patient responded remarkably well to the doxycycline. After a 14-day course was completed, he was discharged to a skilled nursing facility for physical rehabilitation.

Continue to: THE TAKEAWAY

 

 

THE TAKEAWAY

Rickettsia diseases, such as murine typhus, should be considered in the differential if a patient presents with a worsening clinical picture of unresolved delirium; fever despite use of broad-spectrum antibiotics, antifungals, and antivirals; and a history of potential outdoor exposure. Sources include opossums or cats when flea contact is likely. Rickettsia diseases belong in the differential when there is a history of travel to tropical areas, as well. All suspected cases should be reported to the local health department.

CORRESPONDENCE
Tenzin Tsewang MD, 5200 Harry Hines Boulevard, Dallas, TX 75235; [email protected]

ILLUSTRATIVE CASE

A 30-year-old woman presented to the ED after she “passed out” while standing at a concert. She lost consciousness for 10 seconds. After she revived, her friends drove her to the ED. She is healthy, with no chronic medical conditions, no medication use, and no drug or alcohol use. Should she be admitted to the hospital for observation?

Syncope, a transient loss of consciousness followed by spontaneous complete recovery, accounts for 1% of ED visits.² Approximately 10% of patients presenting to the ED will have a serious underlying condition identified and among 3% to 5% of these patients with syncope, the serious condition will be identified only after they leave the ED.¹ Most patients have a benign course, but more than half of all patients presenting to the ED with syncope will be hospitalized, costing $2.4 billion annually.²

Because of the high hospitalization rate of patients with syncope, a practical and accurate tool to risk-stratify patients is vital. Other tools, such as the San Francisco Syncope Rule, Short-Term Prognosis of Syncope, and Risk Stratification of Syncope in the Emergency Department, lack validation or are excessively complex, with extensive lab work or testing.³

The CSRS was previously derived from a large, multisite consecutive cohort, and was internally validated and reported according to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guideline statement.⁴ Patients are assigned points based on clinical findings, test results, and the diagnosis given in the ED (TABLE⁴). The scoring system is used to stratify patients as very low (−3, −2), low (−1, 0), medium (1, 2, 3), high (4, 5), or very high (≥6) risk.⁴

STUDY SUMMARY

Less than 1% of very low– and low-risk patients had serious 30-day outcomes

This multisite Canadian prospective validation cohort study enrolled patients age ≥ 16 years who presented to the ED within 24 hours of syncope. Both discharged and hospitalized patients were included.¹

Patients were excluded if they had loss of consciousness for > 5 minutes, mental status changes at presentation, history of current or previous seizure, or head trauma resulting in loss of consciousness. Patients requiring hospitalization secondary to trauma or those from whom an accurate history could not be obtained (eg, intoxication) were excluded, as were patients with a serious underlying condition identified during the original ED evaluation.

ED physicians confirmed patient eligibility, obtained verbal consent, and completed the data collection form. In addition, research assistants sought to identify eligible patients who were not previously enrolled by reviewing all ED visits during the study period.

Continue to: To examine 30-day outcomes...

To examine 30-day outcomes, researchers reviewed all available patient medical records, including administrative health records at all hospitals within the province; performed a telephone follow-up immediately after 30 days; and if no other information was found, searched the coroner’s database. Two ED physicians (with a third resolving disagreements) determined if a serious outcome occurred, including any arrhythmia, intervention to treat arrythmia, death due to an unknown cause, myocardial infarction, structural heart disease, aortic dissection, pulmonary embolism, severe pulmonary hypertension, significant hemorrhage, or subarachnoid hemorrhage.¹

A total of 4131 patients made up the validation cohort. A serious condition was identified during the initial ED visit in 160 patients (3.9%), who were excluded from the study, and 152 patients (3.7%) were lost to follow-up. Of the 3819 patients included in the final analysis, troponin was not measured in 1566 patients (41%), and an electrocardiogram was not obtained in 114 patients (3%). A serious outcome within 30 days was experienced by 139 patients (3.6%; 95% CI, 3.1%-4.3%). There was good correlation to the model-predicted serious outcome probability of 3.2% (95% CI, 2.7%-3.8%).¹

Three of 1631 (0.2%) patients classified as very low risk and 9 of 1254 (0.7%) low-risk patients experienced a serious outcome, and no patients died. In the group classified as medium risk, 55 of 687 (8%) patients experienced a serious outcome, and there was 1 death. In the high-risk group, 32 of 167 (19.2%) patients experienced a serious outcome, and there were 5 deaths. In the group classified as very high risk, 40 of 78 (51.3%) patients experienced a serious outcome, and there were 7 deaths. The CSRS was able to identify very low– or low-risk patients (score of −1 or better) with a sensitivity of 97.8% (95% CI, 93.8%-99.6%) and a specificity of 44.3% (95% CI, 42.7%-45.9%).¹

WHAT’S NEW

This scoring system offers a validated method to risk-stratify ED patients

Previous recommendations from the American College of Cardiology/American Heart Associationsuggested determining disposition of ED patients by using clinical judgment based on a list of risk factors such as age, chronic conditions, and medications. However, there was no scoring system.³ This new scoring system allows physicians to send home very low– and low-risk patients with reassurance that the likelihood of a serious outcome is less than 1%. High-risk and very high–risk patients should be admitted to the hospital for further evaluation. Most moderate-risk patients (8% risk of serious outcome but 0.1% risk of death) can also be discharged after providers have a risk/benefit discussion, including precautions for signs of arrhythmia or need for urgent return to the hospital.

CAVEATS

The study does not translate to all clinical settings

Because this study was done in EDs, the scoring system cannot necessarily be applied to urgent care or outpatient settings. However, 41% of the patients in the study did not have troponin testing performed. Therefore, physicians could consider using the scoring system in settings where this lab test is not immediately available.

Continue to: This scoring system was also only...

This scoring system was also only validated with adult patients presenting within 24 hours of their syncopal episode. It is unknown how it may predict the outcomes of patients who present > 24 hours after syncope.

CHALLENGES TO IMPLEMENTATION

Clinicians may not be awareof the CSRS scoring system

The main challenge to implementation is practitioner awareness of the CSRS scoring system and how to use it appropriately, as there are several different syncopal scoring systems that may already be in use. Additionally, depending on the electronic health record used, the CSRS scoring system may not be embedded. Using and documenting scores may also be a challenge.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 30-year-old woman presented to the ED after she “passed out” while standing at a concert. She lost consciousness for 10 seconds. After she revived, her friends drove her to the ED. She is healthy, with no chronic medical conditions, no medication use, and no drug or alcohol use. Should she be admitted to the hospital for observation?

Syncope, a transient loss of consciousness followed by spontaneous complete recovery, accounts for 1% of ED visits.² Approximately 10% of patients presenting to the ED will have a serious underlying condition identified and among 3% to 5% of these patients with syncope, the serious condition will be identified only after they leave the ED.¹ Most patients have a benign course, but more than half of all patients presenting to the ED with syncope will be hospitalized, costing $2.4 billion annually.²

Because of the high hospitalization rate of patients with syncope, a practical and accurate tool to risk-stratify patients is vital. Other tools, such as the San Francisco Syncope Rule, Short-Term Prognosis of Syncope, and Risk Stratification of Syncope in the Emergency Department, lack validation or are excessively complex, with extensive lab work or testing.³

The CSRS was previously derived from a large, multisite consecutive cohort, and was internally validated and reported according to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guideline statement.⁴ Patients are assigned points based on clinical findings, test results, and the diagnosis given in the ED (TABLE⁴). The scoring system is used to stratify patients as very low (−3, −2), low (−1, 0), medium (1, 2, 3), high (4, 5), or very high (≥6) risk.⁴

STUDY SUMMARY

Less than 1% of very low– and low-risk patients had serious 30-day outcomes

This multisite Canadian prospective validation cohort study enrolled patients age ≥ 16 years who presented to the ED within 24 hours of syncope. Both discharged and hospitalized patients were included.¹

Patients were excluded if they had loss of consciousness for > 5 minutes, mental status changes at presentation, history of current or previous seizure, or head trauma resulting in loss of consciousness. Patients requiring hospitalization secondary to trauma or those from whom an accurate history could not be obtained (eg, intoxication) were excluded, as were patients with a serious underlying condition identified during the original ED evaluation.

ED physicians confirmed patient eligibility, obtained verbal consent, and completed the data collection form. In addition, research assistants sought to identify eligible patients who were not previously enrolled by reviewing all ED visits during the study period.

Continue to: To examine 30-day outcomes...

To examine 30-day outcomes, researchers reviewed all available patient medical records, including administrative health records at all hospitals within the province; performed a telephone follow-up immediately after 30 days; and if no other information was found, searched the coroner’s database. Two ED physicians (with a third resolving disagreements) determined if a serious outcome occurred, including any arrhythmia, intervention to treat arrythmia, death due to an unknown cause, myocardial infarction, structural heart disease, aortic dissection, pulmonary embolism, severe pulmonary hypertension, significant hemorrhage, or subarachnoid hemorrhage.¹

A total of 4131 patients made up the validation cohort. A serious condition was identified during the initial ED visit in 160 patients (3.9%), who were excluded from the study, and 152 patients (3.7%) were lost to follow-up. Of the 3819 patients included in the final analysis, troponin was not measured in 1566 patients (41%), and an electrocardiogram was not obtained in 114 patients (3%). A serious outcome within 30 days was experienced by 139 patients (3.6%; 95% CI, 3.1%-4.3%). There was good correlation to the model-predicted serious outcome probability of 3.2% (95% CI, 2.7%-3.8%).¹

Three of 1631 (0.2%) patients classified as very low risk and 9 of 1254 (0.7%) low-risk patients experienced a serious outcome, and no patients died. In the group classified as medium risk, 55 of 687 (8%) patients experienced a serious outcome, and there was 1 death. In the high-risk group, 32 of 167 (19.2%) patients experienced a serious outcome, and there were 5 deaths. In the group classified as very high risk, 40 of 78 (51.3%) patients experienced a serious outcome, and there were 7 deaths. The CSRS was able to identify very low– or low-risk patients (score of −1 or better) with a sensitivity of 97.8% (95% CI, 93.8%-99.6%) and a specificity of 44.3% (95% CI, 42.7%-45.9%).¹

WHAT’S NEW

This scoring system offers a validated method to risk-stratify ED patients

Previous recommendations from the American College of Cardiology/American Heart Associationsuggested determining disposition of ED patients by using clinical judgment based on a list of risk factors such as age, chronic conditions, and medications. However, there was no scoring system.³ This new scoring system allows physicians to send home very low– and low-risk patients with reassurance that the likelihood of a serious outcome is less than 1%. High-risk and very high–risk patients should be admitted to the hospital for further evaluation. Most moderate-risk patients (8% risk of serious outcome but 0.1% risk of death) can also be discharged after providers have a risk/benefit discussion, including precautions for signs of arrhythmia or need for urgent return to the hospital.

CAVEATS

The study does not translate to all clinical settings

Because this study was done in EDs, the scoring system cannot necessarily be applied to urgent care or outpatient settings. However, 41% of the patients in the study did not have troponin testing performed. Therefore, physicians could consider using the scoring system in settings where this lab test is not immediately available.

Continue to: This scoring system was also only...

This scoring system was also only validated with adult patients presenting within 24 hours of their syncopal episode. It is unknown how it may predict the outcomes of patients who present > 24 hours after syncope.

CHALLENGES TO IMPLEMENTATION

Clinicians may not be awareof the CSRS scoring system

The main challenge to implementation is practitioner awareness of the CSRS scoring system and how to use it appropriately, as there are several different syncopal scoring systems that may already be in use. Additionally, depending on the electronic health record used, the CSRS scoring system may not be embedded. Using and documenting scores may also be a challenge.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 30-year-old woman presented to the ED after she “passed out” while standing at a concert. She lost consciousness for 10 seconds. After she revived, her friends drove her to the ED. She is healthy, with no chronic medical conditions, no medication use, and no drug or alcohol use. Should she be admitted to the hospital for observation?

Syncope, a transient loss of consciousness followed by spontaneous complete recovery, accounts for 1% of ED visits.² Approximately 10% of patients presenting to the ED will have a serious underlying condition identified and among 3% to 5% of these patients with syncope, the serious condition will be identified only after they leave the ED.¹ Most patients have a benign course, but more than half of all patients presenting to the ED with syncope will be hospitalized, costing $2.4 billion annually.²

Because of the high hospitalization rate of patients with syncope, a practical and accurate tool to risk-stratify patients is vital. Other tools, such as the San Francisco Syncope Rule, Short-Term Prognosis of Syncope, and Risk Stratification of Syncope in the Emergency Department, lack validation or are excessively complex, with extensive lab work or testing.³

The CSRS was previously derived from a large, multisite consecutive cohort, and was internally validated and reported according to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guideline statement.⁴ Patients are assigned points based on clinical findings, test results, and the diagnosis given in the ED (TABLE⁴). The scoring system is used to stratify patients as very low (−3, −2), low (−1, 0), medium (1, 2, 3), high (4, 5), or very high (≥6) risk.⁴

STUDY SUMMARY

Less than 1% of very low– and low-risk patients had serious 30-day outcomes

This multisite Canadian prospective validation cohort study enrolled patients age ≥ 16 years who presented to the ED within 24 hours of syncope. Both discharged and hospitalized patients were included.¹

Patients were excluded if they had loss of consciousness for > 5 minutes, mental status changes at presentation, history of current or previous seizure, or head trauma resulting in loss of consciousness. Patients requiring hospitalization secondary to trauma or those from whom an accurate history could not be obtained (eg, intoxication) were excluded, as were patients with a serious underlying condition identified during the original ED evaluation.

ED physicians confirmed patient eligibility, obtained verbal consent, and completed the data collection form. In addition, research assistants sought to identify eligible patients who were not previously enrolled by reviewing all ED visits during the study period.

Continue to: To examine 30-day outcomes...

To examine 30-day outcomes, researchers reviewed all available patient medical records, including administrative health records at all hospitals within the province; performed a telephone follow-up immediately after 30 days; and if no other information was found, searched the coroner’s database. Two ED physicians (with a third resolving disagreements) determined if a serious outcome occurred, including any arrhythmia, intervention to treat arrythmia, death due to an unknown cause, myocardial infarction, structural heart disease, aortic dissection, pulmonary embolism, severe pulmonary hypertension, significant hemorrhage, or subarachnoid hemorrhage.¹

A total of 4131 patients made up the validation cohort. A serious condition was identified during the initial ED visit in 160 patients (3.9%), who were excluded from the study, and 152 patients (3.7%) were lost to follow-up. Of the 3819 patients included in the final analysis, troponin was not measured in 1566 patients (41%), and an electrocardiogram was not obtained in 114 patients (3%). A serious outcome within 30 days was experienced by 139 patients (3.6%; 95% CI, 3.1%-4.3%). There was good correlation to the model-predicted serious outcome probability of 3.2% (95% CI, 2.7%-3.8%).¹

Three of 1631 (0.2%) patients classified as very low risk and 9 of 1254 (0.7%) low-risk patients experienced a serious outcome, and no patients died. In the group classified as medium risk, 55 of 687 (8%) patients experienced a serious outcome, and there was 1 death. In the high-risk group, 32 of 167 (19.2%) patients experienced a serious outcome, and there were 5 deaths. In the group classified as very high risk, 40 of 78 (51.3%) patients experienced a serious outcome, and there were 7 deaths. The CSRS was able to identify very low– or low-risk patients (score of −1 or better) with a sensitivity of 97.8% (95% CI, 93.8%-99.6%) and a specificity of 44.3% (95% CI, 42.7%-45.9%).¹

WHAT’S NEW

This scoring system offers a validated method to risk-stratify ED patients

Previous recommendations from the American College of Cardiology/American Heart Associationsuggested determining disposition of ED patients by using clinical judgment based on a list of risk factors such as age, chronic conditions, and medications. However, there was no scoring system.³ This new scoring system allows physicians to send home very low– and low-risk patients with reassurance that the likelihood of a serious outcome is less than 1%. High-risk and very high–risk patients should be admitted to the hospital for further evaluation. Most moderate-risk patients (8% risk of serious outcome but 0.1% risk of death) can also be discharged after providers have a risk/benefit discussion, including precautions for signs of arrhythmia or need for urgent return to the hospital.

CAVEATS

The study does not translate to all clinical settings

Because this study was done in EDs, the scoring system cannot necessarily be applied to urgent care or outpatient settings. However, 41% of the patients in the study did not have troponin testing performed. Therefore, physicians could consider using the scoring system in settings where this lab test is not immediately available.

Continue to: This scoring system was also only...

This scoring system was also only validated with adult patients presenting within 24 hours of their syncopal episode. It is unknown how it may predict the outcomes of patients who present > 24 hours after syncope.

CHALLENGES TO IMPLEMENTATION

Clinicians may not be awareof the CSRS scoring system

The main challenge to implementation is practitioner awareness of the CSRS scoring system and how to use it appropriately, as there are several different syncopal scoring systems that may already be in use. Additionally, depending on the electronic health record used, the CSRS scoring system may not be embedded. Using and documenting scores may also be a challenge.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

In a new study, researchers stimulated immune cells to assemble into tertiary lymphoid structures that improved the efficacy of chemotherapy in a preclinical model of pancreatic cancer.

Overall, the evidence generated by the study supports the notion that induction of tertiary lymphoid structures may potentiate chemotherapy’s antitumor activity, at least in a murine model of pancreatic ductal adenocarcinoma (PDAC). A more detailed understanding of tertiary lymphoid structure “kinetics and their induction, owing to multiple host and tumor factors, may help design personalized therapies harnessing the potential of immuno-oncology,” Francesca Delvecchio of Queen Mary University of London and colleagues wrote in Cellular and Molecular Gastroenterology and Hepatology.

While the immune system can play a role in combating cancer, a dense stroma surrounds pancreatic cancer cells, often blocking the ability of certain immune cells, such as T cells, from accessing the tumor. As shown by Young and colleagues, this causes immunotherapies to have very little success in the management of most pancreatic cancers, despite the efficacy of these therapies in other types of cancer.

In a proportion of patients with pancreatic cancer, clusters of immune cells can assemble tertiary lymphoid structures within the stroma that surrounds pancreatic cancer. These structures are associated with improved survival in PDAC. In the study, Mr. Delvecchio and colleagues sought to further elucidate the role of tertiary lymphoid structures in PDAC, particularly the structures’ antitumor potential.

The investigators analyzed donated tissue samples from patients to identify the presence of the structures within chemotherapy-naive human pancreatic cancer. Tertiary lymphoid structures were defined by the presence of tissue zones that were rich in T cells, B cells, and dendritic cells. Staining techniques were used to visualize the various cell types in the samples, revealing tertiary lymphoid structures in approximately 30% of tissue microarrays and 42% of the full section.

Multicolor immunofluorescence and immunohistochemistry were also used to characterize tertiary lymphoid structures in murine models of pancreatic cancer. Additionally, the investigators developed an orthotopic murine model to assess the development of the structures and their role in improving the therapeutic effects of chemotherapy. While tertiary lymphoid structures were not initially present in the preclinical murine model, B cells and T cells subsequently infiltrated into the tumor site following injection of lymphoid chemokines. These cells consequently assembled into the tertiary lymphoid structures.

In addition, the researchers combined chemotherapy gemcitabine with the intratumoral lymphoid chemokine and injected this combination treatment into orthotopic tumors. Following injection, the researchers observed “altered immune cell infiltration,” which facilitated the induction of tertiary lymphoid structures and potentiated antitumor activity of the chemotherapy. As a result, there was a significant reduction in the tumors, an effect the researchers did not find following the use of either treatment alone.

According to the investigators, the antitumor activity observed following induction of the tertiary lymphoid structures within the cancer is associated with B cell–mediated activation of dendritic cells, a key cell type involved in initiating an immune response.

Based on the findings, the researchers concluded that the combination of chemotherapy and lymphoid chemokines might be a viable strategy for promoting an antitumor immune response in pancreatic cancer. In turn, the researchers suggest this strategy may result in better clinical outcomes for patients with the disease. Additionally, the researchers wrote that mature tertiary lymphoid structures in PDAC prior to an immune treatment could “be used as a biomarker to define inclusion criteria of patients in immunotherapy protocols, with the aim to boost the ongoing antitumor immune response.”

The study relied on a mouse model and for this reason, it remains unclear at this time if the findings will be generalizable to humans. In the context of PDAC, the researchers wrote that further investigation and understanding of the formation of tertiary lymphoid structures may support the development of tailored treatments, including those that take advantage of the body’s immune system, to combat cancer and improve patient outcomes.

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

In a new study, researchers stimulated immune cells to assemble into tertiary lymphoid structures that improved the efficacy of chemotherapy in a preclinical model of pancreatic cancer.

Overall, the evidence generated by the study supports the notion that induction of tertiary lymphoid structures may potentiate chemotherapy’s antitumor activity, at least in a murine model of pancreatic ductal adenocarcinoma (PDAC). A more detailed understanding of tertiary lymphoid structure “kinetics and their induction, owing to multiple host and tumor factors, may help design personalized therapies harnessing the potential of immuno-oncology,” Francesca Delvecchio of Queen Mary University of London and colleagues wrote in Cellular and Molecular Gastroenterology and Hepatology.

While the immune system can play a role in combating cancer, a dense stroma surrounds pancreatic cancer cells, often blocking the ability of certain immune cells, such as T cells, from accessing the tumor. As shown by Young and colleagues, this causes immunotherapies to have very little success in the management of most pancreatic cancers, despite the efficacy of these therapies in other types of cancer.

In a proportion of patients with pancreatic cancer, clusters of immune cells can assemble tertiary lymphoid structures within the stroma that surrounds pancreatic cancer. These structures are associated with improved survival in PDAC. In the study, Mr. Delvecchio and colleagues sought to further elucidate the role of tertiary lymphoid structures in PDAC, particularly the structures’ antitumor potential.

The investigators analyzed donated tissue samples from patients to identify the presence of the structures within chemotherapy-naive human pancreatic cancer. Tertiary lymphoid structures were defined by the presence of tissue zones that were rich in T cells, B cells, and dendritic cells. Staining techniques were used to visualize the various cell types in the samples, revealing tertiary lymphoid structures in approximately 30% of tissue microarrays and 42% of the full section.

Multicolor immunofluorescence and immunohistochemistry were also used to characterize tertiary lymphoid structures in murine models of pancreatic cancer. Additionally, the investigators developed an orthotopic murine model to assess the development of the structures and their role in improving the therapeutic effects of chemotherapy. While tertiary lymphoid structures were not initially present in the preclinical murine model, B cells and T cells subsequently infiltrated into the tumor site following injection of lymphoid chemokines. These cells consequently assembled into the tertiary lymphoid structures.

In addition, the researchers combined chemotherapy gemcitabine with the intratumoral lymphoid chemokine and injected this combination treatment into orthotopic tumors. Following injection, the researchers observed “altered immune cell infiltration,” which facilitated the induction of tertiary lymphoid structures and potentiated antitumor activity of the chemotherapy. As a result, there was a significant reduction in the tumors, an effect the researchers did not find following the use of either treatment alone.

According to the investigators, the antitumor activity observed following induction of the tertiary lymphoid structures within the cancer is associated with B cell–mediated activation of dendritic cells, a key cell type involved in initiating an immune response.

Based on the findings, the researchers concluded that the combination of chemotherapy and lymphoid chemokines might be a viable strategy for promoting an antitumor immune response in pancreatic cancer. In turn, the researchers suggest this strategy may result in better clinical outcomes for patients with the disease. Additionally, the researchers wrote that mature tertiary lymphoid structures in PDAC prior to an immune treatment could “be used as a biomarker to define inclusion criteria of patients in immunotherapy protocols, with the aim to boost the ongoing antitumor immune response.”

The study relied on a mouse model and for this reason, it remains unclear at this time if the findings will be generalizable to humans. In the context of PDAC, the researchers wrote that further investigation and understanding of the formation of tertiary lymphoid structures may support the development of tailored treatments, including those that take advantage of the body’s immune system, to combat cancer and improve patient outcomes.

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

In a new study, researchers stimulated immune cells to assemble into tertiary lymphoid structures that improved the efficacy of chemotherapy in a preclinical model of pancreatic cancer.

Overall, the evidence generated by the study supports the notion that induction of tertiary lymphoid structures may potentiate chemotherapy’s antitumor activity, at least in a murine model of pancreatic ductal adenocarcinoma (PDAC). A more detailed understanding of tertiary lymphoid structure “kinetics and their induction, owing to multiple host and tumor factors, may help design personalized therapies harnessing the potential of immuno-oncology,” Francesca Delvecchio of Queen Mary University of London and colleagues wrote in Cellular and Molecular Gastroenterology and Hepatology.

While the immune system can play a role in combating cancer, a dense stroma surrounds pancreatic cancer cells, often blocking the ability of certain immune cells, such as T cells, from accessing the tumor. As shown by Young and colleagues, this causes immunotherapies to have very little success in the management of most pancreatic cancers, despite the efficacy of these therapies in other types of cancer.

In a proportion of patients with pancreatic cancer, clusters of immune cells can assemble tertiary lymphoid structures within the stroma that surrounds pancreatic cancer. These structures are associated with improved survival in PDAC. In the study, Mr. Delvecchio and colleagues sought to further elucidate the role of tertiary lymphoid structures in PDAC, particularly the structures’ antitumor potential.

The investigators analyzed donated tissue samples from patients to identify the presence of the structures within chemotherapy-naive human pancreatic cancer. Tertiary lymphoid structures were defined by the presence of tissue zones that were rich in T cells, B cells, and dendritic cells. Staining techniques were used to visualize the various cell types in the samples, revealing tertiary lymphoid structures in approximately 30% of tissue microarrays and 42% of the full section.

Multicolor immunofluorescence and immunohistochemistry were also used to characterize tertiary lymphoid structures in murine models of pancreatic cancer. Additionally, the investigators developed an orthotopic murine model to assess the development of the structures and their role in improving the therapeutic effects of chemotherapy. While tertiary lymphoid structures were not initially present in the preclinical murine model, B cells and T cells subsequently infiltrated into the tumor site following injection of lymphoid chemokines. These cells consequently assembled into the tertiary lymphoid structures.

In addition, the researchers combined chemotherapy gemcitabine with the intratumoral lymphoid chemokine and injected this combination treatment into orthotopic tumors. Following injection, the researchers observed “altered immune cell infiltration,” which facilitated the induction of tertiary lymphoid structures and potentiated antitumor activity of the chemotherapy. As a result, there was a significant reduction in the tumors, an effect the researchers did not find following the use of either treatment alone.

According to the investigators, the antitumor activity observed following induction of the tertiary lymphoid structures within the cancer is associated with B cell–mediated activation of dendritic cells, a key cell type involved in initiating an immune response.

Based on the findings, the researchers concluded that the combination of chemotherapy and lymphoid chemokines might be a viable strategy for promoting an antitumor immune response in pancreatic cancer. In turn, the researchers suggest this strategy may result in better clinical outcomes for patients with the disease. Additionally, the researchers wrote that mature tertiary lymphoid structures in PDAC prior to an immune treatment could “be used as a biomarker to define inclusion criteria of patients in immunotherapy protocols, with the aim to boost the ongoing antitumor immune response.”

The study relied on a mouse model and for this reason, it remains unclear at this time if the findings will be generalizable to humans. In the context of PDAC, the researchers wrote that further investigation and understanding of the formation of tertiary lymphoid structures may support the development of tailored treatments, including those that take advantage of the body’s immune system, to combat cancer and improve patient outcomes.

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

THE CASE

Michael T,* a 20-year-old cisgender male, visited one of our clinic’s primary care physicians (PCPs). He was reserved and quiet and spoke of his concerns about depression and social anxiety that had been present for several years. He also spoke of his inability to succeed at work and school. Following a thorough PCP review leading to diagnoses of major depressive disorder and social anxiety, the patient agreed to try medication. Over a period of 15 months, trials of medications including fluoxetine, sertraline, aripiprazole, and duloxetine did little to improve the patient’s mood. The PCP decided to consult with our clinic’s integrated health team.

The team reviewed several diagnostic possibilities (TABLE 1) and agreed with the PCP’s diagnoses of major depression and social anxiety. But these disorders alone did not explain the full picture. Team members noted the patient’s unusual communication style, characterized by remarkably long response times and slow processing speed. In particular, when discussing mood, he took several seconds to respond but would respond thoughtfully and with few words.

We administered the Wechsler Adult Intelligence Scale (WAIS-IV). Due to differences between the 4 indices within the WAIS-IV, the Full Scale Intelligence Quotient may under- or overestimate abilities across domains; this was the case for this patient. His General Ability Index (GAI) score was 130, in the very superior range and at the 98th percentile, placing him in the category of gifted intelligence. The patient’s processing speed, however, was at the 18th percentile, which explained his delayed response style and presence of developmental asynchrony, a concept occasionally reported when interpreting socio-emotional and educational maladjustment in gifted individuals.

We determined that Mr. T was twice exceptional—intellectually gifted and also having one or more areas of disability.

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity .

In individuals with gifted intelligence, a discrepancy between cognitive and emotional development can make them vulnerable to behavioral and emotional challenges. It is not uncommon for gifted individuals to experience co-occurring distress, anxiety, depression, social withdrawal, difficulty coping with challenging tasks and experiences, low self-esteem, and excessive perfectionism.^1-6 Giftedness accompanied by a delay in general abilities and processing speed (significant verbal-performance discrepancy) places an individual in the category of twice-exceptionality, or “2E”—having the potential for high achievement while displaying evidence of 1 or more disabilities including emotional or behavioral difficulties.⁷

2E Individuals: Prevalence, characteristics, and outcomes

Reported prevalence of twice-exceptionality varies, from approximately 180,000 to 360,000 students in the United States.⁷ In 2009, the National Commission on Twice Exceptional Students provided the following definition of twice exceptionality:^7,8

2E individuals may excel early due to strong language abilities, but then show signs of disability when curricular demands rise in junior high school or later.

“Twice-exceptional learners are students who demonstrate the potential for high achievement or creative productivity in one or more domains such as math, science, technology, the social arts, the visual, spatial, or performing arts or other areas of human productivity AND who manifest one or more disabilities as defined by federal or state eligibility criteria. These disabilities include specific learning disabilities; speech and language disorders; emotional/behavioral disorders; physical disabilities; Autism Spectrum Disorders (ASD); or other health impairments, such as Attention Deficit/Hyperactivity Disorder (ADHD).”

How twice-exceptionality might manifest. The literature describes 3 unique groupings of 2E children: those who excel early due to strong language abilities, but later show signs of disability, often when curricular demands rise in junior high, high school, or even college; students diagnosed with disability, but who show exceptional gifts in some areas that may be masked by their learning difficulties; and highly intelligent students who seem to be average, because their disabilities mask their giftedness or their talents mask their difficulties.^9,10

Unique behavioral and emotional challenges of 2E individuals may include lower motivation and academic self-efficacy, low self-worth and feelings of failure, or disruptive behaviors.^7,11,12 Anxiety and depression often result from the functional impact of twice-exceptionality as well as resultant withdrawal, social isolation, and delay or hindrance of social skills (such as difficulty interpreting social cues).^13,14 The individual in our case displayed many of these challenges, including lower motivation, self-worth, and self-esteem, and comorbid anxiety and depression (TABLE 1), further clouding diagnostic clarity.

Continue to: The need for improved recognition

The need for improved recognition. Twice-exceptionality commonly manifests as children reach grade-school age, but they are underrepresented in programs for the gifted due to misunderstanding and misdiagnosis by professionals.^15,16 Best practices in identifying 2E children incorporate multidimensional assessments including pre-referral and screening, preliminary intervention, evaluation procedures, and educational planning.¹⁶ Despite research asserting that 2E individuals need more support services, knowing how to best identify and support individuals across various settings can prove difficult.^7,17-19

Primary care, as we will discuss in a bit, is an interdisciplinary setting in which identification and comprehensive and collaborative support can occur. Historically, though, mental and physical health care have been “siloed” and mental health professionals’ functions in medical settings have often been circumscribed.^20,21

A lesson from how our case unfolded

Our integrated health team, known as Integrated Behavioral Health Plus (IBH+), was developed at the University of Colorado School of Medicine, and is a system-level integration of behavioral health professionals working with medical providers to improve outcomes and satisfaction.²² Psychology supervisors and trainees, telepsychiatrists and psychiatry residents, social workers, and pharmacists work together with PCPs and residents to deliver comprehensive patient care. Our model includes a range of behavioral health access points for patients (TABLE 2) and the use of complex patient databases and care team meetings.

In the case we have described here, the nature of the patient’s presentation did not trigger any of the clinical procedures described in TABLE 2, and he fell under the radar of complex patient cases in the clinic. Instead, informal, asynchronous clinical conversations between providers were what eventually lead to diagnostic clarification. Team consultation and psychometric testing provided by IBH+ helped uncover the “hidden diagnosis” of this patient in primary care and identified him as twice-exceptional, experiencing both giftedness and significant emotional suffering (major depression and social anxiety, low self-esteem and self-worth).

Takeaways for primary care

Not all PCPs, of course, have immediate onsite access to a program such as ours. However, innovative ways to tap into available resources might include establishing a partnership with 1 or more behavioral health professionals or bridging less formal relationships with such providers in the community and schools to more easily share patient records.

Continue to: Other presentations within 2E populations

Other presentations within 2E populations. 2E individuals may have other presentations coupled with high cognitive ability⁷: symptoms of hyperactivity disorders; specific learning disabilities; a diagnosis of autism spectrum disorder (previously termed Asperger type); attention, organizational, social, and behavioral issues; and impulsivity or emotional volatility.

We shifted from a “bugs and drugs” perspective of diagnosis and treatment to an approach that explored the interplay between cognitive and emotional functioning for this individual.

Of note, the perspective of our care team shifted from a “bugs and drugs” perspective of diagnosis and treatment—biological explanations and pharmaceutical solutions—to an approach that explored the underlying interplay between cognitive and emotional functioning for this individual. Our treatment focused on a strengths-based and patient-centered approach. Even without the resources of a full IBH+ model, primary care practices may be able to adapt our experience to their ever-growing complex populations.

THE CASE

Our team shifted treatment planning to the needs of the patient. The 2E identification changed the patient’s perspective about himself. After learning of his giftedness, the patient was able to reframe himself as a highly intelligent, capable individual in need of treatment for depression and social anxiety, as opposed to questioning his intelligence and experiencing confusion and hopelessness within the medical system. His PCP collaborated with the team via telecommunication to maintain an efficacious antidepressant plan and to use a strengths-based approach focused on increasing the patient’s self-view and changing the illness narrative. This narrative was changed by practicing skills, such as challenging unhelpful thought patterns, setting beneficial boundaries, and supporting assertive communication to oppose thoughts and relationships that perpetuated old, negative beliefs and assumptions.

CORRESPONDENCE
Kathryn S. Saldaña, PhD, University of Colorado, 12631 East 17th Avenue, AO1 L15, 3rd Floor, Aurora, CO 80045; kathryn. [email protected].

ACKNOWLEDGEMENTS
Our thanks to A.F. Williams Family Medicine Clinic and the University of Colorado Anschutz Medical Campus School of Medicine for their unparalleled models of resident training and multidisciplinary care.

THE CASE

Michael T,* a 20-year-old cisgender male, visited one of our clinic’s primary care physicians (PCPs). He was reserved and quiet and spoke of his concerns about depression and social anxiety that had been present for several years. He also spoke of his inability to succeed at work and school. Following a thorough PCP review leading to diagnoses of major depressive disorder and social anxiety, the patient agreed to try medication. Over a period of 15 months, trials of medications including fluoxetine, sertraline, aripiprazole, and duloxetine did little to improve the patient’s mood. The PCP decided to consult with our clinic’s integrated health team.

The team reviewed several diagnostic possibilities (TABLE 1) and agreed with the PCP’s diagnoses of major depression and social anxiety. But these disorders alone did not explain the full picture. Team members noted the patient’s unusual communication style, characterized by remarkably long response times and slow processing speed. In particular, when discussing mood, he took several seconds to respond but would respond thoughtfully and with few words.

We administered the Wechsler Adult Intelligence Scale (WAIS-IV). Due to differences between the 4 indices within the WAIS-IV, the Full Scale Intelligence Quotient may under- or overestimate abilities across domains; this was the case for this patient. His General Ability Index (GAI) score was 130, in the very superior range and at the 98th percentile, placing him in the category of gifted intelligence. The patient’s processing speed, however, was at the 18th percentile, which explained his delayed response style and presence of developmental asynchrony, a concept occasionally reported when interpreting socio-emotional and educational maladjustment in gifted individuals.

We determined that Mr. T was twice exceptional—intellectually gifted and also having one or more areas of disability.

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity .

In individuals with gifted intelligence, a discrepancy between cognitive and emotional development can make them vulnerable to behavioral and emotional challenges. It is not uncommon for gifted individuals to experience co-occurring distress, anxiety, depression, social withdrawal, difficulty coping with challenging tasks and experiences, low self-esteem, and excessive perfectionism.^1-6 Giftedness accompanied by a delay in general abilities and processing speed (significant verbal-performance discrepancy) places an individual in the category of twice-exceptionality, or “2E”—having the potential for high achievement while displaying evidence of 1 or more disabilities including emotional or behavioral difficulties.⁷

2E Individuals: Prevalence, characteristics, and outcomes

Reported prevalence of twice-exceptionality varies, from approximately 180,000 to 360,000 students in the United States.⁷ In 2009, the National Commission on Twice Exceptional Students provided the following definition of twice exceptionality:^7,8

2E individuals may excel early due to strong language abilities, but then show signs of disability when curricular demands rise in junior high school or later.

“Twice-exceptional learners are students who demonstrate the potential for high achievement or creative productivity in one or more domains such as math, science, technology, the social arts, the visual, spatial, or performing arts or other areas of human productivity AND who manifest one or more disabilities as defined by federal or state eligibility criteria. These disabilities include specific learning disabilities; speech and language disorders; emotional/behavioral disorders; physical disabilities; Autism Spectrum Disorders (ASD); or other health impairments, such as Attention Deficit/Hyperactivity Disorder (ADHD).”

How twice-exceptionality might manifest. The literature describes 3 unique groupings of 2E children: those who excel early due to strong language abilities, but later show signs of disability, often when curricular demands rise in junior high, high school, or even college; students diagnosed with disability, but who show exceptional gifts in some areas that may be masked by their learning difficulties; and highly intelligent students who seem to be average, because their disabilities mask their giftedness or their talents mask their difficulties.^9,10

Unique behavioral and emotional challenges of 2E individuals may include lower motivation and academic self-efficacy, low self-worth and feelings of failure, or disruptive behaviors.^7,11,12 Anxiety and depression often result from the functional impact of twice-exceptionality as well as resultant withdrawal, social isolation, and delay or hindrance of social skills (such as difficulty interpreting social cues).^13,14 The individual in our case displayed many of these challenges, including lower motivation, self-worth, and self-esteem, and comorbid anxiety and depression (TABLE 1), further clouding diagnostic clarity.

Continue to: The need for improved recognition

The need for improved recognition. Twice-exceptionality commonly manifests as children reach grade-school age, but they are underrepresented in programs for the gifted due to misunderstanding and misdiagnosis by professionals.^15,16 Best practices in identifying 2E children incorporate multidimensional assessments including pre-referral and screening, preliminary intervention, evaluation procedures, and educational planning.¹⁶ Despite research asserting that 2E individuals need more support services, knowing how to best identify and support individuals across various settings can prove difficult.^7,17-19

Primary care, as we will discuss in a bit, is an interdisciplinary setting in which identification and comprehensive and collaborative support can occur. Historically, though, mental and physical health care have been “siloed” and mental health professionals’ functions in medical settings have often been circumscribed.^20,21

A lesson from how our case unfolded

Our integrated health team, known as Integrated Behavioral Health Plus (IBH+), was developed at the University of Colorado School of Medicine, and is a system-level integration of behavioral health professionals working with medical providers to improve outcomes and satisfaction.²² Psychology supervisors and trainees, telepsychiatrists and psychiatry residents, social workers, and pharmacists work together with PCPs and residents to deliver comprehensive patient care. Our model includes a range of behavioral health access points for patients (TABLE 2) and the use of complex patient databases and care team meetings.

In the case we have described here, the nature of the patient’s presentation did not trigger any of the clinical procedures described in TABLE 2, and he fell under the radar of complex patient cases in the clinic. Instead, informal, asynchronous clinical conversations between providers were what eventually lead to diagnostic clarification. Team consultation and psychometric testing provided by IBH+ helped uncover the “hidden diagnosis” of this patient in primary care and identified him as twice-exceptional, experiencing both giftedness and significant emotional suffering (major depression and social anxiety, low self-esteem and self-worth).

Takeaways for primary care

Not all PCPs, of course, have immediate onsite access to a program such as ours. However, innovative ways to tap into available resources might include establishing a partnership with 1 or more behavioral health professionals or bridging less formal relationships with such providers in the community and schools to more easily share patient records.

Continue to: Other presentations within 2E populations

Other presentations within 2E populations. 2E individuals may have other presentations coupled with high cognitive ability⁷: symptoms of hyperactivity disorders; specific learning disabilities; a diagnosis of autism spectrum disorder (previously termed Asperger type); attention, organizational, social, and behavioral issues; and impulsivity or emotional volatility.

We shifted from a “bugs and drugs” perspective of diagnosis and treatment to an approach that explored the interplay between cognitive and emotional functioning for this individual.

Of note, the perspective of our care team shifted from a “bugs and drugs” perspective of diagnosis and treatment—biological explanations and pharmaceutical solutions—to an approach that explored the underlying interplay between cognitive and emotional functioning for this individual. Our treatment focused on a strengths-based and patient-centered approach. Even without the resources of a full IBH+ model, primary care practices may be able to adapt our experience to their ever-growing complex populations.

THE CASE

Our team shifted treatment planning to the needs of the patient. The 2E identification changed the patient’s perspective about himself. After learning of his giftedness, the patient was able to reframe himself as a highly intelligent, capable individual in need of treatment for depression and social anxiety, as opposed to questioning his intelligence and experiencing confusion and hopelessness within the medical system. His PCP collaborated with the team via telecommunication to maintain an efficacious antidepressant plan and to use a strengths-based approach focused on increasing the patient’s self-view and changing the illness narrative. This narrative was changed by practicing skills, such as challenging unhelpful thought patterns, setting beneficial boundaries, and supporting assertive communication to oppose thoughts and relationships that perpetuated old, negative beliefs and assumptions.

CORRESPONDENCE
Kathryn S. Saldaña, PhD, University of Colorado, 12631 East 17th Avenue, AO1 L15, 3rd Floor, Aurora, CO 80045; kathryn. [email protected].

ACKNOWLEDGEMENTS
Our thanks to A.F. Williams Family Medicine Clinic and the University of Colorado Anschutz Medical Campus School of Medicine for their unparalleled models of resident training and multidisciplinary care.

THE CASE

Michael T,* a 20-year-old cisgender male, visited one of our clinic’s primary care physicians (PCPs). He was reserved and quiet and spoke of his concerns about depression and social anxiety that had been present for several years. He also spoke of his inability to succeed at work and school. Following a thorough PCP review leading to diagnoses of major depressive disorder and social anxiety, the patient agreed to try medication. Over a period of 15 months, trials of medications including fluoxetine, sertraline, aripiprazole, and duloxetine did little to improve the patient’s mood. The PCP decided to consult with our clinic’s integrated health team.

The team reviewed several diagnostic possibilities (TABLE 1) and agreed with the PCP’s diagnoses of major depression and social anxiety. But these disorders alone did not explain the full picture. Team members noted the patient’s unusual communication style, characterized by remarkably long response times and slow processing speed. In particular, when discussing mood, he took several seconds to respond but would respond thoughtfully and with few words.

We administered the Wechsler Adult Intelligence Scale (WAIS-IV). Due to differences between the 4 indices within the WAIS-IV, the Full Scale Intelligence Quotient may under- or overestimate abilities across domains; this was the case for this patient. His General Ability Index (GAI) score was 130, in the very superior range and at the 98th percentile, placing him in the category of gifted intelligence. The patient’s processing speed, however, was at the 18th percentile, which explained his delayed response style and presence of developmental asynchrony, a concept occasionally reported when interpreting socio-emotional and educational maladjustment in gifted individuals.

We determined that Mr. T was twice exceptional—intellectually gifted and also having one or more areas of disability.

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity .

In individuals with gifted intelligence, a discrepancy between cognitive and emotional development can make them vulnerable to behavioral and emotional challenges. It is not uncommon for gifted individuals to experience co-occurring distress, anxiety, depression, social withdrawal, difficulty coping with challenging tasks and experiences, low self-esteem, and excessive perfectionism.^1-6 Giftedness accompanied by a delay in general abilities and processing speed (significant verbal-performance discrepancy) places an individual in the category of twice-exceptionality, or “2E”—having the potential for high achievement while displaying evidence of 1 or more disabilities including emotional or behavioral difficulties.⁷

2E Individuals: Prevalence, characteristics, and outcomes

Reported prevalence of twice-exceptionality varies, from approximately 180,000 to 360,000 students in the United States.⁷ In 2009, the National Commission on Twice Exceptional Students provided the following definition of twice exceptionality:^7,8

2E individuals may excel early due to strong language abilities, but then show signs of disability when curricular demands rise in junior high school or later.

“Twice-exceptional learners are students who demonstrate the potential for high achievement or creative productivity in one or more domains such as math, science, technology, the social arts, the visual, spatial, or performing arts or other areas of human productivity AND who manifest one or more disabilities as defined by federal or state eligibility criteria. These disabilities include specific learning disabilities; speech and language disorders; emotional/behavioral disorders; physical disabilities; Autism Spectrum Disorders (ASD); or other health impairments, such as Attention Deficit/Hyperactivity Disorder (ADHD).”

How twice-exceptionality might manifest. The literature describes 3 unique groupings of 2E children: those who excel early due to strong language abilities, but later show signs of disability, often when curricular demands rise in junior high, high school, or even college; students diagnosed with disability, but who show exceptional gifts in some areas that may be masked by their learning difficulties; and highly intelligent students who seem to be average, because their disabilities mask their giftedness or their talents mask their difficulties.^9,10

Unique behavioral and emotional challenges of 2E individuals may include lower motivation and academic self-efficacy, low self-worth and feelings of failure, or disruptive behaviors.^7,11,12 Anxiety and depression often result from the functional impact of twice-exceptionality as well as resultant withdrawal, social isolation, and delay or hindrance of social skills (such as difficulty interpreting social cues).^13,14 The individual in our case displayed many of these challenges, including lower motivation, self-worth, and self-esteem, and comorbid anxiety and depression (TABLE 1), further clouding diagnostic clarity.

Continue to: The need for improved recognition

The need for improved recognition. Twice-exceptionality commonly manifests as children reach grade-school age, but they are underrepresented in programs for the gifted due to misunderstanding and misdiagnosis by professionals.^15,16 Best practices in identifying 2E children incorporate multidimensional assessments including pre-referral and screening, preliminary intervention, evaluation procedures, and educational planning.¹⁶ Despite research asserting that 2E individuals need more support services, knowing how to best identify and support individuals across various settings can prove difficult.^7,17-19

Primary care, as we will discuss in a bit, is an interdisciplinary setting in which identification and comprehensive and collaborative support can occur. Historically, though, mental and physical health care have been “siloed” and mental health professionals’ functions in medical settings have often been circumscribed.^20,21

A lesson from how our case unfolded

Our integrated health team, known as Integrated Behavioral Health Plus (IBH+), was developed at the University of Colorado School of Medicine, and is a system-level integration of behavioral health professionals working with medical providers to improve outcomes and satisfaction.²² Psychology supervisors and trainees, telepsychiatrists and psychiatry residents, social workers, and pharmacists work together with PCPs and residents to deliver comprehensive patient care. Our model includes a range of behavioral health access points for patients (TABLE 2) and the use of complex patient databases and care team meetings.

In the case we have described here, the nature of the patient’s presentation did not trigger any of the clinical procedures described in TABLE 2, and he fell under the radar of complex patient cases in the clinic. Instead, informal, asynchronous clinical conversations between providers were what eventually lead to diagnostic clarification. Team consultation and psychometric testing provided by IBH+ helped uncover the “hidden diagnosis” of this patient in primary care and identified him as twice-exceptional, experiencing both giftedness and significant emotional suffering (major depression and social anxiety, low self-esteem and self-worth).

Takeaways for primary care

Not all PCPs, of course, have immediate onsite access to a program such as ours. However, innovative ways to tap into available resources might include establishing a partnership with 1 or more behavioral health professionals or bridging less formal relationships with such providers in the community and schools to more easily share patient records.

Continue to: Other presentations within 2E populations

Other presentations within 2E populations. 2E individuals may have other presentations coupled with high cognitive ability⁷: symptoms of hyperactivity disorders; specific learning disabilities; a diagnosis of autism spectrum disorder (previously termed Asperger type); attention, organizational, social, and behavioral issues; and impulsivity or emotional volatility.

We shifted from a “bugs and drugs” perspective of diagnosis and treatment to an approach that explored the interplay between cognitive and emotional functioning for this individual.

Of note, the perspective of our care team shifted from a “bugs and drugs” perspective of diagnosis and treatment—biological explanations and pharmaceutical solutions—to an approach that explored the underlying interplay between cognitive and emotional functioning for this individual. Our treatment focused on a strengths-based and patient-centered approach. Even without the resources of a full IBH+ model, primary care practices may be able to adapt our experience to their ever-growing complex populations.

THE CASE

Our team shifted treatment planning to the needs of the patient. The 2E identification changed the patient’s perspective about himself. After learning of his giftedness, the patient was able to reframe himself as a highly intelligent, capable individual in need of treatment for depression and social anxiety, as opposed to questioning his intelligence and experiencing confusion and hopelessness within the medical system. His PCP collaborated with the team via telecommunication to maintain an efficacious antidepressant plan and to use a strengths-based approach focused on increasing the patient’s self-view and changing the illness narrative. This narrative was changed by practicing skills, such as challenging unhelpful thought patterns, setting beneficial boundaries, and supporting assertive communication to oppose thoughts and relationships that perpetuated old, negative beliefs and assumptions.

CORRESPONDENCE
Kathryn S. Saldaña, PhD, University of Colorado, 12631 East 17th Avenue, AO1 L15, 3rd Floor, Aurora, CO 80045; kathryn. [email protected].

ACKNOWLEDGEMENTS
Our thanks to A.F. Williams Family Medicine Clinic and the University of Colorado Anschutz Medical Campus School of Medicine for their unparalleled models of resident training and multidisciplinary care.

A 17-year-old high school baseball player presented to a sports medicine clinic for left anterior knee pain. During the exam, a hyperpigmented lesion was incidentally noted on his left palm. The patient, who also played basketball and football, was unsure of how long he’d had the lesion, and he did not recall having any prior lesions on his hand. He denied any discomfort or significant past medical history. There was no known family history of skin cancers, but the patient did report that his brother, also an athlete, had a similar lesion on his hand.

On closer examination, scattered black dots were noted within a 2 × 1–cm thickened keratotic plaque at the hypothenar eminence of the patient’s left hand (Figure). There was no tenderness, erythema, warmth, or disruption of normal skin architecture or drainage.

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

 

 

Diagnosis: Posttraumatic tache noir

Posttraumatic tache noir (also known as talon noir on the volar aspect of the feet) is a subcorneal hematoma. The diagnosis is made clinically.

Identifying “pebbles on a ridge” or “satellite globules” during dermoscopic evaluation can differentiate benign from malignant sources of this type of lesion.

Our patient was a competitive baseball player, and he noted that the knob of his baseball bat rubbed the hypothenar eminence of his nondominant hand when he took a swing. The sheer force of the knob led to the subcorneal hematoma. Tache noir was high on the differential due to the author’s clinical experience with similar cases.

Tache noir occurs predominantly in people ages 12 to 24 years, without regard to gender.¹ The condition is commonly found in athletes who participate in baseball, cricket, racquet sports, weightlifting, and rock climbing.^1-3 Talon noir occurs most commonly in athletes who are frequently jumping, turning, and pivoting, as in football, basketball, tennis, and lacrosse. One should have a high index of suspicion for this diagnosis in patients who participate in any sport that might lead to shearing forces involving the volar aspect of the hands or feet.

Confirmation is obtained through a simple procedure. Dermoscopic evaluation of tache/talon noir will reveal “pebbles on a ridge” or “satellite globules.” Confirmation of tache/talon noir can be made by paring the corneum with a #15 blade, which will reveal blood in the shavings and punctate lesions.⁴

Other lesions may havea similar appearance

Tache noir can be differentiated from other conditions by the presence of preserved architecture of the skin surface and punctate capillaries beneath the stratum corneum. The differential diagnosis includes verruca vulgaris, acral melanoma, and a traumatic tattoo.

Continue to: Verruca vulgaris

Verruca vulgaris similarly contains puncta but typically appears as a raised lesion with a disruption of the stratum corneum.⁵

Acral melanoma can be distinguished from tache/talon noir by dermoscopic evaluation and/or paring of the corneum. On dermoscopic evaluation, both acral melanoma and tache/talon noir will reveal parallel ridge patterns; this finding has an 86% sensitivity and 96% specificity for early acral melanoma.⁶ What differentiates the 2 is the “satellite globules” or “pebbles on a ridge” that are seen with a subcorneal hematoma. Furthermore, paring the corneum would demonstrate an absence of blood within the ridges of the skin shavings, pointing away from tache/talon noir as the diagnosis.^1-3,5-7

Traumatic tattoo can also mimic tache/talon noir, due to foreign-material deposits in the skin (gunpowder, carbon, lead, dirt, and asphalt). A history of penetrating trauma should help to narrow the differential. Attempts at paring with traumatic tattoo may or may not help with differentiation.¹

In this case, time does heal all wounds

Talon/tache noir are benign conditions that do not require treatment and do not affect sports performance. The lesion will usually self-resolve within a matter of weeks from onset or can even be gently scraped with a sterile needle or blade, which can partially or completely remove the pigmentation from within the parallel ridges.^3,5,8

Our patient was advised that the lesion would resolve on its own. His knee pain was determined to be a simple case of patellofemoral syndrome or “runner’s knee” and he opted to complete a home exercise program to obtain relief.

A 17-year-old high school baseball player presented to a sports medicine clinic for left anterior knee pain. During the exam, a hyperpigmented lesion was incidentally noted on his left palm. The patient, who also played basketball and football, was unsure of how long he’d had the lesion, and he did not recall having any prior lesions on his hand. He denied any discomfort or significant past medical history. There was no known family history of skin cancers, but the patient did report that his brother, also an athlete, had a similar lesion on his hand.

On closer examination, scattered black dots were noted within a 2 × 1–cm thickened keratotic plaque at the hypothenar eminence of the patient’s left hand (Figure). There was no tenderness, erythema, warmth, or disruption of normal skin architecture or drainage.

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

 

 

Diagnosis: Posttraumatic tache noir

Posttraumatic tache noir (also known as talon noir on the volar aspect of the feet) is a subcorneal hematoma. The diagnosis is made clinically.

Identifying “pebbles on a ridge” or “satellite globules” during dermoscopic evaluation can differentiate benign from malignant sources of this type of lesion.

Our patient was a competitive baseball player, and he noted that the knob of his baseball bat rubbed the hypothenar eminence of his nondominant hand when he took a swing. The sheer force of the knob led to the subcorneal hematoma. Tache noir was high on the differential due to the author’s clinical experience with similar cases.

Tache noir occurs predominantly in people ages 12 to 24 years, without regard to gender.¹ The condition is commonly found in athletes who participate in baseball, cricket, racquet sports, weightlifting, and rock climbing.^1-3 Talon noir occurs most commonly in athletes who are frequently jumping, turning, and pivoting, as in football, basketball, tennis, and lacrosse. One should have a high index of suspicion for this diagnosis in patients who participate in any sport that might lead to shearing forces involving the volar aspect of the hands or feet.

Confirmation is obtained through a simple procedure. Dermoscopic evaluation of tache/talon noir will reveal “pebbles on a ridge” or “satellite globules.” Confirmation of tache/talon noir can be made by paring the corneum with a #15 blade, which will reveal blood in the shavings and punctate lesions.⁴

Other lesions may havea similar appearance

Tache noir can be differentiated from other conditions by the presence of preserved architecture of the skin surface and punctate capillaries beneath the stratum corneum. The differential diagnosis includes verruca vulgaris, acral melanoma, and a traumatic tattoo.

Continue to: Verruca vulgaris

Verruca vulgaris similarly contains puncta but typically appears as a raised lesion with a disruption of the stratum corneum.⁵

Acral melanoma can be distinguished from tache/talon noir by dermoscopic evaluation and/or paring of the corneum. On dermoscopic evaluation, both acral melanoma and tache/talon noir will reveal parallel ridge patterns; this finding has an 86% sensitivity and 96% specificity for early acral melanoma.⁶ What differentiates the 2 is the “satellite globules” or “pebbles on a ridge” that are seen with a subcorneal hematoma. Furthermore, paring the corneum would demonstrate an absence of blood within the ridges of the skin shavings, pointing away from tache/talon noir as the diagnosis.^1-3,5-7

Traumatic tattoo can also mimic tache/talon noir, due to foreign-material deposits in the skin (gunpowder, carbon, lead, dirt, and asphalt). A history of penetrating trauma should help to narrow the differential. Attempts at paring with traumatic tattoo may or may not help with differentiation.¹

In this case, time does heal all wounds

Talon/tache noir are benign conditions that do not require treatment and do not affect sports performance. The lesion will usually self-resolve within a matter of weeks from onset or can even be gently scraped with a sterile needle or blade, which can partially or completely remove the pigmentation from within the parallel ridges.^3,5,8

Our patient was advised that the lesion would resolve on its own. His knee pain was determined to be a simple case of patellofemoral syndrome or “runner’s knee” and he opted to complete a home exercise program to obtain relief.

A 17-year-old high school baseball player presented to a sports medicine clinic for left anterior knee pain. During the exam, a hyperpigmented lesion was incidentally noted on his left palm. The patient, who also played basketball and football, was unsure of how long he’d had the lesion, and he did not recall having any prior lesions on his hand. He denied any discomfort or significant past medical history. There was no known family history of skin cancers, but the patient did report that his brother, also an athlete, had a similar lesion on his hand.

On closer examination, scattered black dots were noted within a 2 × 1–cm thickened keratotic plaque at the hypothenar eminence of the patient’s left hand (Figure). There was no tenderness, erythema, warmth, or disruption of normal skin architecture or drainage.

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

 

 

Diagnosis: Posttraumatic tache noir

Posttraumatic tache noir (also known as talon noir on the volar aspect of the feet) is a subcorneal hematoma. The diagnosis is made clinically.

Identifying “pebbles on a ridge” or “satellite globules” during dermoscopic evaluation can differentiate benign from malignant sources of this type of lesion.

Our patient was a competitive baseball player, and he noted that the knob of his baseball bat rubbed the hypothenar eminence of his nondominant hand when he took a swing. The sheer force of the knob led to the subcorneal hematoma. Tache noir was high on the differential due to the author’s clinical experience with similar cases.

Tache noir occurs predominantly in people ages 12 to 24 years, without regard to gender.¹ The condition is commonly found in athletes who participate in baseball, cricket, racquet sports, weightlifting, and rock climbing.^1-3 Talon noir occurs most commonly in athletes who are frequently jumping, turning, and pivoting, as in football, basketball, tennis, and lacrosse. One should have a high index of suspicion for this diagnosis in patients who participate in any sport that might lead to shearing forces involving the volar aspect of the hands or feet.

Confirmation is obtained through a simple procedure. Dermoscopic evaluation of tache/talon noir will reveal “pebbles on a ridge” or “satellite globules.” Confirmation of tache/talon noir can be made by paring the corneum with a #15 blade, which will reveal blood in the shavings and punctate lesions.⁴

Other lesions may havea similar appearance

Tache noir can be differentiated from other conditions by the presence of preserved architecture of the skin surface and punctate capillaries beneath the stratum corneum. The differential diagnosis includes verruca vulgaris, acral melanoma, and a traumatic tattoo.

Continue to: Verruca vulgaris

Verruca vulgaris similarly contains puncta but typically appears as a raised lesion with a disruption of the stratum corneum.⁵

Acral melanoma can be distinguished from tache/talon noir by dermoscopic evaluation and/or paring of the corneum. On dermoscopic evaluation, both acral melanoma and tache/talon noir will reveal parallel ridge patterns; this finding has an 86% sensitivity and 96% specificity for early acral melanoma.⁶ What differentiates the 2 is the “satellite globules” or “pebbles on a ridge” that are seen with a subcorneal hematoma. Furthermore, paring the corneum would demonstrate an absence of blood within the ridges of the skin shavings, pointing away from tache/talon noir as the diagnosis.^1-3,5-7

Traumatic tattoo can also mimic tache/talon noir, due to foreign-material deposits in the skin (gunpowder, carbon, lead, dirt, and asphalt). A history of penetrating trauma should help to narrow the differential. Attempts at paring with traumatic tattoo may or may not help with differentiation.¹

In this case, time does heal all wounds

Talon/tache noir are benign conditions that do not require treatment and do not affect sports performance. The lesion will usually self-resolve within a matter of weeks from onset or can even be gently scraped with a sterile needle or blade, which can partially or completely remove the pigmentation from within the parallel ridges.^3,5,8

Our patient was advised that the lesion would resolve on its own. His knee pain was determined to be a simple case of patellofemoral syndrome or “runner’s knee” and he opted to complete a home exercise program to obtain relief.