The first study to systematically address the problem of persistent hair loss in patients who undergo radiation to the scalp for central nervous system or head and neck tumors has found that treatment with topical minoxidil leads to improvement in hair loss.

The study was published online on Aug. 5 in JAMA Dermatology.

Minoxidil has been used for many years to treat age-associated baldness in men, noted the authors. It was used off label in this study to treat radiation-associated persistent hair loss; 82% of patients showed at least some improvement.

For patients who do not improve with minoxidil, hair transplant and scalp reconstruction with plastic surgery were other options, the authors comment.

“Almost in all instances, there is something that can be done to improve persistent hair loss after radiation and give patients a sense of control,” senior author Mario E. Lacouture, MD, said in an interview. He is director of the Oncodermatology Program at Memorial Sloan Kettering Cancer Center in New York City.

About 60% of people with CNS tumors and 30% with head and neck cancer receive radiation to the head, and 75%-100% of these patients experience acute hair loss. For many, hair grows back in 2-3 months. However, for about 60%, hair loss persists for 6 or more months after completion of radiotherapy, the authors note.

In past work, Dr. Lacouture and colleagues found that persistent hair loss in cancer survivors is associated with depression, anxiety, and psychosocial distress.

“There are therapies and procedures that may mitigate persistent radiation therapy hair loss that can bring back psychosocial well-being to many of these patients,” Dr. Lacouture said. “These approaches are likely underutilized because patients are not being referred to specialists in hair or scalp reconstruction.”

Specialists can be found through the International Society for Hair Restoration Surgery and the American Academy of Dermatology, he added.

Study details

The retrospective cohort study included 71 children and adults who developed persistent hair loss after radiotherapy for primary CNS tumors (90%, n = 64) or head and neck sarcoma (10%, n = 7). The median age of the patients was 27 years (range, 4-75 years); 72% (n = 51) were female and 82% (n = 58) were White.

These patients had been treated at Memorial Sloan Kettering Cancer Center in New York City or St. Jude Children’s Hospital in Memphis from January 2011 to January 2019.

The team analyzed standardized clinical photographs of the scalp using the Common Terminology Criteria for Adverse Events version 5.0. Grade 1 alopecia was defined as hair loss of less than 50% of normal that does not require camouflage with hair pieces, scarves, or similar items. Grade 2 alopecia was defined as hair loss greater than 50% of normal that requires camouflage and is associated with negative psychosocial effects.

Over half of patients (56%, 40/70) had grade 1 hair loss. Clinical images were available for 54 patients; for most of these patients, hair loss was attributable to radiation alone (74%, n = 40). Evaluation of clinical imaging showed three variants of hair loss: localized (54%, 29/54), diffuse (24%, 13/54), and mixed pattern (22%, 12/54). Data on dermatologic imaging of the scalp (trichoscopy) were available for 28 patients; the main finding was white patches (57%, 16/28).

The median scalp radiation dose was 39.6 Gy (range, 15.1-50.0 Gy). The researchers estimate that a dose of 36.1 Gy (95% CI, 33.7-39.6 Gy) was sufficient to induce grade 2 hair loss in 50% of patients.

Severity of hair loss appeared to increase with radiation dose. For every 1-unit increase in radiation dose, the odds of grade 2 hair loss increased by 15% (odds ratio, 1.15; 95% CI, 1.04-1.28; P < .001). Proton irradiation was associated with even higher odds of severe hair loss (OR, 5.7; 95% CI, 1.05-30.8; P < .001). Results remained significant when analyses were controlled for sex, age at time of radiotherapy, and concurrent chemotherapy.

The majority of evaluable patients who were treated with topical minoxidil (5%) twice daily showed a response (82%, 28/34) during a median follow-up of 61 weeks (interquartile range, 21-105 weeks).

Among 25 of these patients for whom clinical images were available, 16% (4/25) showed complete response. Two patients improved with hair transplant, and one showed complete response with plastic surgery reconstruction of the hair.

The study had several limitations, including its retrospective design and a lack of complete data for certain variables, such as standardized clinical photographs, trichoscopy images, and radiotherapy treatment plans.

On the basis of these results, the authors are seeking funding for a prospective study of the use of minoxidil for persistent radiation-induced alopecia.

The study was funded in part by the National Institutes of Health/National Cancer Institute Cancer Center. One or more authors has relationships with pharmaceutical companies, as listed in the original article.

This article first appeared on Medscape.com.

The first study to systematically address the problem of persistent hair loss in patients who undergo radiation to the scalp for central nervous system or head and neck tumors has found that treatment with topical minoxidil leads to improvement in hair loss.

The study was published online on Aug. 5 in JAMA Dermatology.

Minoxidil has been used for many years to treat age-associated baldness in men, noted the authors. It was used off label in this study to treat radiation-associated persistent hair loss; 82% of patients showed at least some improvement.

For patients who do not improve with minoxidil, hair transplant and scalp reconstruction with plastic surgery were other options, the authors comment.

“Almost in all instances, there is something that can be done to improve persistent hair loss after radiation and give patients a sense of control,” senior author Mario E. Lacouture, MD, said in an interview. He is director of the Oncodermatology Program at Memorial Sloan Kettering Cancer Center in New York City.

About 60% of people with CNS tumors and 30% with head and neck cancer receive radiation to the head, and 75%-100% of these patients experience acute hair loss. For many, hair grows back in 2-3 months. However, for about 60%, hair loss persists for 6 or more months after completion of radiotherapy, the authors note.

In past work, Dr. Lacouture and colleagues found that persistent hair loss in cancer survivors is associated with depression, anxiety, and psychosocial distress.

“There are therapies and procedures that may mitigate persistent radiation therapy hair loss that can bring back psychosocial well-being to many of these patients,” Dr. Lacouture said. “These approaches are likely underutilized because patients are not being referred to specialists in hair or scalp reconstruction.”

Specialists can be found through the International Society for Hair Restoration Surgery and the American Academy of Dermatology, he added.

Study details

The retrospective cohort study included 71 children and adults who developed persistent hair loss after radiotherapy for primary CNS tumors (90%, n = 64) or head and neck sarcoma (10%, n = 7). The median age of the patients was 27 years (range, 4-75 years); 72% (n = 51) were female and 82% (n = 58) were White.

These patients had been treated at Memorial Sloan Kettering Cancer Center in New York City or St. Jude Children’s Hospital in Memphis from January 2011 to January 2019.

The team analyzed standardized clinical photographs of the scalp using the Common Terminology Criteria for Adverse Events version 5.0. Grade 1 alopecia was defined as hair loss of less than 50% of normal that does not require camouflage with hair pieces, scarves, or similar items. Grade 2 alopecia was defined as hair loss greater than 50% of normal that requires camouflage and is associated with negative psychosocial effects.

Over half of patients (56%, 40/70) had grade 1 hair loss. Clinical images were available for 54 patients; for most of these patients, hair loss was attributable to radiation alone (74%, n = 40). Evaluation of clinical imaging showed three variants of hair loss: localized (54%, 29/54), diffuse (24%, 13/54), and mixed pattern (22%, 12/54). Data on dermatologic imaging of the scalp (trichoscopy) were available for 28 patients; the main finding was white patches (57%, 16/28).

The median scalp radiation dose was 39.6 Gy (range, 15.1-50.0 Gy). The researchers estimate that a dose of 36.1 Gy (95% CI, 33.7-39.6 Gy) was sufficient to induce grade 2 hair loss in 50% of patients.

Severity of hair loss appeared to increase with radiation dose. For every 1-unit increase in radiation dose, the odds of grade 2 hair loss increased by 15% (odds ratio, 1.15; 95% CI, 1.04-1.28; P < .001). Proton irradiation was associated with even higher odds of severe hair loss (OR, 5.7; 95% CI, 1.05-30.8; P < .001). Results remained significant when analyses were controlled for sex, age at time of radiotherapy, and concurrent chemotherapy.

The majority of evaluable patients who were treated with topical minoxidil (5%) twice daily showed a response (82%, 28/34) during a median follow-up of 61 weeks (interquartile range, 21-105 weeks).

Among 25 of these patients for whom clinical images were available, 16% (4/25) showed complete response. Two patients improved with hair transplant, and one showed complete response with plastic surgery reconstruction of the hair.

The study had several limitations, including its retrospective design and a lack of complete data for certain variables, such as standardized clinical photographs, trichoscopy images, and radiotherapy treatment plans.

On the basis of these results, the authors are seeking funding for a prospective study of the use of minoxidil for persistent radiation-induced alopecia.

The study was funded in part by the National Institutes of Health/National Cancer Institute Cancer Center. One or more authors has relationships with pharmaceutical companies, as listed in the original article.

This article first appeared on Medscape.com.

The first study to systematically address the problem of persistent hair loss in patients who undergo radiation to the scalp for central nervous system or head and neck tumors has found that treatment with topical minoxidil leads to improvement in hair loss.

The study was published online on Aug. 5 in JAMA Dermatology.

Minoxidil has been used for many years to treat age-associated baldness in men, noted the authors. It was used off label in this study to treat radiation-associated persistent hair loss; 82% of patients showed at least some improvement.

For patients who do not improve with minoxidil, hair transplant and scalp reconstruction with plastic surgery were other options, the authors comment.

“Almost in all instances, there is something that can be done to improve persistent hair loss after radiation and give patients a sense of control,” senior author Mario E. Lacouture, MD, said in an interview. He is director of the Oncodermatology Program at Memorial Sloan Kettering Cancer Center in New York City.

About 60% of people with CNS tumors and 30% with head and neck cancer receive radiation to the head, and 75%-100% of these patients experience acute hair loss. For many, hair grows back in 2-3 months. However, for about 60%, hair loss persists for 6 or more months after completion of radiotherapy, the authors note.

In past work, Dr. Lacouture and colleagues found that persistent hair loss in cancer survivors is associated with depression, anxiety, and psychosocial distress.

“There are therapies and procedures that may mitigate persistent radiation therapy hair loss that can bring back psychosocial well-being to many of these patients,” Dr. Lacouture said. “These approaches are likely underutilized because patients are not being referred to specialists in hair or scalp reconstruction.”

Specialists can be found through the International Society for Hair Restoration Surgery and the American Academy of Dermatology, he added.

Study details

The retrospective cohort study included 71 children and adults who developed persistent hair loss after radiotherapy for primary CNS tumors (90%, n = 64) or head and neck sarcoma (10%, n = 7). The median age of the patients was 27 years (range, 4-75 years); 72% (n = 51) were female and 82% (n = 58) were White.

These patients had been treated at Memorial Sloan Kettering Cancer Center in New York City or St. Jude Children’s Hospital in Memphis from January 2011 to January 2019.

The team analyzed standardized clinical photographs of the scalp using the Common Terminology Criteria for Adverse Events version 5.0. Grade 1 alopecia was defined as hair loss of less than 50% of normal that does not require camouflage with hair pieces, scarves, or similar items. Grade 2 alopecia was defined as hair loss greater than 50% of normal that requires camouflage and is associated with negative psychosocial effects.

Over half of patients (56%, 40/70) had grade 1 hair loss. Clinical images were available for 54 patients; for most of these patients, hair loss was attributable to radiation alone (74%, n = 40). Evaluation of clinical imaging showed three variants of hair loss: localized (54%, 29/54), diffuse (24%, 13/54), and mixed pattern (22%, 12/54). Data on dermatologic imaging of the scalp (trichoscopy) were available for 28 patients; the main finding was white patches (57%, 16/28).

The median scalp radiation dose was 39.6 Gy (range, 15.1-50.0 Gy). The researchers estimate that a dose of 36.1 Gy (95% CI, 33.7-39.6 Gy) was sufficient to induce grade 2 hair loss in 50% of patients.

Severity of hair loss appeared to increase with radiation dose. For every 1-unit increase in radiation dose, the odds of grade 2 hair loss increased by 15% (odds ratio, 1.15; 95% CI, 1.04-1.28; P < .001). Proton irradiation was associated with even higher odds of severe hair loss (OR, 5.7; 95% CI, 1.05-30.8; P < .001). Results remained significant when analyses were controlled for sex, age at time of radiotherapy, and concurrent chemotherapy.

The majority of evaluable patients who were treated with topical minoxidil (5%) twice daily showed a response (82%, 28/34) during a median follow-up of 61 weeks (interquartile range, 21-105 weeks).

Among 25 of these patients for whom clinical images were available, 16% (4/25) showed complete response. Two patients improved with hair transplant, and one showed complete response with plastic surgery reconstruction of the hair.

The study had several limitations, including its retrospective design and a lack of complete data for certain variables, such as standardized clinical photographs, trichoscopy images, and radiotherapy treatment plans.

On the basis of these results, the authors are seeking funding for a prospective study of the use of minoxidil for persistent radiation-induced alopecia.

The study was funded in part by the National Institutes of Health/National Cancer Institute Cancer Center. One or more authors has relationships with pharmaceutical companies, as listed in the original article.

This article first appeared on Medscape.com.

Patients with RA were at lower risk for developing incident type 2 diabetes mellitus (T2DM) in comparison with patients with hypertension, psoriatic arthritis (PsA), or osteoarthritis, as well as the general population without RA in a retrospective cohort study of a large, nationwide, commercial health insurance claims database.

This result goes against what the study researchers from the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, initially hypothesized: The “risk of incident T2DM in RA patients would be similar to or less than PsA and [hypertension] patients, but higher, compared to general non-RA and OA patients.”

Prior epidemiologic studies of the relationship between RA and incident diabetes have yielded inconclusive results suggesting a small increase or no increase in risk of T2DM in patients with RA, possibly because of differences in the risk of T2DM in comparison groups used by previous studies to calculate relative risk, first author Yinzhu Jin and colleagues noted in their report published in Arthritis Care & Research.

After mining a nationwide U.S. commercial health insurance claims database, the Optum Clinformatics Data Mart, for claims data from Jan. 1, 2005, to Dec. 31, 2017, the researchers matched a total of 108,568 patients in RA, general population non-RA, hypertension, and OA cohorts based on age, sex, and index date (the date of disease-specific medication dispensing). Overall, 77% of those patients were female and had a mean age of nearly 56 years, whereas 48% of patients with PsA were female and their mean age was nearly 49 years. (PsA patients were not matched because of smaller numbers.)

During a median follow-up period of 1.4-1.8 years across the comparison groups, the crude incidence rate for diabetes per 1,000 person-years in the cohorts was 7.0 for RA, 7.4 for general non-RA, 12.3 for hypertension, 7.8 for OA, and 9.9 for PsA. The hazard ratios and 95% confidence interval for risk of diabetes in patients with RA – after adjustment for more than 40 baseline covariates that included demographics, comorbidities, medication use, and health care utilization – was 0.72 (0.66-0.78) in comparison withh the general non-RA cohort, 0.65 (0.60-0.71) in comparison with the hypertension cohort, 0.75 (0.69-0.81) in comparison with the OA cohort, and 0.76 (0.67-0.86) in comparison with the PsA cohort. These values correspond to RA patients having a 24%-35% lower risk of incident diabetes versus the comparison groups, the researchers noted. They observed results consistent to these when they conducted a sensitivity analysis using a 1-year lag time from the index date before starting follow-up.

The lower risk of T2DM in patients with RA in comparison with patients in the non-RA cohort “may be, in part, due to the effect of biologic DMARD [disease-modifying antirheumatic drug] treatment in RA which likely modifies the risk of DM,” the researchers wrote. “Both the increasing use of biologic DMARDs for RA in the U.S. over the last decade and our cohort entry criteria for the RA cohort (i.e., at least one dispensing of a DMARD) may explain the finding of the lower risk of DM in RA.”

The results found with the other three cohorts did not surprise the researchers. The reduced risk of diabetes among RA patients versus those with OA jibes with “higher rates of obesity and other comorbidities in patients with OA” as well as findings from a recent study that found a higher incidence rate of diabetes in OA, compared with RA. Ms. Jin and colleagues also acknowledged it is well known that “hypertension and PsA are associated with metabolic dysregulation and increase the risk of diabetes.”

The researchers defined patients with RA as having at least twoinpatient or outpatient ICD-9 or ICD-10 diagnosis codes of RA, separated by 7-365 days and having at least one dispensing for DMARDs within 1 year from the first RA diagnosis date, and defined the primary outcome of incident T2DM as at least one inpatient or outpatient diagnosis of T2DM plus at least one dispensing of an antidiabetic drug. They set the general non-RA cohort by selecting patients with any inpatient or outpatient diagnosis codes and a dispensing of any medications, and the hypertension, PsA, and OA comparator groups as having at least two inpatient or outpatient disease-specific ICD-9/ICD-10 codes separated by 7-365 days and at least one dispensing of disease-specific medication within 1 year from the first diagnosis date. They excluded patients with RA, PsA, or psoriasis diagnosis or disease-specific medication dispensing any time prior to or on the index date (the date of disease-specific medication dispensing).

The researchers recognized that the conclusions that can be drawn from the study are limited by the “potential misclassification of cohorts and covariates” because they “mainly used diagnosis codes and pharmacy dispensing records in claims data,” and some “important covariates such as baseline obesity are likely underreported and not adequately captured in claims data.” The level of covariate misclassification also may have been different across the study cohorts on “unmeasured covariates such as body mass index, diet, and physical activity, as well as disease specific measures,” thus introducing residual confounding. They also could not “examine potential difference in the risk of T2DM in untreated or undertreated RA patients” because “RA and all the non-RA comparator cohorts were required to use a disease-specific drug,” they wrote.

“While systemic inflammation in RA is thought to increase the risk of [cardiovascular disease] and cardiovascular risk factors such as DM, our findings suggest having RA itself does not confer an increased risk of DM. Future study should determine whether untreated RA or undertreated RA is associated with a greater risk of developing DM,” the researchers concluded.

The study was supported by a research grant from Bristol-Myers Squibb, which “played no role in the study design, data analysis or interpretation of data or presentation of results,” the researchers said. The company was “given the opportunity to make nonbinding comments on a draft of the manuscript, but the authors retained the right of publication and to determine the final wording.” One author reported receiving research grants from Brigham and Women’s Hospital from Pfizer, AbbVie, Bristol-Myers Squibb, and Roche for unrelated topics.

[email protected]

SOURCE: Jin Y et al. Arthritis Care Res. 2020 Aug 4. doi: 10.1002/acr.24343.

Patients with RA were at lower risk for developing incident type 2 diabetes mellitus (T2DM) in comparison with patients with hypertension, psoriatic arthritis (PsA), or osteoarthritis, as well as the general population without RA in a retrospective cohort study of a large, nationwide, commercial health insurance claims database.

This result goes against what the study researchers from the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, initially hypothesized: The “risk of incident T2DM in RA patients would be similar to or less than PsA and [hypertension] patients, but higher, compared to general non-RA and OA patients.”

Prior epidemiologic studies of the relationship between RA and incident diabetes have yielded inconclusive results suggesting a small increase or no increase in risk of T2DM in patients with RA, possibly because of differences in the risk of T2DM in comparison groups used by previous studies to calculate relative risk, first author Yinzhu Jin and colleagues noted in their report published in Arthritis Care & Research.

After mining a nationwide U.S. commercial health insurance claims database, the Optum Clinformatics Data Mart, for claims data from Jan. 1, 2005, to Dec. 31, 2017, the researchers matched a total of 108,568 patients in RA, general population non-RA, hypertension, and OA cohorts based on age, sex, and index date (the date of disease-specific medication dispensing). Overall, 77% of those patients were female and had a mean age of nearly 56 years, whereas 48% of patients with PsA were female and their mean age was nearly 49 years. (PsA patients were not matched because of smaller numbers.)

During a median follow-up period of 1.4-1.8 years across the comparison groups, the crude incidence rate for diabetes per 1,000 person-years in the cohorts was 7.0 for RA, 7.4 for general non-RA, 12.3 for hypertension, 7.8 for OA, and 9.9 for PsA. The hazard ratios and 95% confidence interval for risk of diabetes in patients with RA – after adjustment for more than 40 baseline covariates that included demographics, comorbidities, medication use, and health care utilization – was 0.72 (0.66-0.78) in comparison withh the general non-RA cohort, 0.65 (0.60-0.71) in comparison with the hypertension cohort, 0.75 (0.69-0.81) in comparison with the OA cohort, and 0.76 (0.67-0.86) in comparison with the PsA cohort. These values correspond to RA patients having a 24%-35% lower risk of incident diabetes versus the comparison groups, the researchers noted. They observed results consistent to these when they conducted a sensitivity analysis using a 1-year lag time from the index date before starting follow-up.

The lower risk of T2DM in patients with RA in comparison with patients in the non-RA cohort “may be, in part, due to the effect of biologic DMARD [disease-modifying antirheumatic drug] treatment in RA which likely modifies the risk of DM,” the researchers wrote. “Both the increasing use of biologic DMARDs for RA in the U.S. over the last decade and our cohort entry criteria for the RA cohort (i.e., at least one dispensing of a DMARD) may explain the finding of the lower risk of DM in RA.”

The results found with the other three cohorts did not surprise the researchers. The reduced risk of diabetes among RA patients versus those with OA jibes with “higher rates of obesity and other comorbidities in patients with OA” as well as findings from a recent study that found a higher incidence rate of diabetes in OA, compared with RA. Ms. Jin and colleagues also acknowledged it is well known that “hypertension and PsA are associated with metabolic dysregulation and increase the risk of diabetes.”

The researchers defined patients with RA as having at least twoinpatient or outpatient ICD-9 or ICD-10 diagnosis codes of RA, separated by 7-365 days and having at least one dispensing for DMARDs within 1 year from the first RA diagnosis date, and defined the primary outcome of incident T2DM as at least one inpatient or outpatient diagnosis of T2DM plus at least one dispensing of an antidiabetic drug. They set the general non-RA cohort by selecting patients with any inpatient or outpatient diagnosis codes and a dispensing of any medications, and the hypertension, PsA, and OA comparator groups as having at least two inpatient or outpatient disease-specific ICD-9/ICD-10 codes separated by 7-365 days and at least one dispensing of disease-specific medication within 1 year from the first diagnosis date. They excluded patients with RA, PsA, or psoriasis diagnosis or disease-specific medication dispensing any time prior to or on the index date (the date of disease-specific medication dispensing).

The researchers recognized that the conclusions that can be drawn from the study are limited by the “potential misclassification of cohorts and covariates” because they “mainly used diagnosis codes and pharmacy dispensing records in claims data,” and some “important covariates such as baseline obesity are likely underreported and not adequately captured in claims data.” The level of covariate misclassification also may have been different across the study cohorts on “unmeasured covariates such as body mass index, diet, and physical activity, as well as disease specific measures,” thus introducing residual confounding. They also could not “examine potential difference in the risk of T2DM in untreated or undertreated RA patients” because “RA and all the non-RA comparator cohorts were required to use a disease-specific drug,” they wrote.

“While systemic inflammation in RA is thought to increase the risk of [cardiovascular disease] and cardiovascular risk factors such as DM, our findings suggest having RA itself does not confer an increased risk of DM. Future study should determine whether untreated RA or undertreated RA is associated with a greater risk of developing DM,” the researchers concluded.

The study was supported by a research grant from Bristol-Myers Squibb, which “played no role in the study design, data analysis or interpretation of data or presentation of results,” the researchers said. The company was “given the opportunity to make nonbinding comments on a draft of the manuscript, but the authors retained the right of publication and to determine the final wording.” One author reported receiving research grants from Brigham and Women’s Hospital from Pfizer, AbbVie, Bristol-Myers Squibb, and Roche for unrelated topics.

[email protected]

SOURCE: Jin Y et al. Arthritis Care Res. 2020 Aug 4. doi: 10.1002/acr.24343.

Patients with RA were at lower risk for developing incident type 2 diabetes mellitus (T2DM) in comparison with patients with hypertension, psoriatic arthritis (PsA), or osteoarthritis, as well as the general population without RA in a retrospective cohort study of a large, nationwide, commercial health insurance claims database.

This result goes against what the study researchers from the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, initially hypothesized: The “risk of incident T2DM in RA patients would be similar to or less than PsA and [hypertension] patients, but higher, compared to general non-RA and OA patients.”

Prior epidemiologic studies of the relationship between RA and incident diabetes have yielded inconclusive results suggesting a small increase or no increase in risk of T2DM in patients with RA, possibly because of differences in the risk of T2DM in comparison groups used by previous studies to calculate relative risk, first author Yinzhu Jin and colleagues noted in their report published in Arthritis Care & Research.

After mining a nationwide U.S. commercial health insurance claims database, the Optum Clinformatics Data Mart, for claims data from Jan. 1, 2005, to Dec. 31, 2017, the researchers matched a total of 108,568 patients in RA, general population non-RA, hypertension, and OA cohorts based on age, sex, and index date (the date of disease-specific medication dispensing). Overall, 77% of those patients were female and had a mean age of nearly 56 years, whereas 48% of patients with PsA were female and their mean age was nearly 49 years. (PsA patients were not matched because of smaller numbers.)

During a median follow-up period of 1.4-1.8 years across the comparison groups, the crude incidence rate for diabetes per 1,000 person-years in the cohorts was 7.0 for RA, 7.4 for general non-RA, 12.3 for hypertension, 7.8 for OA, and 9.9 for PsA. The hazard ratios and 95% confidence interval for risk of diabetes in patients with RA – after adjustment for more than 40 baseline covariates that included demographics, comorbidities, medication use, and health care utilization – was 0.72 (0.66-0.78) in comparison withh the general non-RA cohort, 0.65 (0.60-0.71) in comparison with the hypertension cohort, 0.75 (0.69-0.81) in comparison with the OA cohort, and 0.76 (0.67-0.86) in comparison with the PsA cohort. These values correspond to RA patients having a 24%-35% lower risk of incident diabetes versus the comparison groups, the researchers noted. They observed results consistent to these when they conducted a sensitivity analysis using a 1-year lag time from the index date before starting follow-up.

The lower risk of T2DM in patients with RA in comparison with patients in the non-RA cohort “may be, in part, due to the effect of biologic DMARD [disease-modifying antirheumatic drug] treatment in RA which likely modifies the risk of DM,” the researchers wrote. “Both the increasing use of biologic DMARDs for RA in the U.S. over the last decade and our cohort entry criteria for the RA cohort (i.e., at least one dispensing of a DMARD) may explain the finding of the lower risk of DM in RA.”

The results found with the other three cohorts did not surprise the researchers. The reduced risk of diabetes among RA patients versus those with OA jibes with “higher rates of obesity and other comorbidities in patients with OA” as well as findings from a recent study that found a higher incidence rate of diabetes in OA, compared with RA. Ms. Jin and colleagues also acknowledged it is well known that “hypertension and PsA are associated with metabolic dysregulation and increase the risk of diabetes.”

The researchers defined patients with RA as having at least twoinpatient or outpatient ICD-9 or ICD-10 diagnosis codes of RA, separated by 7-365 days and having at least one dispensing for DMARDs within 1 year from the first RA diagnosis date, and defined the primary outcome of incident T2DM as at least one inpatient or outpatient diagnosis of T2DM plus at least one dispensing of an antidiabetic drug. They set the general non-RA cohort by selecting patients with any inpatient or outpatient diagnosis codes and a dispensing of any medications, and the hypertension, PsA, and OA comparator groups as having at least two inpatient or outpatient disease-specific ICD-9/ICD-10 codes separated by 7-365 days and at least one dispensing of disease-specific medication within 1 year from the first diagnosis date. They excluded patients with RA, PsA, or psoriasis diagnosis or disease-specific medication dispensing any time prior to or on the index date (the date of disease-specific medication dispensing).

The researchers recognized that the conclusions that can be drawn from the study are limited by the “potential misclassification of cohorts and covariates” because they “mainly used diagnosis codes and pharmacy dispensing records in claims data,” and some “important covariates such as baseline obesity are likely underreported and not adequately captured in claims data.” The level of covariate misclassification also may have been different across the study cohorts on “unmeasured covariates such as body mass index, diet, and physical activity, as well as disease specific measures,” thus introducing residual confounding. They also could not “examine potential difference in the risk of T2DM in untreated or undertreated RA patients” because “RA and all the non-RA comparator cohorts were required to use a disease-specific drug,” they wrote.

“While systemic inflammation in RA is thought to increase the risk of [cardiovascular disease] and cardiovascular risk factors such as DM, our findings suggest having RA itself does not confer an increased risk of DM. Future study should determine whether untreated RA or undertreated RA is associated with a greater risk of developing DM,” the researchers concluded.

The study was supported by a research grant from Bristol-Myers Squibb, which “played no role in the study design, data analysis or interpretation of data or presentation of results,” the researchers said. The company was “given the opportunity to make nonbinding comments on a draft of the manuscript, but the authors retained the right of publication and to determine the final wording.” One author reported receiving research grants from Brigham and Women’s Hospital from Pfizer, AbbVie, Bristol-Myers Squibb, and Roche for unrelated topics.

[email protected]

SOURCE: Jin Y et al. Arthritis Care Res. 2020 Aug 4. doi: 10.1002/acr.24343.

Bilateral lower extremity edema is a common condition with a broad differential diagnosis. New, severe peripheral edema implies a more nefarious underlying etiology than chronic venous insufficiency and should prompt a thorough evaluation for underlying conditions, such as congestive heart failure (CHF), cirrhosis, nephrotic syndrome, hypoalbuminemia, or lymphatic or venous obstruction. We present a case of a patient with sudden onset new bilateral lower extremity edema due to a rare adverse drug reaction (ADR) from valproate.

Case Presentation

A 63-year-old male with a history of seizures, bipolar disorder type I, and memory impairment due to traumatic brain injury (TBI) from a gunshot wound 24 years prior presented to the emergency department for witnessed seizure activity in the community. The patient had been incarcerated for the past 20 years, throughout which he had been taking the antiepileptic drugs (AEDs) phenytoin and divalproex and did not have any seizure activity. No records prior to his incarceration were available for review.

The patient recently had been released from prison and was nonadherent with his AEDs, leading to a witnessed seizure. This episode was described as preceded by an electric sensation, followed by rhythmic shaking of the right upper extremity without loss of consciousness. His regimen prior to admission included divalproex 1,000 mg daily and phenytoin 200 mg daily. His only other medication was folic acid.

Neurology was consulted on admission. An awake and asleep 4-hour electroencephalogram showed intermittent focal slowing of the right frontocentral region and frequent epileptiform discharges in the right prefrontal region during sleep, corresponding to areas of chronic right anterior frontal and temporal encephalomalacia seen on brain imaging. His seizures were thought likely to be secondary to prior head trauma. While the described seizure activity involving the right upper extremity was not consistent with the location of his prior TBI, neurology considered that he might have simple partial seizures with multiple foci or that his seizure event prior to admission was not accurately described. The neurology consult recommended switching from phenytoin 200 mg daily to lacosamide 100 mg twice daily on admission. His prior dose of divalproex 1,000 mg daily also was resumed for its antiepileptic effect and the added benefit of mood stabilization, as the patient reported elevated mood and decreased need for sleep on admission.

Eight days after changing his AED regimen, the patient was found to have new onset bilateral grade 1+ pitting edema to the level of his shins. He had no history of dyspnea, orthopnea, paroxysmal nocturnal dyspnea, dysuria, or changes in his urination. Although medical records from his incarceration were not available for review, the patient reported that he had never had peripheral edema.

On physical examination, the patient had no periorbital edema, jugular venous pressure of 8 cm H₂O, negative hepatojugular reflex, unremarkable cardiac and lung examination, and grade 2+ posterior tibial and dorsalis pedis pulses bilaterally. He underwent extensive laboratory evaluation for potential underlying causes, including nephrotic syndrome, cirrhosis, hypothyroidism, and CHF (Table). Valproate levels were initially subtherapeutic on admission (< 10 µg/mL, reference range 50-125 µg/mL) then rose to within therapeutic range (54 µg/mL-80 µg/mL throughout admission) after neurology recommended increasing the dose from 1,000 mg daily to 1,500 mg daily. His measured valproate levels were never supratherapeutic.

An electrocardiogram showed normal sinus rhythm unchanged from admission. Transthoracic echocardiogram showed normal left ventricular (LV) size and estimated LV ejection fraction of 55 to 60%. Abdominal ultrasound showed no evidence of cirrhosis and normal portal vein flow. Ultrasound of the lower extremities showed no deep venous thrombosis or valvular insufficiency. The patient was prescribed compression stockings. However, due to memory impairment, he was relatively nonadherent, and his lower extremity edema worsened to grade 3+ over several days. Due to the progressive swelling with no identified cause, a computed tomographic venogram of the abdomen and pelvis was performed to determine whether an inferior vena cava (IVC) thrombus was present. This study was unremarkable and did not show any external IVC compression.

After extensive evaluation did not reveal any other cause, the temporal course of events suggested an association between the patient’s peripheral edema and resumption of divalproex. His swelling remained stable. Discontinuation of divalproex was considered, but the patient’s mood remained euthymic, and he had no further seizure activity while on this medication, so the benefit of continuation was felt to outweigh any risks of switching to another agent.

Discussion

Valproate and its related forms, such as divalproex, often are used in the treatment of generalized or partial seizures, psychiatric disorders, and the prophylaxis of migraine headaches. Common ADRs include gastrointestinal symptoms, sedation, and dose-related thrombocytopenia, among many others. Rare ADRs include fulminant hepatitis, pancreatitis, hyperammonemia, and peripheral edema.¹ There have been case reports of valproate-induced peripheral edema, which seems to be an idiosyncratic ADR that occurs after long-term administration of the medication.^2,3 Early studies reported valproate-related edema in the context of valproate-induced hepatic injury.⁴ However, in more recent case reports, valproate-related edema has been found in patients without hepatotoxicity or supratherapeutic drug levels.^1,2

The exact mechanism by which valproate causes peripheral edema is unknown. It has been reported that medications affecting the γ-aminobutyric acid (GABA) system such as benzodiazepines, for example, can cause this rare ADR.⁵ Unlike benzodiazepines, valproate has an indirect effect on the GABA system, through increasing availability of GABA.⁶ GABA receptors have been identified on peripheral tissues, suggesting that GABAergic medications also may have an effect on regional vascular resistance.⁷ This mechanism was proposed by prior case reports but has yet to be proven in studies.²

In this case, initiation of lacosamide temporally coinciding with development of the patient’s edema leads one to question whether lacosamide may have caused this ADR. Other medications commonly used in seizure management (such as benzodiazepines and gabapentin) have been reported to cause new onset peripheral edema.^5,8 To date, however, there are no reported cases of peripheral edema due to lacosamide. While there are known interactions between various AEDs that may impact drug levels of valproate, there are no reported drug-drug interactions between lacosamide and valproate.⁹

Conclusions

Our case adds to the small but growing body of literature that suggests peripheral edema is a rare but clinically significant ADR of valproate. With its broad differential diagnosis, new onset peripheral edema is a concern that often warrants an extensive evaluation for underlying causes. Clinicians should be aware of this ADR as use of valproate becomes increasingly common so that an extensive workup is not always performed on patients with peripheral edema.

Bilateral lower extremity edema is a common condition with a broad differential diagnosis. New, severe peripheral edema implies a more nefarious underlying etiology than chronic venous insufficiency and should prompt a thorough evaluation for underlying conditions, such as congestive heart failure (CHF), cirrhosis, nephrotic syndrome, hypoalbuminemia, or lymphatic or venous obstruction. We present a case of a patient with sudden onset new bilateral lower extremity edema due to a rare adverse drug reaction (ADR) from valproate.

Case Presentation

A 63-year-old male with a history of seizures, bipolar disorder type I, and memory impairment due to traumatic brain injury (TBI) from a gunshot wound 24 years prior presented to the emergency department for witnessed seizure activity in the community. The patient had been incarcerated for the past 20 years, throughout which he had been taking the antiepileptic drugs (AEDs) phenytoin and divalproex and did not have any seizure activity. No records prior to his incarceration were available for review.

The patient recently had been released from prison and was nonadherent with his AEDs, leading to a witnessed seizure. This episode was described as preceded by an electric sensation, followed by rhythmic shaking of the right upper extremity without loss of consciousness. His regimen prior to admission included divalproex 1,000 mg daily and phenytoin 200 mg daily. His only other medication was folic acid.

Neurology was consulted on admission. An awake and asleep 4-hour electroencephalogram showed intermittent focal slowing of the right frontocentral region and frequent epileptiform discharges in the right prefrontal region during sleep, corresponding to areas of chronic right anterior frontal and temporal encephalomalacia seen on brain imaging. His seizures were thought likely to be secondary to prior head trauma. While the described seizure activity involving the right upper extremity was not consistent with the location of his prior TBI, neurology considered that he might have simple partial seizures with multiple foci or that his seizure event prior to admission was not accurately described. The neurology consult recommended switching from phenytoin 200 mg daily to lacosamide 100 mg twice daily on admission. His prior dose of divalproex 1,000 mg daily also was resumed for its antiepileptic effect and the added benefit of mood stabilization, as the patient reported elevated mood and decreased need for sleep on admission.

Eight days after changing his AED regimen, the patient was found to have new onset bilateral grade 1+ pitting edema to the level of his shins. He had no history of dyspnea, orthopnea, paroxysmal nocturnal dyspnea, dysuria, or changes in his urination. Although medical records from his incarceration were not available for review, the patient reported that he had never had peripheral edema.

On physical examination, the patient had no periorbital edema, jugular venous pressure of 8 cm H₂O, negative hepatojugular reflex, unremarkable cardiac and lung examination, and grade 2+ posterior tibial and dorsalis pedis pulses bilaterally. He underwent extensive laboratory evaluation for potential underlying causes, including nephrotic syndrome, cirrhosis, hypothyroidism, and CHF (Table). Valproate levels were initially subtherapeutic on admission (< 10 µg/mL, reference range 50-125 µg/mL) then rose to within therapeutic range (54 µg/mL-80 µg/mL throughout admission) after neurology recommended increasing the dose from 1,000 mg daily to 1,500 mg daily. His measured valproate levels were never supratherapeutic.

An electrocardiogram showed normal sinus rhythm unchanged from admission. Transthoracic echocardiogram showed normal left ventricular (LV) size and estimated LV ejection fraction of 55 to 60%. Abdominal ultrasound showed no evidence of cirrhosis and normal portal vein flow. Ultrasound of the lower extremities showed no deep venous thrombosis or valvular insufficiency. The patient was prescribed compression stockings. However, due to memory impairment, he was relatively nonadherent, and his lower extremity edema worsened to grade 3+ over several days. Due to the progressive swelling with no identified cause, a computed tomographic venogram of the abdomen and pelvis was performed to determine whether an inferior vena cava (IVC) thrombus was present. This study was unremarkable and did not show any external IVC compression.

After extensive evaluation did not reveal any other cause, the temporal course of events suggested an association between the patient’s peripheral edema and resumption of divalproex. His swelling remained stable. Discontinuation of divalproex was considered, but the patient’s mood remained euthymic, and he had no further seizure activity while on this medication, so the benefit of continuation was felt to outweigh any risks of switching to another agent.

Discussion

Valproate and its related forms, such as divalproex, often are used in the treatment of generalized or partial seizures, psychiatric disorders, and the prophylaxis of migraine headaches. Common ADRs include gastrointestinal symptoms, sedation, and dose-related thrombocytopenia, among many others. Rare ADRs include fulminant hepatitis, pancreatitis, hyperammonemia, and peripheral edema.¹ There have been case reports of valproate-induced peripheral edema, which seems to be an idiosyncratic ADR that occurs after long-term administration of the medication.^2,3 Early studies reported valproate-related edema in the context of valproate-induced hepatic injury.⁴ However, in more recent case reports, valproate-related edema has been found in patients without hepatotoxicity or supratherapeutic drug levels.^1,2

The exact mechanism by which valproate causes peripheral edema is unknown. It has been reported that medications affecting the γ-aminobutyric acid (GABA) system such as benzodiazepines, for example, can cause this rare ADR.⁵ Unlike benzodiazepines, valproate has an indirect effect on the GABA system, through increasing availability of GABA.⁶ GABA receptors have been identified on peripheral tissues, suggesting that GABAergic medications also may have an effect on regional vascular resistance.⁷ This mechanism was proposed by prior case reports but has yet to be proven in studies.²

In this case, initiation of lacosamide temporally coinciding with development of the patient’s edema leads one to question whether lacosamide may have caused this ADR. Other medications commonly used in seizure management (such as benzodiazepines and gabapentin) have been reported to cause new onset peripheral edema.^5,8 To date, however, there are no reported cases of peripheral edema due to lacosamide. While there are known interactions between various AEDs that may impact drug levels of valproate, there are no reported drug-drug interactions between lacosamide and valproate.⁹

Conclusions

Our case adds to the small but growing body of literature that suggests peripheral edema is a rare but clinically significant ADR of valproate. With its broad differential diagnosis, new onset peripheral edema is a concern that often warrants an extensive evaluation for underlying causes. Clinicians should be aware of this ADR as use of valproate becomes increasingly common so that an extensive workup is not always performed on patients with peripheral edema.

Bilateral lower extremity edema is a common condition with a broad differential diagnosis. New, severe peripheral edema implies a more nefarious underlying etiology than chronic venous insufficiency and should prompt a thorough evaluation for underlying conditions, such as congestive heart failure (CHF), cirrhosis, nephrotic syndrome, hypoalbuminemia, or lymphatic or venous obstruction. We present a case of a patient with sudden onset new bilateral lower extremity edema due to a rare adverse drug reaction (ADR) from valproate.

Case Presentation

A 63-year-old male with a history of seizures, bipolar disorder type I, and memory impairment due to traumatic brain injury (TBI) from a gunshot wound 24 years prior presented to the emergency department for witnessed seizure activity in the community. The patient had been incarcerated for the past 20 years, throughout which he had been taking the antiepileptic drugs (AEDs) phenytoin and divalproex and did not have any seizure activity. No records prior to his incarceration were available for review.

The patient recently had been released from prison and was nonadherent with his AEDs, leading to a witnessed seizure. This episode was described as preceded by an electric sensation, followed by rhythmic shaking of the right upper extremity without loss of consciousness. His regimen prior to admission included divalproex 1,000 mg daily and phenytoin 200 mg daily. His only other medication was folic acid.

Neurology was consulted on admission. An awake and asleep 4-hour electroencephalogram showed intermittent focal slowing of the right frontocentral region and frequent epileptiform discharges in the right prefrontal region during sleep, corresponding to areas of chronic right anterior frontal and temporal encephalomalacia seen on brain imaging. His seizures were thought likely to be secondary to prior head trauma. While the described seizure activity involving the right upper extremity was not consistent with the location of his prior TBI, neurology considered that he might have simple partial seizures with multiple foci or that his seizure event prior to admission was not accurately described. The neurology consult recommended switching from phenytoin 200 mg daily to lacosamide 100 mg twice daily on admission. His prior dose of divalproex 1,000 mg daily also was resumed for its antiepileptic effect and the added benefit of mood stabilization, as the patient reported elevated mood and decreased need for sleep on admission.

Eight days after changing his AED regimen, the patient was found to have new onset bilateral grade 1+ pitting edema to the level of his shins. He had no history of dyspnea, orthopnea, paroxysmal nocturnal dyspnea, dysuria, or changes in his urination. Although medical records from his incarceration were not available for review, the patient reported that he had never had peripheral edema.

On physical examination, the patient had no periorbital edema, jugular venous pressure of 8 cm H₂O, negative hepatojugular reflex, unremarkable cardiac and lung examination, and grade 2+ posterior tibial and dorsalis pedis pulses bilaterally. He underwent extensive laboratory evaluation for potential underlying causes, including nephrotic syndrome, cirrhosis, hypothyroidism, and CHF (Table). Valproate levels were initially subtherapeutic on admission (< 10 µg/mL, reference range 50-125 µg/mL) then rose to within therapeutic range (54 µg/mL-80 µg/mL throughout admission) after neurology recommended increasing the dose from 1,000 mg daily to 1,500 mg daily. His measured valproate levels were never supratherapeutic.

An electrocardiogram showed normal sinus rhythm unchanged from admission. Transthoracic echocardiogram showed normal left ventricular (LV) size and estimated LV ejection fraction of 55 to 60%. Abdominal ultrasound showed no evidence of cirrhosis and normal portal vein flow. Ultrasound of the lower extremities showed no deep venous thrombosis or valvular insufficiency. The patient was prescribed compression stockings. However, due to memory impairment, he was relatively nonadherent, and his lower extremity edema worsened to grade 3+ over several days. Due to the progressive swelling with no identified cause, a computed tomographic venogram of the abdomen and pelvis was performed to determine whether an inferior vena cava (IVC) thrombus was present. This study was unremarkable and did not show any external IVC compression.

After extensive evaluation did not reveal any other cause, the temporal course of events suggested an association between the patient’s peripheral edema and resumption of divalproex. His swelling remained stable. Discontinuation of divalproex was considered, but the patient’s mood remained euthymic, and he had no further seizure activity while on this medication, so the benefit of continuation was felt to outweigh any risks of switching to another agent.

Discussion

Valproate and its related forms, such as divalproex, often are used in the treatment of generalized or partial seizures, psychiatric disorders, and the prophylaxis of migraine headaches. Common ADRs include gastrointestinal symptoms, sedation, and dose-related thrombocytopenia, among many others. Rare ADRs include fulminant hepatitis, pancreatitis, hyperammonemia, and peripheral edema.¹ There have been case reports of valproate-induced peripheral edema, which seems to be an idiosyncratic ADR that occurs after long-term administration of the medication.^2,3 Early studies reported valproate-related edema in the context of valproate-induced hepatic injury.⁴ However, in more recent case reports, valproate-related edema has been found in patients without hepatotoxicity or supratherapeutic drug levels.^1,2

The exact mechanism by which valproate causes peripheral edema is unknown. It has been reported that medications affecting the γ-aminobutyric acid (GABA) system such as benzodiazepines, for example, can cause this rare ADR.⁵ Unlike benzodiazepines, valproate has an indirect effect on the GABA system, through increasing availability of GABA.⁶ GABA receptors have been identified on peripheral tissues, suggesting that GABAergic medications also may have an effect on regional vascular resistance.⁷ This mechanism was proposed by prior case reports but has yet to be proven in studies.²

In this case, initiation of lacosamide temporally coinciding with development of the patient’s edema leads one to question whether lacosamide may have caused this ADR. Other medications commonly used in seizure management (such as benzodiazepines and gabapentin) have been reported to cause new onset peripheral edema.^5,8 To date, however, there are no reported cases of peripheral edema due to lacosamide. While there are known interactions between various AEDs that may impact drug levels of valproate, there are no reported drug-drug interactions between lacosamide and valproate.⁹

Conclusions

Our case adds to the small but growing body of literature that suggests peripheral edema is a rare but clinically significant ADR of valproate. With its broad differential diagnosis, new onset peripheral edema is a concern that often warrants an extensive evaluation for underlying causes. Clinicians should be aware of this ADR as use of valproate becomes increasingly common so that an extensive workup is not always performed on patients with peripheral edema.

Frailty is a highly prevalent syndrome in nursing homes, occurring in at least 50% of patients.¹ The frailty phenotype has been described by Fried and colleagues as impairment in ≥ 3 of 5 domains: unintentional weight loss, self-reported exhaustion, muscle weakness, slow gait speed, and low physical activity. By this definition, frailty is highly associated with poor quality of life and mortality.^2,3

In recent years, there has been evolving evidence of a relationship between frailty and chronic systemic inflammation.^4-6 Some degree of chronic inflammation is likely inherent to the aging process and increases the risk of frailty (so-called inflammaging) but is seen to a greater degree in many pathologic conditions in nursing homes, including cancer, organ failure, and chronic infection.^4,6-8

Dysphagia also is highly prevalent in nursing homes, affecting up to 60% of patients and is a strong predictor of hospital utilization and of mortality.^9,10 Overt aspiration pneumonitis and pneumonia are perhaps the best studied sequelae, but chronic occult microaspiration also is prevalent in this population.¹¹ Just as normal systemic inflammatory changes in aging may increase vulnerability to frailty with additional illness burden, normal aging changes in swallowing function may increase vulnerability to dysphagia and to microaspiration with additional illness burden.^12,13 In older adults, important risk factors for microaspiration include not only overt dysphagia, dementia, and other neurologic illnesses, but also general debility, weakness, and immobility.¹⁴

Matsuse and colleagues have described diffuse aspiration bronchiolitis (DAB) in patients with chronic microaspiration.¹⁴ DAB often goes undiagnosed.^14-16 As in frailty, weight loss and chronic anemia may be seen, and many of these patients are bedridden.^14,17 Episodes of macroaspiration and overt lobar pneumonia also may occur.¹⁴ Lung biopsy or autopsy reveals chronic bronchiolar inflammation and sometimes pulmonary fibrosis, but to date there have been no reports suggesting chronic systemic inflammation or elevated proinflammatory cytokines.^14,15,17 We present 3 patients with progressive weight loss, functional decline, and frailty in whom chronic microaspiration likely played a significant role.

Case 1 Presentation

A 68-year-old man with a 6-year history of rapidly progressive Parkinson disease was admitted to the Haley’s Cove Community Living Center (CLC) on the James A. Haley Veterans’ Hospital campus in Tampa, Florida for long-term care. The patient’s medical history also was significant for bipolar illness and for small cell carcinoma of the lung in sustained remission.

Medications included levodopa/carbidopa 50 mg/200 mg 4 times daily, entacapone 200 mg 4 times daily, lithium carbonate 600 mg every night at bedtime, lamotrigine 150 mg daily, quetiapine 200 mg every night at bedtime, pravastatin 40 mg every night at bedtime, omeprazole 20 mg daily, tamsulosin 0.4 mg every night at bedtime, and aspirin 81 mg daily. He initially did well, but after 6 months the nursing staff began to notice the patient coughing during and after meals. Speech pathology evaluation revealed moderate oropharyngeal dysphagia, and his diet was downgraded to nectar-thickened liquids.

Over the subsequent 10 months, he became progressively weaker in physical therapy and more inactive, with about a 20-lb weight loss and mild hypoalbuminemia of 3.0 gm/dL. He had developed 3 episodes of aspiration pneumonia during this period; a repeat swallow evaluation after the last episode revealed worsened dysphagia, and his physician suggested nil per os (NPO) status and an alternative feeding route. His guardian declined placement of a percutaneous endoscopic gastrostomy (PEG) tube, he was transferred to the inpatient hospice unit, and died 2 weeks later. An autopsy was declined.

Case 2 Presentation

A 66-year-old man with a medical history of multiple traumatic brain injuries (TBIs) was admitted to the CLC for long-term care. Sequelae of the TBIs included moderate dementia, spastic paraparesis with multiple pressure injuries, a well-controlled seizure disorder, and severe oropharyngeal dysphagia with NPO status and a percutaneous endoscopic gastrostomy (PEG) tube. His medical history included TBIs and hepatitis C virus infection; medications included levetiracetam 1,000 mg twice daily, lamotrigine 25 mg twice daily, and cholecalciferol 2,000 U daily. He had multiple stage III pressure injuries and an ischial stage IV injury at the time of admission.

His 11-month stay in the CLC was characterized by progressively worsening weakness and inactivity, with a 25-lb weight loss in spite of adequate tube feeding. Serum albumin remained in the 2.0 to 2.5 gm/dL range, hemoglobin in the 7 to 9 gm/dL range without any obvious source of anemia. Most of the pressure injuries worsened during his stay in spite of aggressive wound care, and he developed a second stage IV sacral wound. A single C-reactive protein (CRP) level 2 months prior to his death was markedly elevated at 19.5 mg/dL. In spite of maintaining NPO status, he developed 3 episodes of aspiration pneumonia, all of which responded well to treatment. Ultimately, he was found pulseless and apneic and resuscitation was unsuccessful. An autopsy revealed purulent material in the small airways.

Case 3 Presentation

A 65-year-old man with a long history of paranoid schizophrenia and severe gastroesophageal reflux disease had resided in the CLC for about 10 years. Medications included risperidone microspheres 37.5 mg every 2 weeks, valproic acid 500 mg 3 times daily and 1,000 mg every night at bedtime, lansoprazole 30 mg twice daily, ranitidine 150 mg every night at bedtime, sucralfate 1,000 mg 3 times daily, simvastatin 20 mg every night at bedtime, and tamsulosin 0.4 mg every night at bedtime. He had done well for many years but developed some drooling and a modest resting tremor (but no other signs of pseudoparkinsonism) about 8 years after admission.

There had been no changes to his risperidone dosage. He also lost about 20 lb over a period of 1 year and became increasingly weak and dependent in gait, serum albumin dropped as low as 1.6 gm/dL, hemoglobin dropped to the 7 to 8 gm/dL range (without any other obvious source of anemia), and he developed a gradually worsening right-sided pleural effusion. CRP was chronically elevated at this point, in the 6 to 15 mg/dL range and as high as 17.2 mg/dL. Ultimately, he developed 3 episodes of aspiration pneumonia over a period of 2 months. Swallowing evaluation at that time revealed severe oropharyngeal dysphagia and a PEG tube was placed. Due to concerns for possible antipsychotic-induced dysphagia, risperidone was discontinued, and quetiapine 400 mg a day was substituted. He did well over the subsequent year with no further pneumonia and advancement back to a regular diet. He regained all of the lost weight and began independent ambulation. Albumin improved to the 3 gm/dL range, hemoglobin to the 12 to 13 gm/dL range, and CRP had decreased to 0.7 mg/dL. The pleural effusion (believed to have been a parapneumonic effusion) had resolved.

Discussion

All 3 patients met the Fried criteria for frailty, although there were several confounding issues.² All 3 patients lost between 20 and 25 lb; all had clearly become weaker according to nursing and rehabilitation staff (although none were formally assessed for grip strength); and all had clear declines in their activity level. Patient 3 had a clear decrement in gait speed, but patient 1 had severe gait impairment due to Parkinson disease (although his gait in therapy had clearly worsened). Patient 2 was paraparetic and unable to ambulate. There also was evidence of limited biomarkers of systemic inflammation; all 3 patients’ albumin had decreased, and patients 2 and 3 had significant decrease in hemoglobin; but these commonplace clinical biomarkers are obviously multifactorially determined. We have limited data on our patients’ CRP levels; serial levels would have been more specific for systemic inflammation but were infrequently performed on the patients.

Multimorbidity and medical complexity are more the rule than the exception in frail geriatric patients,and it is difficult to separate the role of microaspiration from other confounding conditions that might have contributed to these patients’ evolving systemic inflammation and frailty.¹⁸ It might be argued that the decline for patient 1 was related to the underlying Parkinson disease (a progressive neurologic illness in which systemic inflammation has been reported), or that the decline of patient 2 was related to the worsening pressure injuries rather than to covert microaspiration.¹⁹ However, the TBIs for patient 2 and the schizophrenia for patient 3 would not be expected to be associated with frailty or with systemic inflammation. Furthermore, the frailty symptoms of patient 3 and inflammatory biomarkers improved after the risperidone, which was likely responsible for his microaspiration, was discontinued. All 3 patients were at risk for oropharyngeal dysphagia (antipsychotic medication is clearly associated with dysphagia²⁰); patient 2 demonstrated pathologic evidence of DAB at autopsy.

There is evolving evidence that chronic systemic inflammation and immune activation are key mechanisms in the pathogenesis of frailty.^4-6 It is known that elevated serum levels of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and CRP are directly associated with frailty and are inversely associated with levels of albumin, hemoglobin, insulin-like growth factor-1, and several micronutrients in frail individuals.^4-7,21,22 Chronic inflammation contributes to the pathophysiology of frailty through detrimental effects on a broad range of systems, including the musculoskeletal, endocrine, and hematopoietic systems and through nutritional dysregulation.^2,4,23 These changes may lead to further deleterious effects, creating a downward spiral of worsening frailty. For example, it seems likely that our patients’ progressive weakness further compromised airway protection, creating a vicious cycle of worsening microaspiration and chronic inflammation.

Conclusions

To date, the role of chronic microaspiration and DAB in chronic systemic inflammation or in frailty has not been explored. Given the prevalence of microaspiration in nursing home residents and the devastating consequences of frailty, though, this seems to be a crucial area of investigation. It is equally crucial for long-term care staff, both providers and nursing staff, to have a heightened awareness of covert microaspiration and a low threshold for referral to speech pathology for further investigation. Staff also should be aware of the utility of the Fried criteria to improve identification of frailty in general. It is probable that covert microaspiration will prove to be an important part of the differential diagnosis of frailty.

Frailty is a highly prevalent syndrome in nursing homes, occurring in at least 50% of patients.¹ The frailty phenotype has been described by Fried and colleagues as impairment in ≥ 3 of 5 domains: unintentional weight loss, self-reported exhaustion, muscle weakness, slow gait speed, and low physical activity. By this definition, frailty is highly associated with poor quality of life and mortality.^2,3

In recent years, there has been evolving evidence of a relationship between frailty and chronic systemic inflammation.^4-6 Some degree of chronic inflammation is likely inherent to the aging process and increases the risk of frailty (so-called inflammaging) but is seen to a greater degree in many pathologic conditions in nursing homes, including cancer, organ failure, and chronic infection.^4,6-8

Dysphagia also is highly prevalent in nursing homes, affecting up to 60% of patients and is a strong predictor of hospital utilization and of mortality.^9,10 Overt aspiration pneumonitis and pneumonia are perhaps the best studied sequelae, but chronic occult microaspiration also is prevalent in this population.¹¹ Just as normal systemic inflammatory changes in aging may increase vulnerability to frailty with additional illness burden, normal aging changes in swallowing function may increase vulnerability to dysphagia and to microaspiration with additional illness burden.^12,13 In older adults, important risk factors for microaspiration include not only overt dysphagia, dementia, and other neurologic illnesses, but also general debility, weakness, and immobility.¹⁴

Matsuse and colleagues have described diffuse aspiration bronchiolitis (DAB) in patients with chronic microaspiration.¹⁴ DAB often goes undiagnosed.^14-16 As in frailty, weight loss and chronic anemia may be seen, and many of these patients are bedridden.^14,17 Episodes of macroaspiration and overt lobar pneumonia also may occur.¹⁴ Lung biopsy or autopsy reveals chronic bronchiolar inflammation and sometimes pulmonary fibrosis, but to date there have been no reports suggesting chronic systemic inflammation or elevated proinflammatory cytokines.^14,15,17 We present 3 patients with progressive weight loss, functional decline, and frailty in whom chronic microaspiration likely played a significant role.

Case 1 Presentation

A 68-year-old man with a 6-year history of rapidly progressive Parkinson disease was admitted to the Haley’s Cove Community Living Center (CLC) on the James A. Haley Veterans’ Hospital campus in Tampa, Florida for long-term care. The patient’s medical history also was significant for bipolar illness and for small cell carcinoma of the lung in sustained remission.

Medications included levodopa/carbidopa 50 mg/200 mg 4 times daily, entacapone 200 mg 4 times daily, lithium carbonate 600 mg every night at bedtime, lamotrigine 150 mg daily, quetiapine 200 mg every night at bedtime, pravastatin 40 mg every night at bedtime, omeprazole 20 mg daily, tamsulosin 0.4 mg every night at bedtime, and aspirin 81 mg daily. He initially did well, but after 6 months the nursing staff began to notice the patient coughing during and after meals. Speech pathology evaluation revealed moderate oropharyngeal dysphagia, and his diet was downgraded to nectar-thickened liquids.

Over the subsequent 10 months, he became progressively weaker in physical therapy and more inactive, with about a 20-lb weight loss and mild hypoalbuminemia of 3.0 gm/dL. He had developed 3 episodes of aspiration pneumonia during this period; a repeat swallow evaluation after the last episode revealed worsened dysphagia, and his physician suggested nil per os (NPO) status and an alternative feeding route. His guardian declined placement of a percutaneous endoscopic gastrostomy (PEG) tube, he was transferred to the inpatient hospice unit, and died 2 weeks later. An autopsy was declined.

Case 2 Presentation

A 66-year-old man with a medical history of multiple traumatic brain injuries (TBIs) was admitted to the CLC for long-term care. Sequelae of the TBIs included moderate dementia, spastic paraparesis with multiple pressure injuries, a well-controlled seizure disorder, and severe oropharyngeal dysphagia with NPO status and a percutaneous endoscopic gastrostomy (PEG) tube. His medical history included TBIs and hepatitis C virus infection; medications included levetiracetam 1,000 mg twice daily, lamotrigine 25 mg twice daily, and cholecalciferol 2,000 U daily. He had multiple stage III pressure injuries and an ischial stage IV injury at the time of admission.

His 11-month stay in the CLC was characterized by progressively worsening weakness and inactivity, with a 25-lb weight loss in spite of adequate tube feeding. Serum albumin remained in the 2.0 to 2.5 gm/dL range, hemoglobin in the 7 to 9 gm/dL range without any obvious source of anemia. Most of the pressure injuries worsened during his stay in spite of aggressive wound care, and he developed a second stage IV sacral wound. A single C-reactive protein (CRP) level 2 months prior to his death was markedly elevated at 19.5 mg/dL. In spite of maintaining NPO status, he developed 3 episodes of aspiration pneumonia, all of which responded well to treatment. Ultimately, he was found pulseless and apneic and resuscitation was unsuccessful. An autopsy revealed purulent material in the small airways.

Case 3 Presentation

A 65-year-old man with a long history of paranoid schizophrenia and severe gastroesophageal reflux disease had resided in the CLC for about 10 years. Medications included risperidone microspheres 37.5 mg every 2 weeks, valproic acid 500 mg 3 times daily and 1,000 mg every night at bedtime, lansoprazole 30 mg twice daily, ranitidine 150 mg every night at bedtime, sucralfate 1,000 mg 3 times daily, simvastatin 20 mg every night at bedtime, and tamsulosin 0.4 mg every night at bedtime. He had done well for many years but developed some drooling and a modest resting tremor (but no other signs of pseudoparkinsonism) about 8 years after admission.

There had been no changes to his risperidone dosage. He also lost about 20 lb over a period of 1 year and became increasingly weak and dependent in gait, serum albumin dropped as low as 1.6 gm/dL, hemoglobin dropped to the 7 to 8 gm/dL range (without any other obvious source of anemia), and he developed a gradually worsening right-sided pleural effusion. CRP was chronically elevated at this point, in the 6 to 15 mg/dL range and as high as 17.2 mg/dL. Ultimately, he developed 3 episodes of aspiration pneumonia over a period of 2 months. Swallowing evaluation at that time revealed severe oropharyngeal dysphagia and a PEG tube was placed. Due to concerns for possible antipsychotic-induced dysphagia, risperidone was discontinued, and quetiapine 400 mg a day was substituted. He did well over the subsequent year with no further pneumonia and advancement back to a regular diet. He regained all of the lost weight and began independent ambulation. Albumin improved to the 3 gm/dL range, hemoglobin to the 12 to 13 gm/dL range, and CRP had decreased to 0.7 mg/dL. The pleural effusion (believed to have been a parapneumonic effusion) had resolved.

Discussion

All 3 patients met the Fried criteria for frailty, although there were several confounding issues.² All 3 patients lost between 20 and 25 lb; all had clearly become weaker according to nursing and rehabilitation staff (although none were formally assessed for grip strength); and all had clear declines in their activity level. Patient 3 had a clear decrement in gait speed, but patient 1 had severe gait impairment due to Parkinson disease (although his gait in therapy had clearly worsened). Patient 2 was paraparetic and unable to ambulate. There also was evidence of limited biomarkers of systemic inflammation; all 3 patients’ albumin had decreased, and patients 2 and 3 had significant decrease in hemoglobin; but these commonplace clinical biomarkers are obviously multifactorially determined. We have limited data on our patients’ CRP levels; serial levels would have been more specific for systemic inflammation but were infrequently performed on the patients.

Multimorbidity and medical complexity are more the rule than the exception in frail geriatric patients,and it is difficult to separate the role of microaspiration from other confounding conditions that might have contributed to these patients’ evolving systemic inflammation and frailty.¹⁸ It might be argued that the decline for patient 1 was related to the underlying Parkinson disease (a progressive neurologic illness in which systemic inflammation has been reported), or that the decline of patient 2 was related to the worsening pressure injuries rather than to covert microaspiration.¹⁹ However, the TBIs for patient 2 and the schizophrenia for patient 3 would not be expected to be associated with frailty or with systemic inflammation. Furthermore, the frailty symptoms of patient 3 and inflammatory biomarkers improved after the risperidone, which was likely responsible for his microaspiration, was discontinued. All 3 patients were at risk for oropharyngeal dysphagia (antipsychotic medication is clearly associated with dysphagia²⁰); patient 2 demonstrated pathologic evidence of DAB at autopsy.

There is evolving evidence that chronic systemic inflammation and immune activation are key mechanisms in the pathogenesis of frailty.^4-6 It is known that elevated serum levels of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and CRP are directly associated with frailty and are inversely associated with levels of albumin, hemoglobin, insulin-like growth factor-1, and several micronutrients in frail individuals.^4-7,21,22 Chronic inflammation contributes to the pathophysiology of frailty through detrimental effects on a broad range of systems, including the musculoskeletal, endocrine, and hematopoietic systems and through nutritional dysregulation.^2,4,23 These changes may lead to further deleterious effects, creating a downward spiral of worsening frailty. For example, it seems likely that our patients’ progressive weakness further compromised airway protection, creating a vicious cycle of worsening microaspiration and chronic inflammation.

Conclusions

To date, the role of chronic microaspiration and DAB in chronic systemic inflammation or in frailty has not been explored. Given the prevalence of microaspiration in nursing home residents and the devastating consequences of frailty, though, this seems to be a crucial area of investigation. It is equally crucial for long-term care staff, both providers and nursing staff, to have a heightened awareness of covert microaspiration and a low threshold for referral to speech pathology for further investigation. Staff also should be aware of the utility of the Fried criteria to improve identification of frailty in general. It is probable that covert microaspiration will prove to be an important part of the differential diagnosis of frailty.

Frailty is a highly prevalent syndrome in nursing homes, occurring in at least 50% of patients.¹ The frailty phenotype has been described by Fried and colleagues as impairment in ≥ 3 of 5 domains: unintentional weight loss, self-reported exhaustion, muscle weakness, slow gait speed, and low physical activity. By this definition, frailty is highly associated with poor quality of life and mortality.^2,3

In recent years, there has been evolving evidence of a relationship between frailty and chronic systemic inflammation.^4-6 Some degree of chronic inflammation is likely inherent to the aging process and increases the risk of frailty (so-called inflammaging) but is seen to a greater degree in many pathologic conditions in nursing homes, including cancer, organ failure, and chronic infection.^4,6-8

Dysphagia also is highly prevalent in nursing homes, affecting up to 60% of patients and is a strong predictor of hospital utilization and of mortality.^9,10 Overt aspiration pneumonitis and pneumonia are perhaps the best studied sequelae, but chronic occult microaspiration also is prevalent in this population.¹¹ Just as normal systemic inflammatory changes in aging may increase vulnerability to frailty with additional illness burden, normal aging changes in swallowing function may increase vulnerability to dysphagia and to microaspiration with additional illness burden.^12,13 In older adults, important risk factors for microaspiration include not only overt dysphagia, dementia, and other neurologic illnesses, but also general debility, weakness, and immobility.¹⁴

Matsuse and colleagues have described diffuse aspiration bronchiolitis (DAB) in patients with chronic microaspiration.¹⁴ DAB often goes undiagnosed.^14-16 As in frailty, weight loss and chronic anemia may be seen, and many of these patients are bedridden.^14,17 Episodes of macroaspiration and overt lobar pneumonia also may occur.¹⁴ Lung biopsy or autopsy reveals chronic bronchiolar inflammation and sometimes pulmonary fibrosis, but to date there have been no reports suggesting chronic systemic inflammation or elevated proinflammatory cytokines.^14,15,17 We present 3 patients with progressive weight loss, functional decline, and frailty in whom chronic microaspiration likely played a significant role.

Case 1 Presentation

A 68-year-old man with a 6-year history of rapidly progressive Parkinson disease was admitted to the Haley’s Cove Community Living Center (CLC) on the James A. Haley Veterans’ Hospital campus in Tampa, Florida for long-term care. The patient’s medical history also was significant for bipolar illness and for small cell carcinoma of the lung in sustained remission.

Medications included levodopa/carbidopa 50 mg/200 mg 4 times daily, entacapone 200 mg 4 times daily, lithium carbonate 600 mg every night at bedtime, lamotrigine 150 mg daily, quetiapine 200 mg every night at bedtime, pravastatin 40 mg every night at bedtime, omeprazole 20 mg daily, tamsulosin 0.4 mg every night at bedtime, and aspirin 81 mg daily. He initially did well, but after 6 months the nursing staff began to notice the patient coughing during and after meals. Speech pathology evaluation revealed moderate oropharyngeal dysphagia, and his diet was downgraded to nectar-thickened liquids.

Over the subsequent 10 months, he became progressively weaker in physical therapy and more inactive, with about a 20-lb weight loss and mild hypoalbuminemia of 3.0 gm/dL. He had developed 3 episodes of aspiration pneumonia during this period; a repeat swallow evaluation after the last episode revealed worsened dysphagia, and his physician suggested nil per os (NPO) status and an alternative feeding route. His guardian declined placement of a percutaneous endoscopic gastrostomy (PEG) tube, he was transferred to the inpatient hospice unit, and died 2 weeks later. An autopsy was declined.

Case 2 Presentation

A 66-year-old man with a medical history of multiple traumatic brain injuries (TBIs) was admitted to the CLC for long-term care. Sequelae of the TBIs included moderate dementia, spastic paraparesis with multiple pressure injuries, a well-controlled seizure disorder, and severe oropharyngeal dysphagia with NPO status and a percutaneous endoscopic gastrostomy (PEG) tube. His medical history included TBIs and hepatitis C virus infection; medications included levetiracetam 1,000 mg twice daily, lamotrigine 25 mg twice daily, and cholecalciferol 2,000 U daily. He had multiple stage III pressure injuries and an ischial stage IV injury at the time of admission.

His 11-month stay in the CLC was characterized by progressively worsening weakness and inactivity, with a 25-lb weight loss in spite of adequate tube feeding. Serum albumin remained in the 2.0 to 2.5 gm/dL range, hemoglobin in the 7 to 9 gm/dL range without any obvious source of anemia. Most of the pressure injuries worsened during his stay in spite of aggressive wound care, and he developed a second stage IV sacral wound. A single C-reactive protein (CRP) level 2 months prior to his death was markedly elevated at 19.5 mg/dL. In spite of maintaining NPO status, he developed 3 episodes of aspiration pneumonia, all of which responded well to treatment. Ultimately, he was found pulseless and apneic and resuscitation was unsuccessful. An autopsy revealed purulent material in the small airways.

Case 3 Presentation

A 65-year-old man with a long history of paranoid schizophrenia and severe gastroesophageal reflux disease had resided in the CLC for about 10 years. Medications included risperidone microspheres 37.5 mg every 2 weeks, valproic acid 500 mg 3 times daily and 1,000 mg every night at bedtime, lansoprazole 30 mg twice daily, ranitidine 150 mg every night at bedtime, sucralfate 1,000 mg 3 times daily, simvastatin 20 mg every night at bedtime, and tamsulosin 0.4 mg every night at bedtime. He had done well for many years but developed some drooling and a modest resting tremor (but no other signs of pseudoparkinsonism) about 8 years after admission.

There had been no changes to his risperidone dosage. He also lost about 20 lb over a period of 1 year and became increasingly weak and dependent in gait, serum albumin dropped as low as 1.6 gm/dL, hemoglobin dropped to the 7 to 8 gm/dL range (without any other obvious source of anemia), and he developed a gradually worsening right-sided pleural effusion. CRP was chronically elevated at this point, in the 6 to 15 mg/dL range and as high as 17.2 mg/dL. Ultimately, he developed 3 episodes of aspiration pneumonia over a period of 2 months. Swallowing evaluation at that time revealed severe oropharyngeal dysphagia and a PEG tube was placed. Due to concerns for possible antipsychotic-induced dysphagia, risperidone was discontinued, and quetiapine 400 mg a day was substituted. He did well over the subsequent year with no further pneumonia and advancement back to a regular diet. He regained all of the lost weight and began independent ambulation. Albumin improved to the 3 gm/dL range, hemoglobin to the 12 to 13 gm/dL range, and CRP had decreased to 0.7 mg/dL. The pleural effusion (believed to have been a parapneumonic effusion) had resolved.

Discussion

All 3 patients met the Fried criteria for frailty, although there were several confounding issues.² All 3 patients lost between 20 and 25 lb; all had clearly become weaker according to nursing and rehabilitation staff (although none were formally assessed for grip strength); and all had clear declines in their activity level. Patient 3 had a clear decrement in gait speed, but patient 1 had severe gait impairment due to Parkinson disease (although his gait in therapy had clearly worsened). Patient 2 was paraparetic and unable to ambulate. There also was evidence of limited biomarkers of systemic inflammation; all 3 patients’ albumin had decreased, and patients 2 and 3 had significant decrease in hemoglobin; but these commonplace clinical biomarkers are obviously multifactorially determined. We have limited data on our patients’ CRP levels; serial levels would have been more specific for systemic inflammation but were infrequently performed on the patients.

Multimorbidity and medical complexity are more the rule than the exception in frail geriatric patients,and it is difficult to separate the role of microaspiration from other confounding conditions that might have contributed to these patients’ evolving systemic inflammation and frailty.¹⁸ It might be argued that the decline for patient 1 was related to the underlying Parkinson disease (a progressive neurologic illness in which systemic inflammation has been reported), or that the decline of patient 2 was related to the worsening pressure injuries rather than to covert microaspiration.¹⁹ However, the TBIs for patient 2 and the schizophrenia for patient 3 would not be expected to be associated with frailty or with systemic inflammation. Furthermore, the frailty symptoms of patient 3 and inflammatory biomarkers improved after the risperidone, which was likely responsible for his microaspiration, was discontinued. All 3 patients were at risk for oropharyngeal dysphagia (antipsychotic medication is clearly associated with dysphagia²⁰); patient 2 demonstrated pathologic evidence of DAB at autopsy.

There is evolving evidence that chronic systemic inflammation and immune activation are key mechanisms in the pathogenesis of frailty.^4-6 It is known that elevated serum levels of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and CRP are directly associated with frailty and are inversely associated with levels of albumin, hemoglobin, insulin-like growth factor-1, and several micronutrients in frail individuals.^4-7,21,22 Chronic inflammation contributes to the pathophysiology of frailty through detrimental effects on a broad range of systems, including the musculoskeletal, endocrine, and hematopoietic systems and through nutritional dysregulation.^2,4,23 These changes may lead to further deleterious effects, creating a downward spiral of worsening frailty. For example, it seems likely that our patients’ progressive weakness further compromised airway protection, creating a vicious cycle of worsening microaspiration and chronic inflammation.

Conclusions

To date, the role of chronic microaspiration and DAB in chronic systemic inflammation or in frailty has not been explored. Given the prevalence of microaspiration in nursing home residents and the devastating consequences of frailty, though, this seems to be a crucial area of investigation. It is equally crucial for long-term care staff, both providers and nursing staff, to have a heightened awareness of covert microaspiration and a low threshold for referral to speech pathology for further investigation. Staff also should be aware of the utility of the Fried criteria to improve identification of frailty in general. It is probable that covert microaspiration will prove to be an important part of the differential diagnosis of frailty.

Hospitalizations related to ambulatory care sensitive conditions (ACSCs) are potentially avoidable if timely and effective care is provided to the patient. The Agency of Healthcare Research and Quality has identified type 2 diabetes mellitus (T2DM), chronic obstructive pulmonary disease (COPD), hypertension, congestive heart failure (CHF), urinary tract infections (UTIs), asthma, dehydration, bacterial pneumonia, angina without an inhospital procedure, and perforated appendix as ACSCs.^1,2 Identifying patients with ACSCs who are at risk for hospitalization is a potential measure to enhance primary care delivery and reduce preventable hospitalizations

The US Department of Veterans Affairs (VA) Clinical Pharmacy Practice Office implemented a guidance statement describing the role and impact of a clinical pharmacy specialist (CPS) in managing ACSCs.¹ Within the Veterans Health Administration, the CPS may function under a scope of practice within their area of expertise with the ability to prescribe medications, place consults, and order laboratory tests and additional referrals as appropriate. As hospitalizations related to ACSCs are potentially preventable with effective primary care, the CPS can play an essential primary care role to implement interventions targeted at reducing these hospitalizations.

At the William S. Middleton Memorial Veterans Hospital, in Madison, Wisconsin, multiple transitions of care and postdischarge services have been established to capture those patients who are at a high risk of rehospitalization. Studies have been completed regarding implementation of intensive case management programs for high-risk patients.³ Currently though, no standardized process or protocol exists that can identify and optimize primary care for patients with ACSCs who have been hospitalized but are predicted to be at low risk for rehospitalization. Although these patients may not require intensive case management like that of those at high risk, improvements can be made to optimize clinical resources, education, and patient self-monitoring to mitigate risk for hospitalization or rehospitalization. Therefore, this project aimed to evaluate the implementation of offering further referrals and care for patients who have been hospitalized but are considered low risk for hospitalization from ACSCs.

Methods

This quality improvement project to offer further referrals and care to patients considered low risk for hospitalization was implemented to enhance ambulatory-care provided services. All patients identified as being a low risk for hospitalization via a VA dashboard from July through September 2018 were included. Patients were identified based on age, chronic diseases, gender, and other patient-specific factors predetermined by the VA dashboard algorithm. Patients receiving hospice or palliative care and those no longer receiving primary care through the facility were excluded.

A pharmacy resident conducted a baseline chart review using a standardized template in the computerized patient record system (CPRS) to identify additional referrals or interventions a patient may benefit from based on any identified ACSC. Potential referral options included a CPS or nurse care manager disease management, whole health/wellness, educational classes, home monitoring equipment, specialty clinics, nutrition, cardiac or pulmonary rehabilitation, social work, and mental health. A pharmacy resident or the patient aligned care team (PACT) CPS reviewed the identified referrals with PACT members at interdisciplinary team meetings and determined which referrals to offer the patient. The pharmacy resident or designated PACT member reached out to the patient via telephone or during a clinic visit to offer and enter the referrals. If the patient agreed to any referrals, a chart review was conducted 3 months later to determine the percentage of initially agreed-upon referrals that the patient completed. Additionally, the number of emergency department (ED) visits and hospitalizations related to an ACSC at 3 months was collected.

Feasibility was assessed to evaluate potential service implementation and was measured by the time in minutes to complete the baseline chart review, time in minutes to offer referrals to the patient, and proportion of referrals that were completed at 3 months.⁴ As this quality improvement project was undertaken for programmatic evaluation, the University of Wisconsin-Madison Health Sciences Institutional Review Board determined that this project did not meet the federal definition of research and therefore review was not required. Data were analyzed using descriptive statistics.

Results

A total of 78 veterans who had ≥ 1 ACSC-related hospitalization in the past year and who were categorized as low risk were identified, and 69 veterans were reviewed. Nine patients were not included based on hospice care and no longer receiving primary care through the facility. Eight patients were found to have optimized care with no further action warranted after review. Based on their assigned PACT, there was a range of 0 to 5 patients identified per team. Fifty-one patients were contacted, and 37 accepted ≥ 1 referral. Most of the patients were white and male (Table). The most common ACSCs were hypertension (68%), COPD (46%), and T2DM (30%); additional ACSCs included angina (18%), pneumonia (15%), UTIs (10%), CHF (6%), and asthma, dehydration, and perforated appendix (1.5% for each). Any ACSC listed as a diagnosis for a patient was included, regardless of whether it was related to a hospitalization. Most referrals were offered by pharmacists (pharmacy resident, 41%; CPS, 29%), followed by the nurse care manager (18%) and the primary care provider (12%). One patient passed away related to heart failure complications prior to being contacted to offer additional referrals. Of the 9 patients that were unable to be contacted, 4 did not respond to 3 phone call attempts and 5 had no documentation of referrals being offered after the initial chart review and recommendation was completed.

Most of the initially accepted referrals (n = 68) were for CPS disease management, whole health/wellness, and educational classes (Figure). Of the 28 initially accepted referrals for CPS disease management, most were for COPD (10) and hypertension (8), followed by neuropathic pain (3), vitamin D deficiency (3), hyperlipidemia (2), and T2DM (2). At 3 months, all referrals were completed except for 1 hypertension, 1 vitamin D deficiency, and 2 hyperlipidemia referrals. There were 6 COPD, 4 T2DM self-management, and 1 chronic pain class referrals made with 3 COPD and 1 T2DM referrals completed at 3 months. Two tobacco treatment and 2 palliative care referrals were specialty referrals accepted by patients with 1 palliative care referral completed at 3 months.

In terms of feasibility, the chart review took an average (SD) of 13 (4) minutes, and contacting the patient to offer referrals took an average of 8 (5) minutes. Most of the accepted referrals were completed by 3 months (42/68, 62%).

Comparing the 3 months prior to and the 3 months after offering referrals, there was a cumulative quantitative decrease in the number of ED visits (5 to 1) and hospitalizations (11 to 5). The 1 ED visit was for a patient who was unable to be contacted to offer additional referrals as were 4 of the hospitalizations. One of the hospitalizations was for a patient who was deemed to have optimized care with no additional referrals necessary.

Discussion

Evaluation of the review and referral process for patients at low risk for hospitalization from an ACSC was a proactive approach toward optimizing primary care for veterans, and the process increased patient access to education and primary care. There was a high initial patient acceptance rate of referrals and a high completion rate when offered by PACT members. Based on the number of identified patients, the time spent completing chart reviews and contacting patients to offer referrals for each PACT CPS and team was feasible to conduct.

As there were 69 eligible patients identified over a 3-month period for a single VA facility, including all community-based outpatient clinics serving an estimated 130,000 veterans, the additional time and workload for an individual PACT to reach out to these patients is minimal. Completing the review and outreach process for an average of 21 minutes per patient for at most 5 patients per primary care provider team is feasible to complete during the recommended 4 hours of weekly CPS population health management responsibilities.

Limitations

Several limitations were identified with the implementation of the project. A variety of PACT members completed initial outreach to veterans regarding additional referrals, which may have resulted in a lack of consistency in the approach and discussion of offering referrals to patients. Although there may be a difference in how the team members made referral offers to patients and therefore varying acceptance rates by patients, the process was thought to be more generalizable to the PACT approach for providing care in the VA. In addition, the time to contact patients to offer referrals was not always documented in the electronic health record, making the documented time an estimate. Given that patients identified were managed by a variety of PACT members, there were differences noted among PACTs in terms of acceptability of offering referrals to patients.

While there was a decrease noted in ED visits and hospitalizations when comparing 3 months before and afterward, additional data are needed to provide further insight into this relationship. As the patients identified were at low risk for hospitalization from an ACSC and had 1 or 2 hospitalizations within the year prior, additional time is warranted to compare 12-month ED visits and hospitalization rates postintervention. Finally, these findings may be limited in generalizability to other health care systems as the project was conducted among a specific, veteran patient population with PACT CPSs practicing independently within an established broad scope of practice.

Future Directions

Future directions include incorporating the review and referral process into the PACT CPS population health management responsibilities as a way to use all PACT members to enhance primary care delivered to veterans. To further elucidate the relationship between the referral process and hospitalization rates, a longer data collection period is needed.

Conclusions

Identifying patients at risk for hospitalization from an ACSC via a review and referral process by using the VA PACT structure and team members was feasible and led to increased patient access to primary care and additional services. The PACT CPS would benefit from using a similar approach for population health management for low risk for hospitalization patients or other identified chronic conditions.

Acknowledgments

Presented at the Wisconsin Pharmacy Residency Conference at the Pharmacy Society of Wisconsin Educational Conference April 10, 2019, in Madison, Wisconsin.

Hospitalizations related to ambulatory care sensitive conditions (ACSCs) are potentially avoidable if timely and effective care is provided to the patient. The Agency of Healthcare Research and Quality has identified type 2 diabetes mellitus (T2DM), chronic obstructive pulmonary disease (COPD), hypertension, congestive heart failure (CHF), urinary tract infections (UTIs), asthma, dehydration, bacterial pneumonia, angina without an inhospital procedure, and perforated appendix as ACSCs.^1,2 Identifying patients with ACSCs who are at risk for hospitalization is a potential measure to enhance primary care delivery and reduce preventable hospitalizations

The US Department of Veterans Affairs (VA) Clinical Pharmacy Practice Office implemented a guidance statement describing the role and impact of a clinical pharmacy specialist (CPS) in managing ACSCs.¹ Within the Veterans Health Administration, the CPS may function under a scope of practice within their area of expertise with the ability to prescribe medications, place consults, and order laboratory tests and additional referrals as appropriate. As hospitalizations related to ACSCs are potentially preventable with effective primary care, the CPS can play an essential primary care role to implement interventions targeted at reducing these hospitalizations.

At the William S. Middleton Memorial Veterans Hospital, in Madison, Wisconsin, multiple transitions of care and postdischarge services have been established to capture those patients who are at a high risk of rehospitalization. Studies have been completed regarding implementation of intensive case management programs for high-risk patients.³ Currently though, no standardized process or protocol exists that can identify and optimize primary care for patients with ACSCs who have been hospitalized but are predicted to be at low risk for rehospitalization. Although these patients may not require intensive case management like that of those at high risk, improvements can be made to optimize clinical resources, education, and patient self-monitoring to mitigate risk for hospitalization or rehospitalization. Therefore, this project aimed to evaluate the implementation of offering further referrals and care for patients who have been hospitalized but are considered low risk for hospitalization from ACSCs.

Methods

This quality improvement project to offer further referrals and care to patients considered low risk for hospitalization was implemented to enhance ambulatory-care provided services. All patients identified as being a low risk for hospitalization via a VA dashboard from July through September 2018 were included. Patients were identified based on age, chronic diseases, gender, and other patient-specific factors predetermined by the VA dashboard algorithm. Patients receiving hospice or palliative care and those no longer receiving primary care through the facility were excluded.

A pharmacy resident conducted a baseline chart review using a standardized template in the computerized patient record system (CPRS) to identify additional referrals or interventions a patient may benefit from based on any identified ACSC. Potential referral options included a CPS or nurse care manager disease management, whole health/wellness, educational classes, home monitoring equipment, specialty clinics, nutrition, cardiac or pulmonary rehabilitation, social work, and mental health. A pharmacy resident or the patient aligned care team (PACT) CPS reviewed the identified referrals with PACT members at interdisciplinary team meetings and determined which referrals to offer the patient. The pharmacy resident or designated PACT member reached out to the patient via telephone or during a clinic visit to offer and enter the referrals. If the patient agreed to any referrals, a chart review was conducted 3 months later to determine the percentage of initially agreed-upon referrals that the patient completed. Additionally, the number of emergency department (ED) visits and hospitalizations related to an ACSC at 3 months was collected.

Feasibility was assessed to evaluate potential service implementation and was measured by the time in minutes to complete the baseline chart review, time in minutes to offer referrals to the patient, and proportion of referrals that were completed at 3 months.⁴ As this quality improvement project was undertaken for programmatic evaluation, the University of Wisconsin-Madison Health Sciences Institutional Review Board determined that this project did not meet the federal definition of research and therefore review was not required. Data were analyzed using descriptive statistics.

Results

A total of 78 veterans who had ≥ 1 ACSC-related hospitalization in the past year and who were categorized as low risk were identified, and 69 veterans were reviewed. Nine patients were not included based on hospice care and no longer receiving primary care through the facility. Eight patients were found to have optimized care with no further action warranted after review. Based on their assigned PACT, there was a range of 0 to 5 patients identified per team. Fifty-one patients were contacted, and 37 accepted ≥ 1 referral. Most of the patients were white and male (Table). The most common ACSCs were hypertension (68%), COPD (46%), and T2DM (30%); additional ACSCs included angina (18%), pneumonia (15%), UTIs (10%), CHF (6%), and asthma, dehydration, and perforated appendix (1.5% for each). Any ACSC listed as a diagnosis for a patient was included, regardless of whether it was related to a hospitalization. Most referrals were offered by pharmacists (pharmacy resident, 41%; CPS, 29%), followed by the nurse care manager (18%) and the primary care provider (12%). One patient passed away related to heart failure complications prior to being contacted to offer additional referrals. Of the 9 patients that were unable to be contacted, 4 did not respond to 3 phone call attempts and 5 had no documentation of referrals being offered after the initial chart review and recommendation was completed.

Most of the initially accepted referrals (n = 68) were for CPS disease management, whole health/wellness, and educational classes (Figure). Of the 28 initially accepted referrals for CPS disease management, most were for COPD (10) and hypertension (8), followed by neuropathic pain (3), vitamin D deficiency (3), hyperlipidemia (2), and T2DM (2). At 3 months, all referrals were completed except for 1 hypertension, 1 vitamin D deficiency, and 2 hyperlipidemia referrals. There were 6 COPD, 4 T2DM self-management, and 1 chronic pain class referrals made with 3 COPD and 1 T2DM referrals completed at 3 months. Two tobacco treatment and 2 palliative care referrals were specialty referrals accepted by patients with 1 palliative care referral completed at 3 months.

In terms of feasibility, the chart review took an average (SD) of 13 (4) minutes, and contacting the patient to offer referrals took an average of 8 (5) minutes. Most of the accepted referrals were completed by 3 months (42/68, 62%).

Comparing the 3 months prior to and the 3 months after offering referrals, there was a cumulative quantitative decrease in the number of ED visits (5 to 1) and hospitalizations (11 to 5). The 1 ED visit was for a patient who was unable to be contacted to offer additional referrals as were 4 of the hospitalizations. One of the hospitalizations was for a patient who was deemed to have optimized care with no additional referrals necessary.

Discussion

Evaluation of the review and referral process for patients at low risk for hospitalization from an ACSC was a proactive approach toward optimizing primary care for veterans, and the process increased patient access to education and primary care. There was a high initial patient acceptance rate of referrals and a high completion rate when offered by PACT members. Based on the number of identified patients, the time spent completing chart reviews and contacting patients to offer referrals for each PACT CPS and team was feasible to conduct.

As there were 69 eligible patients identified over a 3-month period for a single VA facility, including all community-based outpatient clinics serving an estimated 130,000 veterans, the additional time and workload for an individual PACT to reach out to these patients is minimal. Completing the review and outreach process for an average of 21 minutes per patient for at most 5 patients per primary care provider team is feasible to complete during the recommended 4 hours of weekly CPS population health management responsibilities.

Limitations

Several limitations were identified with the implementation of the project. A variety of PACT members completed initial outreach to veterans regarding additional referrals, which may have resulted in a lack of consistency in the approach and discussion of offering referrals to patients. Although there may be a difference in how the team members made referral offers to patients and therefore varying acceptance rates by patients, the process was thought to be more generalizable to the PACT approach for providing care in the VA. In addition, the time to contact patients to offer referrals was not always documented in the electronic health record, making the documented time an estimate. Given that patients identified were managed by a variety of PACT members, there were differences noted among PACTs in terms of acceptability of offering referrals to patients.

While there was a decrease noted in ED visits and hospitalizations when comparing 3 months before and afterward, additional data are needed to provide further insight into this relationship. As the patients identified were at low risk for hospitalization from an ACSC and had 1 or 2 hospitalizations within the year prior, additional time is warranted to compare 12-month ED visits and hospitalization rates postintervention. Finally, these findings may be limited in generalizability to other health care systems as the project was conducted among a specific, veteran patient population with PACT CPSs practicing independently within an established broad scope of practice.

Future Directions

Future directions include incorporating the review and referral process into the PACT CPS population health management responsibilities as a way to use all PACT members to enhance primary care delivered to veterans. To further elucidate the relationship between the referral process and hospitalization rates, a longer data collection period is needed.

Conclusions

Identifying patients at risk for hospitalization from an ACSC via a review and referral process by using the VA PACT structure and team members was feasible and led to increased patient access to primary care and additional services. The PACT CPS would benefit from using a similar approach for population health management for low risk for hospitalization patients or other identified chronic conditions.

Acknowledgments

Presented at the Wisconsin Pharmacy Residency Conference at the Pharmacy Society of Wisconsin Educational Conference April 10, 2019, in Madison, Wisconsin.

Hospitalizations related to ambulatory care sensitive conditions (ACSCs) are potentially avoidable if timely and effective care is provided to the patient. The Agency of Healthcare Research and Quality has identified type 2 diabetes mellitus (T2DM), chronic obstructive pulmonary disease (COPD), hypertension, congestive heart failure (CHF), urinary tract infections (UTIs), asthma, dehydration, bacterial pneumonia, angina without an inhospital procedure, and perforated appendix as ACSCs.^1,2 Identifying patients with ACSCs who are at risk for hospitalization is a potential measure to enhance primary care delivery and reduce preventable hospitalizations

The US Department of Veterans Affairs (VA) Clinical Pharmacy Practice Office implemented a guidance statement describing the role and impact of a clinical pharmacy specialist (CPS) in managing ACSCs.¹ Within the Veterans Health Administration, the CPS may function under a scope of practice within their area of expertise with the ability to prescribe medications, place consults, and order laboratory tests and additional referrals as appropriate. As hospitalizations related to ACSCs are potentially preventable with effective primary care, the CPS can play an essential primary care role to implement interventions targeted at reducing these hospitalizations.

At the William S. Middleton Memorial Veterans Hospital, in Madison, Wisconsin, multiple transitions of care and postdischarge services have been established to capture those patients who are at a high risk of rehospitalization. Studies have been completed regarding implementation of intensive case management programs for high-risk patients.³ Currently though, no standardized process or protocol exists that can identify and optimize primary care for patients with ACSCs who have been hospitalized but are predicted to be at low risk for rehospitalization. Although these patients may not require intensive case management like that of those at high risk, improvements can be made to optimize clinical resources, education, and patient self-monitoring to mitigate risk for hospitalization or rehospitalization. Therefore, this project aimed to evaluate the implementation of offering further referrals and care for patients who have been hospitalized but are considered low risk for hospitalization from ACSCs.

Methods

This quality improvement project to offer further referrals and care to patients considered low risk for hospitalization was implemented to enhance ambulatory-care provided services. All patients identified as being a low risk for hospitalization via a VA dashboard from July through September 2018 were included. Patients were identified based on age, chronic diseases, gender, and other patient-specific factors predetermined by the VA dashboard algorithm. Patients receiving hospice or palliative care and those no longer receiving primary care through the facility were excluded.

A pharmacy resident conducted a baseline chart review using a standardized template in the computerized patient record system (CPRS) to identify additional referrals or interventions a patient may benefit from based on any identified ACSC. Potential referral options included a CPS or nurse care manager disease management, whole health/wellness, educational classes, home monitoring equipment, specialty clinics, nutrition, cardiac or pulmonary rehabilitation, social work, and mental health. A pharmacy resident or the patient aligned care team (PACT) CPS reviewed the identified referrals with PACT members at interdisciplinary team meetings and determined which referrals to offer the patient. The pharmacy resident or designated PACT member reached out to the patient via telephone or during a clinic visit to offer and enter the referrals. If the patient agreed to any referrals, a chart review was conducted 3 months later to determine the percentage of initially agreed-upon referrals that the patient completed. Additionally, the number of emergency department (ED) visits and hospitalizations related to an ACSC at 3 months was collected.

Feasibility was assessed to evaluate potential service implementation and was measured by the time in minutes to complete the baseline chart review, time in minutes to offer referrals to the patient, and proportion of referrals that were completed at 3 months.⁴ As this quality improvement project was undertaken for programmatic evaluation, the University of Wisconsin-Madison Health Sciences Institutional Review Board determined that this project did not meet the federal definition of research and therefore review was not required. Data were analyzed using descriptive statistics.

Results

A total of 78 veterans who had ≥ 1 ACSC-related hospitalization in the past year and who were categorized as low risk were identified, and 69 veterans were reviewed. Nine patients were not included based on hospice care and no longer receiving primary care through the facility. Eight patients were found to have optimized care with no further action warranted after review. Based on their assigned PACT, there was a range of 0 to 5 patients identified per team. Fifty-one patients were contacted, and 37 accepted ≥ 1 referral. Most of the patients were white and male (Table). The most common ACSCs were hypertension (68%), COPD (46%), and T2DM (30%); additional ACSCs included angina (18%), pneumonia (15%), UTIs (10%), CHF (6%), and asthma, dehydration, and perforated appendix (1.5% for each). Any ACSC listed as a diagnosis for a patient was included, regardless of whether it was related to a hospitalization. Most referrals were offered by pharmacists (pharmacy resident, 41%; CPS, 29%), followed by the nurse care manager (18%) and the primary care provider (12%). One patient passed away related to heart failure complications prior to being contacted to offer additional referrals. Of the 9 patients that were unable to be contacted, 4 did not respond to 3 phone call attempts and 5 had no documentation of referrals being offered after the initial chart review and recommendation was completed.

Most of the initially accepted referrals (n = 68) were for CPS disease management, whole health/wellness, and educational classes (Figure). Of the 28 initially accepted referrals for CPS disease management, most were for COPD (10) and hypertension (8), followed by neuropathic pain (3), vitamin D deficiency (3), hyperlipidemia (2), and T2DM (2). At 3 months, all referrals were completed except for 1 hypertension, 1 vitamin D deficiency, and 2 hyperlipidemia referrals. There were 6 COPD, 4 T2DM self-management, and 1 chronic pain class referrals made with 3 COPD and 1 T2DM referrals completed at 3 months. Two tobacco treatment and 2 palliative care referrals were specialty referrals accepted by patients with 1 palliative care referral completed at 3 months.

In terms of feasibility, the chart review took an average (SD) of 13 (4) minutes, and contacting the patient to offer referrals took an average of 8 (5) minutes. Most of the accepted referrals were completed by 3 months (42/68, 62%).

Comparing the 3 months prior to and the 3 months after offering referrals, there was a cumulative quantitative decrease in the number of ED visits (5 to 1) and hospitalizations (11 to 5). The 1 ED visit was for a patient who was unable to be contacted to offer additional referrals as were 4 of the hospitalizations. One of the hospitalizations was for a patient who was deemed to have optimized care with no additional referrals necessary.

Discussion

Evaluation of the review and referral process for patients at low risk for hospitalization from an ACSC was a proactive approach toward optimizing primary care for veterans, and the process increased patient access to education and primary care. There was a high initial patient acceptance rate of referrals and a high completion rate when offered by PACT members. Based on the number of identified patients, the time spent completing chart reviews and contacting patients to offer referrals for each PACT CPS and team was feasible to conduct.

As there were 69 eligible patients identified over a 3-month period for a single VA facility, including all community-based outpatient clinics serving an estimated 130,000 veterans, the additional time and workload for an individual PACT to reach out to these patients is minimal. Completing the review and outreach process for an average of 21 minutes per patient for at most 5 patients per primary care provider team is feasible to complete during the recommended 4 hours of weekly CPS population health management responsibilities.

Limitations

Several limitations were identified with the implementation of the project. A variety of PACT members completed initial outreach to veterans regarding additional referrals, which may have resulted in a lack of consistency in the approach and discussion of offering referrals to patients. Although there may be a difference in how the team members made referral offers to patients and therefore varying acceptance rates by patients, the process was thought to be more generalizable to the PACT approach for providing care in the VA. In addition, the time to contact patients to offer referrals was not always documented in the electronic health record, making the documented time an estimate. Given that patients identified were managed by a variety of PACT members, there were differences noted among PACTs in terms of acceptability of offering referrals to patients.

While there was a decrease noted in ED visits and hospitalizations when comparing 3 months before and afterward, additional data are needed to provide further insight into this relationship. As the patients identified were at low risk for hospitalization from an ACSC and had 1 or 2 hospitalizations within the year prior, additional time is warranted to compare 12-month ED visits and hospitalization rates postintervention. Finally, these findings may be limited in generalizability to other health care systems as the project was conducted among a specific, veteran patient population with PACT CPSs practicing independently within an established broad scope of practice.

Future Directions

Future directions include incorporating the review and referral process into the PACT CPS population health management responsibilities as a way to use all PACT members to enhance primary care delivered to veterans. To further elucidate the relationship between the referral process and hospitalization rates, a longer data collection period is needed.

Conclusions

Identifying patients at risk for hospitalization from an ACSC via a review and referral process by using the VA PACT structure and team members was feasible and led to increased patient access to primary care and additional services. The PACT CPS would benefit from using a similar approach for population health management for low risk for hospitalization patients or other identified chronic conditions.

Acknowledgments

Presented at the Wisconsin Pharmacy Residency Conference at the Pharmacy Society of Wisconsin Educational Conference April 10, 2019, in Madison, Wisconsin.

Parkinson disease (PD) is a progressive neurodegenerative disorder, characterized by diverse clinical symptoms. PD can present with rest tremor, bradykinesia, rigidity, falls, postural instability, and multiple nonmotor symptoms. Marras and colleagues estimated in a comprehensive meta-analysis that there were 680,000 individuals with PD in the US in 2010; this number is expected to double by 2030 based on the US Census Bureau population projections.¹ An estimated 110,000 veterans may be affected by PD; hence, understanding of PD pathology, clinical progression, and effective treatment strategies is of paramount importance to the Veterans Health Administration (VHA).²

The exact pathogenesis underlying clinical features is still being studied. Pathologic diagnosis of PD relies on loss of dopamine neurons in the substantia nigra and accumulation of the abnormal protein, α-synuclein, in the form of Lewy bodies and Lewy neurites. Lewy bodies and neurites accumulate predominantly in the substantia nigra in addition to other brain stem nuclei and cerebral cortex. Lewy bodies are intraneuronal inclusions with a hyaline core and a pale peripheral halo. Central core stains positive for α-synuclein.^3,4 Lewy neurites are widespread and are believed to play a larger role in the pathogenesis of PD compared with those of Lewy bodies.⁵

α-Synuclein

α-synuclein is a small 140 amino-acid protein with a N-terminal region that can interact with cell membranes and a highly acidic unstructured C-terminal region.⁶ α-synuclein is physiologically present in the presynaptic terminals of neurons and involved in synaptic plasticity and vesicle trafficking.⁷ There are different hypotheses about the native structure of α-synuclein. The first suggests that it exists in tetrameric form and may be broken down to monomer, which is the pathogenic form of α-synuclein. The second hypothesis suggests that it exists primarily in monomeric form, whereas other studies have shown that both forms exist and with pathologic changes, monomer accumulates in abundance and is neurotoxic.^8-11 Work by Burré and colleagues shows that native α-synuclein exists in 2 forms: a soluble, cytosolic α-synuclein, which is monomeric, and a membrane-bound multimeric form.^12,13

Alteration in aggregation properties of this protein is believed to play a central role in the pathogenesis of PD.^14,15 Pathologic α-synuclein exists in insoluble forms that can aggregate into oligomers and fibrillar structures.¹⁶ Lysosomal dysfunction may promote accumulation of insoluble α-synuclein. Prior work has shown that several degradation pathways in lysosomes, including the ubiquitin-proteasome system and autophagy-lysosomal pathway, are down regulated, thus contributing to the accumulation of abnormal α-synuclein.^17,18 Accumulation of pathologic α-synuclein leads to mitochondrial dysfunction in PD animal models, contributing further to neurotoxicity.^19,20 Aggregates of phosphorylated α-synuclein have been demonstrated in dementia with Lewy body.²¹

In addition, α-synuclein aggregates may be released into extracellular spaces to be taken up by adjacent cells, where they can cause further misfolding and aggregation of protein.²² Previous work in animal models suggested a prion proteinlike spread of α-synuclein.²³ This finding can have long-term therapeutic implications, as preventing extracellular release of abnormal form of α-synuclein will prevent the spread of pathologic protein. This can form the basis of neuroprotection in patients with PD.²⁴

It has been proposed that α-synuclein accumulation and extracellular release initiates an immune response that leads to activation of microglia. This has been shown in PD animal models, overexpressing α-synuclein. In 2008 Park and colleagues demonstrated that microglial activation is enhanced by monomeric α-synuclein, not by the aggregated variant.²⁵ Other studies have reported activated microglia around dopaminergic cells in substantia nigra.²⁶ Sulzer and colleagues showed that peptides from α-synuclein can act as antigens and trigger an autoimmune reaction via T cells.²⁷ PD may be associated with certain HLA-haplotypes.²⁸ In other words, α-synuclein can induce neurodegeneration via different mechanisms, including alteration in synaptic vesicle transmission, mitochondrial dysfunction, neuroinflammation, and induction of humoral immunity.

Immunization

Due to these observations, there had been huge interest in developing antibody-based therapies for PD. A similar approach had been tested in Alzheimer disease (AD). Intracellular tangles of tau protein and extracellular aggregates of amyloid are the pathologic substrates in AD. Clinical trials utilizing antibodies targeting amyloid showed reduction in abnormal protein accumulation but no significant improvement in cognition.²⁹ In addition, adverse events (AEs), such as vasogenic edema and intracerebral hemorrhage, were reported.³⁰ Careful analysis of the data suggested that inadequate patient selection or targeting only amyloid, may have contributed to unfavorable results.³¹ Since then, more recent clinical trials have focused on careful patient selection, use of second generation anti-amyloid antibodies and immunotherapies targeting tau.³²

Several studies have tested immunotherapies in PD animal models with the aim of targeting α-synuclein. Immunotherapies can be instituted in 2 ways: active immunization in which the immune system is stimulated to produce antibodies against α-synuclein or passive immunization in which antibodies against α-synuclein are administered directly. Once α-synuclein antibodies have crossed the blood-brain barrier, they are hypothesized to clear the existing α-synuclein. Animal studies have demonstrated the presence of these antibodies within the neurons. The mechanism of entry is unknown. Once inside the cells, the antibodies activate the lysosomal clearance, affecting intracellular accumulation of α-synuclein. Extracellularly, they can bind to receptors on scavenger cells, mainly microglia, activating them to facilitate uptake of extracellular α-synuclein. Binding of the antibodies to α-synuclein directly prevents the uptake of toxic protein by the cells, blocking the transfer and spread of PD pathology.³³

Active Immunization

Active immunization against α-synuclein was demonstrated by Masliah and colleagues almost a decade ago. They administered recombinant human α-synuclein in transgenic mice expressing α-synuclein under the control of platelet-derived growth factor β. Reduction of accumulated α-synuclein in neurons with mild microglia activation was noted. It was proposed that the antibodies produced were able to bind to abnormal α-synuclein, were recognized by the lysosomal pathways, and degraded.³⁴ Ghochikyan and colleagues developed vaccines by using α-synuclein-derived peptides. This induced formation of antibodies against α-synuclein in Lewy-bodies and neurites.³⁵ Over time, other animal studies have been able to expand on these results.³⁶

AFFiRiS, an Austrian biotechnology company, has developed 2 peptide vaccines PD01A and PD03A. Both peptides when administered to PD animal models caused antibody-based immune response against aggregated α-synuclein. Humoral autoimmune response was not observed in these studies; no neuroinflammation or neurotoxicity was noted. These peptides did not affect levels of physiologic α-synuclein, targeting only the aggregated form.³⁷ These animal models showed improved motor and cognitive function. Similar results were noted in multiple system atrophy (MSA) animal models.^38,39

The first human phase 1, randomized, parallel-group, single-center study recruited 32 subjects with early PD. Twelve subjects each were included in low- or high-dose treatment group, and 8 were included in the control group. Test subjects randomly received 4 vaccinations of low- or high-dose PD01A. Both doses were well tolerated, and no drug-related serious AEs were reported. The study confirmed the tolerability and safety of subcutaneous PD01A vaccine administration. These subjects were included in a 12-month, phase 1b follow-up extension study, AFF008E. In 2018, it was reported that administration of 6 doses of PD01A, 4 primary and 2 booster immunization, was safe. The vaccine showed a clear immune response against the peptide and cross-reactivity against α-synuclein targeted epitope. Booster doses stabilized the antibody titers. Significant increase in antibody titers against PD01A was seen over time, which was translated into a humoral immune response against α-synuclein. In addition, PD01A antibodies also were reported in cerebrospinal fluid.⁴⁰

AFFiRiS presented results of a phase 1 randomized, placebo-controlled trial in 2017, confirming the safety of PD03A in patients with PD. The study showed a clear dose-dependent immune response against the peptide and cross-reactivity against α-synuclein targeted epitope.⁴¹ AFFiRiS recently presented results of another phase 1 clinical study assessing the safety and tolerability of vaccines PD01A and PD03A in patients with early MSA. Both vaccines were well tolerated, and PD01A induced an immune response against the peptide and α-synuclein epitope.⁴² These results have provided hope for further endeavors to develop active immunization strategies for PD.

Passive Immunization

Passive immunization against α-synuclein was first reported by Masliah and colleagues in 2011. A monoclonal antibody against the C-terminus of α-synuclein, 9E4, was injected into a transgenic mouse model of PD. There was reduction in α-synuclein aggregates in the brain along with improvement in motor and cognitive impairment.⁴³ The C-terminus of α-synuclein plays a key role in the pathogenesis of PD. Changes in the C-terminus of α-synuclein induces formation of α-synuclein oligomers and subsequent neuronal spread. Antibody binds to the C-terminus and prevents structural changes that can lead to oligomerization of α-synuclein. Since the first study by Masliah, few other immunization studies utilized different antibodies against the C-terminus of α-synuclein. It was shown in a mouse model that binding of such antibodies promoted clearance of the α-synuclein by microglia.⁴⁴

Based on these animal studies, Prothena Biosciences (South San Francisco, CA) designed a phase 1, double-blind, randomized, placebo-controlled clinical trial of prasinezumab (investigational monoclonal antibody against C-terminus of α-synuclein), in subjects without PD. The results showed that it was well tolerated, and there was dose-dependent reduction in the levels of free α-synuclein in plasma.⁴⁵ A 6-month phase 1b trial to evaluate the safety, tolerability and immune system response to multiple ascending doses of prasinezumab via IV infusion once every 28 days was conducted in 64 patients with PD. The drug was found to be safe, and levels of free serum α-synuclein were reduced up to 97%.⁴⁶ Roche (Basel, Switzerland) and Prothena are conducting a multicenter, randomized, double-blind phase 2 trial in patients with early PD to evaluate the efficacy of prasinezumab vs placebo.⁴⁷

BIIB054 is another monoclonal antibody that targets the N-terminal of α-synuclein. In animal models, antibodies targeting the N-terminus reduced α-synuclein triggered cell death and reduced the number of activated microglia.⁴⁸ BIIB054, from Biogen (Cambridge, MA), was studied in 40 healthy subjects and was well tolerated with a favorable safety profile and could cross the blood-brain barrier. Like the prasinezumab study, this also was an ascending-dose study to assess safety and tolerability. In 2018, a randomized, double-blind, placebo-controlled, single-ascending dose study in patients with PD reported that BIIB054 was well tolerated, and the presence of BIIB054-synuclein complexes in the plasma were confirmed.⁴⁹ A phase 2, multicenter, randomized, double-blind, placebo-controlled study (SPARK) with an active-treatment dose-blinded period, designed to evaluate the safety, pharmacokinetics, and the pharmacodynamics of BIIB054 is currently recruiting patients with PD.

Finally, BioArctic (Stockholm, Sweden) developed antibodies that are selective for oligomeric forms of α-synuclein, which it licensed to AbbVie (North Chicago, Il).⁵⁰ These antibodies do not target the N- or C-terminus of α-synuclein. Since α-synuclein oligomers play an important role in the pathogenesis of PD, targeting them with antibodies at an early stage may prove to be an effective strategy for removal of pathogenic α-synuclein. Clinical trials are forthcoming.

Conclusions

Immunotherapy against α-synuclein has provided a new therapeutic avenue in the field of neuroprotection. Results from the first human clinical trial are promising, but despite these results, more work is needed to clarify the role of α-synuclein in the pathogenesis of PD in humans. Most of the work concerning α-synuclein aggregation and propagation has been reported in animal models. Whether similar process exists in humans is a debatable question. Similarly, more knowledge is needed about how and where in the human brain antibodies act to give neuroprotective effects. Timing of administration of immunotherapies in real time will be a crucial question.

PD is clinically evident once 80% of dopaminergic neurons in substantia nigra are lost due to neurodegeneration. Should immunotherapy be administered to symptomatic patients with PD, or if it will be beneficial only for presymptomatic, high-risk patients needs to be determined. Like AD trials, not only careful selection of patients, but determination of optimal timing for treatment will be essential. As the understanding of PD pathogenesis and therapeutics evolves, it will become clear whether immunization targeting α-synuclein will modify disease progression.

Parkinson disease (PD) is a progressive neurodegenerative disorder, characterized by diverse clinical symptoms. PD can present with rest tremor, bradykinesia, rigidity, falls, postural instability, and multiple nonmotor symptoms. Marras and colleagues estimated in a comprehensive meta-analysis that there were 680,000 individuals with PD in the US in 2010; this number is expected to double by 2030 based on the US Census Bureau population projections.¹ An estimated 110,000 veterans may be affected by PD; hence, understanding of PD pathology, clinical progression, and effective treatment strategies is of paramount importance to the Veterans Health Administration (VHA).²

The exact pathogenesis underlying clinical features is still being studied. Pathologic diagnosis of PD relies on loss of dopamine neurons in the substantia nigra and accumulation of the abnormal protein, α-synuclein, in the form of Lewy bodies and Lewy neurites. Lewy bodies and neurites accumulate predominantly in the substantia nigra in addition to other brain stem nuclei and cerebral cortex. Lewy bodies are intraneuronal inclusions with a hyaline core and a pale peripheral halo. Central core stains positive for α-synuclein.^3,4 Lewy neurites are widespread and are believed to play a larger role in the pathogenesis of PD compared with those of Lewy bodies.⁵

α-Synuclein

α-synuclein is a small 140 amino-acid protein with a N-terminal region that can interact with cell membranes and a highly acidic unstructured C-terminal region.⁶ α-synuclein is physiologically present in the presynaptic terminals of neurons and involved in synaptic plasticity and vesicle trafficking.⁷ There are different hypotheses about the native structure of α-synuclein. The first suggests that it exists in tetrameric form and may be broken down to monomer, which is the pathogenic form of α-synuclein. The second hypothesis suggests that it exists primarily in monomeric form, whereas other studies have shown that both forms exist and with pathologic changes, monomer accumulates in abundance and is neurotoxic.^8-11 Work by Burré and colleagues shows that native α-synuclein exists in 2 forms: a soluble, cytosolic α-synuclein, which is monomeric, and a membrane-bound multimeric form.^12,13

Alteration in aggregation properties of this protein is believed to play a central role in the pathogenesis of PD.^14,15 Pathologic α-synuclein exists in insoluble forms that can aggregate into oligomers and fibrillar structures.¹⁶ Lysosomal dysfunction may promote accumulation of insoluble α-synuclein. Prior work has shown that several degradation pathways in lysosomes, including the ubiquitin-proteasome system and autophagy-lysosomal pathway, are down regulated, thus contributing to the accumulation of abnormal α-synuclein.^17,18 Accumulation of pathologic α-synuclein leads to mitochondrial dysfunction in PD animal models, contributing further to neurotoxicity.^19,20 Aggregates of phosphorylated α-synuclein have been demonstrated in dementia with Lewy body.²¹

In addition, α-synuclein aggregates may be released into extracellular spaces to be taken up by adjacent cells, where they can cause further misfolding and aggregation of protein.²² Previous work in animal models suggested a prion proteinlike spread of α-synuclein.²³ This finding can have long-term therapeutic implications, as preventing extracellular release of abnormal form of α-synuclein will prevent the spread of pathologic protein. This can form the basis of neuroprotection in patients with PD.²⁴

It has been proposed that α-synuclein accumulation and extracellular release initiates an immune response that leads to activation of microglia. This has been shown in PD animal models, overexpressing α-synuclein. In 2008 Park and colleagues demonstrated that microglial activation is enhanced by monomeric α-synuclein, not by the aggregated variant.²⁵ Other studies have reported activated microglia around dopaminergic cells in substantia nigra.²⁶ Sulzer and colleagues showed that peptides from α-synuclein can act as antigens and trigger an autoimmune reaction via T cells.²⁷ PD may be associated with certain HLA-haplotypes.²⁸ In other words, α-synuclein can induce neurodegeneration via different mechanisms, including alteration in synaptic vesicle transmission, mitochondrial dysfunction, neuroinflammation, and induction of humoral immunity.

Immunization

Due to these observations, there had been huge interest in developing antibody-based therapies for PD. A similar approach had been tested in Alzheimer disease (AD). Intracellular tangles of tau protein and extracellular aggregates of amyloid are the pathologic substrates in AD. Clinical trials utilizing antibodies targeting amyloid showed reduction in abnormal protein accumulation but no significant improvement in cognition.²⁹ In addition, adverse events (AEs), such as vasogenic edema and intracerebral hemorrhage, were reported.³⁰ Careful analysis of the data suggested that inadequate patient selection or targeting only amyloid, may have contributed to unfavorable results.³¹ Since then, more recent clinical trials have focused on careful patient selection, use of second generation anti-amyloid antibodies and immunotherapies targeting tau.³²

Several studies have tested immunotherapies in PD animal models with the aim of targeting α-synuclein. Immunotherapies can be instituted in 2 ways: active immunization in which the immune system is stimulated to produce antibodies against α-synuclein or passive immunization in which antibodies against α-synuclein are administered directly. Once α-synuclein antibodies have crossed the blood-brain barrier, they are hypothesized to clear the existing α-synuclein. Animal studies have demonstrated the presence of these antibodies within the neurons. The mechanism of entry is unknown. Once inside the cells, the antibodies activate the lysosomal clearance, affecting intracellular accumulation of α-synuclein. Extracellularly, they can bind to receptors on scavenger cells, mainly microglia, activating them to facilitate uptake of extracellular α-synuclein. Binding of the antibodies to α-synuclein directly prevents the uptake of toxic protein by the cells, blocking the transfer and spread of PD pathology.³³

Active Immunization

Active immunization against α-synuclein was demonstrated by Masliah and colleagues almost a decade ago. They administered recombinant human α-synuclein in transgenic mice expressing α-synuclein under the control of platelet-derived growth factor β. Reduction of accumulated α-synuclein in neurons with mild microglia activation was noted. It was proposed that the antibodies produced were able to bind to abnormal α-synuclein, were recognized by the lysosomal pathways, and degraded.³⁴ Ghochikyan and colleagues developed vaccines by using α-synuclein-derived peptides. This induced formation of antibodies against α-synuclein in Lewy-bodies and neurites.³⁵ Over time, other animal studies have been able to expand on these results.³⁶

AFFiRiS, an Austrian biotechnology company, has developed 2 peptide vaccines PD01A and PD03A. Both peptides when administered to PD animal models caused antibody-based immune response against aggregated α-synuclein. Humoral autoimmune response was not observed in these studies; no neuroinflammation or neurotoxicity was noted. These peptides did not affect levels of physiologic α-synuclein, targeting only the aggregated form.³⁷ These animal models showed improved motor and cognitive function. Similar results were noted in multiple system atrophy (MSA) animal models.^38,39

The first human phase 1, randomized, parallel-group, single-center study recruited 32 subjects with early PD. Twelve subjects each were included in low- or high-dose treatment group, and 8 were included in the control group. Test subjects randomly received 4 vaccinations of low- or high-dose PD01A. Both doses were well tolerated, and no drug-related serious AEs were reported. The study confirmed the tolerability and safety of subcutaneous PD01A vaccine administration. These subjects were included in a 12-month, phase 1b follow-up extension study, AFF008E. In 2018, it was reported that administration of 6 doses of PD01A, 4 primary and 2 booster immunization, was safe. The vaccine showed a clear immune response against the peptide and cross-reactivity against α-synuclein targeted epitope. Booster doses stabilized the antibody titers. Significant increase in antibody titers against PD01A was seen over time, which was translated into a humoral immune response against α-synuclein. In addition, PD01A antibodies also were reported in cerebrospinal fluid.⁴⁰

AFFiRiS presented results of a phase 1 randomized, placebo-controlled trial in 2017, confirming the safety of PD03A in patients with PD. The study showed a clear dose-dependent immune response against the peptide and cross-reactivity against α-synuclein targeted epitope.⁴¹ AFFiRiS recently presented results of another phase 1 clinical study assessing the safety and tolerability of vaccines PD01A and PD03A in patients with early MSA. Both vaccines were well tolerated, and PD01A induced an immune response against the peptide and α-synuclein epitope.⁴² These results have provided hope for further endeavors to develop active immunization strategies for PD.

Passive Immunization

Passive immunization against α-synuclein was first reported by Masliah and colleagues in 2011. A monoclonal antibody against the C-terminus of α-synuclein, 9E4, was injected into a transgenic mouse model of PD. There was reduction in α-synuclein aggregates in the brain along with improvement in motor and cognitive impairment.⁴³ The C-terminus of α-synuclein plays a key role in the pathogenesis of PD. Changes in the C-terminus of α-synuclein induces formation of α-synuclein oligomers and subsequent neuronal spread. Antibody binds to the C-terminus and prevents structural changes that can lead to oligomerization of α-synuclein. Since the first study by Masliah, few other immunization studies utilized different antibodies against the C-terminus of α-synuclein. It was shown in a mouse model that binding of such antibodies promoted clearance of the α-synuclein by microglia.⁴⁴

Based on these animal studies, Prothena Biosciences (South San Francisco, CA) designed a phase 1, double-blind, randomized, placebo-controlled clinical trial of prasinezumab (investigational monoclonal antibody against C-terminus of α-synuclein), in subjects without PD. The results showed that it was well tolerated, and there was dose-dependent reduction in the levels of free α-synuclein in plasma.⁴⁵ A 6-month phase 1b trial to evaluate the safety, tolerability and immune system response to multiple ascending doses of prasinezumab via IV infusion once every 28 days was conducted in 64 patients with PD. The drug was found to be safe, and levels of free serum α-synuclein were reduced up to 97%.⁴⁶ Roche (Basel, Switzerland) and Prothena are conducting a multicenter, randomized, double-blind phase 2 trial in patients with early PD to evaluate the efficacy of prasinezumab vs placebo.⁴⁷

BIIB054 is another monoclonal antibody that targets the N-terminal of α-synuclein. In animal models, antibodies targeting the N-terminus reduced α-synuclein triggered cell death and reduced the number of activated microglia.⁴⁸ BIIB054, from Biogen (Cambridge, MA), was studied in 40 healthy subjects and was well tolerated with a favorable safety profile and could cross the blood-brain barrier. Like the prasinezumab study, this also was an ascending-dose study to assess safety and tolerability. In 2018, a randomized, double-blind, placebo-controlled, single-ascending dose study in patients with PD reported that BIIB054 was well tolerated, and the presence of BIIB054-synuclein complexes in the plasma were confirmed.⁴⁹ A phase 2, multicenter, randomized, double-blind, placebo-controlled study (SPARK) with an active-treatment dose-blinded period, designed to evaluate the safety, pharmacokinetics, and the pharmacodynamics of BIIB054 is currently recruiting patients with PD.

Finally, BioArctic (Stockholm, Sweden) developed antibodies that are selective for oligomeric forms of α-synuclein, which it licensed to AbbVie (North Chicago, Il).⁵⁰ These antibodies do not target the N- or C-terminus of α-synuclein. Since α-synuclein oligomers play an important role in the pathogenesis of PD, targeting them with antibodies at an early stage may prove to be an effective strategy for removal of pathogenic α-synuclein. Clinical trials are forthcoming.

Conclusions

Immunotherapy against α-synuclein has provided a new therapeutic avenue in the field of neuroprotection. Results from the first human clinical trial are promising, but despite these results, more work is needed to clarify the role of α-synuclein in the pathogenesis of PD in humans. Most of the work concerning α-synuclein aggregation and propagation has been reported in animal models. Whether similar process exists in humans is a debatable question. Similarly, more knowledge is needed about how and where in the human brain antibodies act to give neuroprotective effects. Timing of administration of immunotherapies in real time will be a crucial question.

PD is clinically evident once 80% of dopaminergic neurons in substantia nigra are lost due to neurodegeneration. Should immunotherapy be administered to symptomatic patients with PD, or if it will be beneficial only for presymptomatic, high-risk patients needs to be determined. Like AD trials, not only careful selection of patients, but determination of optimal timing for treatment will be essential. As the understanding of PD pathogenesis and therapeutics evolves, it will become clear whether immunization targeting α-synuclein will modify disease progression.

Parkinson disease (PD) is a progressive neurodegenerative disorder, characterized by diverse clinical symptoms. PD can present with rest tremor, bradykinesia, rigidity, falls, postural instability, and multiple nonmotor symptoms. Marras and colleagues estimated in a comprehensive meta-analysis that there were 680,000 individuals with PD in the US in 2010; this number is expected to double by 2030 based on the US Census Bureau population projections.¹ An estimated 110,000 veterans may be affected by PD; hence, understanding of PD pathology, clinical progression, and effective treatment strategies is of paramount importance to the Veterans Health Administration (VHA).²

The exact pathogenesis underlying clinical features is still being studied. Pathologic diagnosis of PD relies on loss of dopamine neurons in the substantia nigra and accumulation of the abnormal protein, α-synuclein, in the form of Lewy bodies and Lewy neurites. Lewy bodies and neurites accumulate predominantly in the substantia nigra in addition to other brain stem nuclei and cerebral cortex. Lewy bodies are intraneuronal inclusions with a hyaline core and a pale peripheral halo. Central core stains positive for α-synuclein.^3,4 Lewy neurites are widespread and are believed to play a larger role in the pathogenesis of PD compared with those of Lewy bodies.⁵

α-Synuclein

α-synuclein is a small 140 amino-acid protein with a N-terminal region that can interact with cell membranes and a highly acidic unstructured C-terminal region.⁶ α-synuclein is physiologically present in the presynaptic terminals of neurons and involved in synaptic plasticity and vesicle trafficking.⁷ There are different hypotheses about the native structure of α-synuclein. The first suggests that it exists in tetrameric form and may be broken down to monomer, which is the pathogenic form of α-synuclein. The second hypothesis suggests that it exists primarily in monomeric form, whereas other studies have shown that both forms exist and with pathologic changes, monomer accumulates in abundance and is neurotoxic.^8-11 Work by Burré and colleagues shows that native α-synuclein exists in 2 forms: a soluble, cytosolic α-synuclein, which is monomeric, and a membrane-bound multimeric form.^12,13

Alteration in aggregation properties of this protein is believed to play a central role in the pathogenesis of PD.^14,15 Pathologic α-synuclein exists in insoluble forms that can aggregate into oligomers and fibrillar structures.¹⁶ Lysosomal dysfunction may promote accumulation of insoluble α-synuclein. Prior work has shown that several degradation pathways in lysosomes, including the ubiquitin-proteasome system and autophagy-lysosomal pathway, are down regulated, thus contributing to the accumulation of abnormal α-synuclein.^17,18 Accumulation of pathologic α-synuclein leads to mitochondrial dysfunction in PD animal models, contributing further to neurotoxicity.^19,20 Aggregates of phosphorylated α-synuclein have been demonstrated in dementia with Lewy body.²¹

In addition, α-synuclein aggregates may be released into extracellular spaces to be taken up by adjacent cells, where they can cause further misfolding and aggregation of protein.²² Previous work in animal models suggested a prion proteinlike spread of α-synuclein.²³ This finding can have long-term therapeutic implications, as preventing extracellular release of abnormal form of α-synuclein will prevent the spread of pathologic protein. This can form the basis of neuroprotection in patients with PD.²⁴

It has been proposed that α-synuclein accumulation and extracellular release initiates an immune response that leads to activation of microglia. This has been shown in PD animal models, overexpressing α-synuclein. In 2008 Park and colleagues demonstrated that microglial activation is enhanced by monomeric α-synuclein, not by the aggregated variant.²⁵ Other studies have reported activated microglia around dopaminergic cells in substantia nigra.²⁶ Sulzer and colleagues showed that peptides from α-synuclein can act as antigens and trigger an autoimmune reaction via T cells.²⁷ PD may be associated with certain HLA-haplotypes.²⁸ In other words, α-synuclein can induce neurodegeneration via different mechanisms, including alteration in synaptic vesicle transmission, mitochondrial dysfunction, neuroinflammation, and induction of humoral immunity.

Immunization

Due to these observations, there had been huge interest in developing antibody-based therapies for PD. A similar approach had been tested in Alzheimer disease (AD). Intracellular tangles of tau protein and extracellular aggregates of amyloid are the pathologic substrates in AD. Clinical trials utilizing antibodies targeting amyloid showed reduction in abnormal protein accumulation but no significant improvement in cognition.²⁹ In addition, adverse events (AEs), such as vasogenic edema and intracerebral hemorrhage, were reported.³⁰ Careful analysis of the data suggested that inadequate patient selection or targeting only amyloid, may have contributed to unfavorable results.³¹ Since then, more recent clinical trials have focused on careful patient selection, use of second generation anti-amyloid antibodies and immunotherapies targeting tau.³²

Several studies have tested immunotherapies in PD animal models with the aim of targeting α-synuclein. Immunotherapies can be instituted in 2 ways: active immunization in which the immune system is stimulated to produce antibodies against α-synuclein or passive immunization in which antibodies against α-synuclein are administered directly. Once α-synuclein antibodies have crossed the blood-brain barrier, they are hypothesized to clear the existing α-synuclein. Animal studies have demonstrated the presence of these antibodies within the neurons. The mechanism of entry is unknown. Once inside the cells, the antibodies activate the lysosomal clearance, affecting intracellular accumulation of α-synuclein. Extracellularly, they can bind to receptors on scavenger cells, mainly microglia, activating them to facilitate uptake of extracellular α-synuclein. Binding of the antibodies to α-synuclein directly prevents the uptake of toxic protein by the cells, blocking the transfer and spread of PD pathology.³³

Active Immunization

Active immunization against α-synuclein was demonstrated by Masliah and colleagues almost a decade ago. They administered recombinant human α-synuclein in transgenic mice expressing α-synuclein under the control of platelet-derived growth factor β. Reduction of accumulated α-synuclein in neurons with mild microglia activation was noted. It was proposed that the antibodies produced were able to bind to abnormal α-synuclein, were recognized by the lysosomal pathways, and degraded.³⁴ Ghochikyan and colleagues developed vaccines by using α-synuclein-derived peptides. This induced formation of antibodies against α-synuclein in Lewy-bodies and neurites.³⁵ Over time, other animal studies have been able to expand on these results.³⁶

AFFiRiS, an Austrian biotechnology company, has developed 2 peptide vaccines PD01A and PD03A. Both peptides when administered to PD animal models caused antibody-based immune response against aggregated α-synuclein. Humoral autoimmune response was not observed in these studies; no neuroinflammation or neurotoxicity was noted. These peptides did not affect levels of physiologic α-synuclein, targeting only the aggregated form.³⁷ These animal models showed improved motor and cognitive function. Similar results were noted in multiple system atrophy (MSA) animal models.^38,39

The first human phase 1, randomized, parallel-group, single-center study recruited 32 subjects with early PD. Twelve subjects each were included in low- or high-dose treatment group, and 8 were included in the control group. Test subjects randomly received 4 vaccinations of low- or high-dose PD01A. Both doses were well tolerated, and no drug-related serious AEs were reported. The study confirmed the tolerability and safety of subcutaneous PD01A vaccine administration. These subjects were included in a 12-month, phase 1b follow-up extension study, AFF008E. In 2018, it was reported that administration of 6 doses of PD01A, 4 primary and 2 booster immunization, was safe. The vaccine showed a clear immune response against the peptide and cross-reactivity against α-synuclein targeted epitope. Booster doses stabilized the antibody titers. Significant increase in antibody titers against PD01A was seen over time, which was translated into a humoral immune response against α-synuclein. In addition, PD01A antibodies also were reported in cerebrospinal fluid.⁴⁰

AFFiRiS presented results of a phase 1 randomized, placebo-controlled trial in 2017, confirming the safety of PD03A in patients with PD. The study showed a clear dose-dependent immune response against the peptide and cross-reactivity against α-synuclein targeted epitope.⁴¹ AFFiRiS recently presented results of another phase 1 clinical study assessing the safety and tolerability of vaccines PD01A and PD03A in patients with early MSA. Both vaccines were well tolerated, and PD01A induced an immune response against the peptide and α-synuclein epitope.⁴² These results have provided hope for further endeavors to develop active immunization strategies for PD.

Passive Immunization

Passive immunization against α-synuclein was first reported by Masliah and colleagues in 2011. A monoclonal antibody against the C-terminus of α-synuclein, 9E4, was injected into a transgenic mouse model of PD. There was reduction in α-synuclein aggregates in the brain along with improvement in motor and cognitive impairment.⁴³ The C-terminus of α-synuclein plays a key role in the pathogenesis of PD. Changes in the C-terminus of α-synuclein induces formation of α-synuclein oligomers and subsequent neuronal spread. Antibody binds to the C-terminus and prevents structural changes that can lead to oligomerization of α-synuclein. Since the first study by Masliah, few other immunization studies utilized different antibodies against the C-terminus of α-synuclein. It was shown in a mouse model that binding of such antibodies promoted clearance of the α-synuclein by microglia.⁴⁴

Based on these animal studies, Prothena Biosciences (South San Francisco, CA) designed a phase 1, double-blind, randomized, placebo-controlled clinical trial of prasinezumab (investigational monoclonal antibody against C-terminus of α-synuclein), in subjects without PD. The results showed that it was well tolerated, and there was dose-dependent reduction in the levels of free α-synuclein in plasma.⁴⁵ A 6-month phase 1b trial to evaluate the safety, tolerability and immune system response to multiple ascending doses of prasinezumab via IV infusion once every 28 days was conducted in 64 patients with PD. The drug was found to be safe, and levels of free serum α-synuclein were reduced up to 97%.⁴⁶ Roche (Basel, Switzerland) and Prothena are conducting a multicenter, randomized, double-blind phase 2 trial in patients with early PD to evaluate the efficacy of prasinezumab vs placebo.⁴⁷

BIIB054 is another monoclonal antibody that targets the N-terminal of α-synuclein. In animal models, antibodies targeting the N-terminus reduced α-synuclein triggered cell death and reduced the number of activated microglia.⁴⁸ BIIB054, from Biogen (Cambridge, MA), was studied in 40 healthy subjects and was well tolerated with a favorable safety profile and could cross the blood-brain barrier. Like the prasinezumab study, this also was an ascending-dose study to assess safety and tolerability. In 2018, a randomized, double-blind, placebo-controlled, single-ascending dose study in patients with PD reported that BIIB054 was well tolerated, and the presence of BIIB054-synuclein complexes in the plasma were confirmed.⁴⁹ A phase 2, multicenter, randomized, double-blind, placebo-controlled study (SPARK) with an active-treatment dose-blinded period, designed to evaluate the safety, pharmacokinetics, and the pharmacodynamics of BIIB054 is currently recruiting patients with PD.

Finally, BioArctic (Stockholm, Sweden) developed antibodies that are selective for oligomeric forms of α-synuclein, which it licensed to AbbVie (North Chicago, Il).⁵⁰ These antibodies do not target the N- or C-terminus of α-synuclein. Since α-synuclein oligomers play an important role in the pathogenesis of PD, targeting them with antibodies at an early stage may prove to be an effective strategy for removal of pathogenic α-synuclein. Clinical trials are forthcoming.

Conclusions

Immunotherapy against α-synuclein has provided a new therapeutic avenue in the field of neuroprotection. Results from the first human clinical trial are promising, but despite these results, more work is needed to clarify the role of α-synuclein in the pathogenesis of PD in humans. Most of the work concerning α-synuclein aggregation and propagation has been reported in animal models. Whether similar process exists in humans is a debatable question. Similarly, more knowledge is needed about how and where in the human brain antibodies act to give neuroprotective effects. Timing of administration of immunotherapies in real time will be a crucial question.

PD is clinically evident once 80% of dopaminergic neurons in substantia nigra are lost due to neurodegeneration. Should immunotherapy be administered to symptomatic patients with PD, or if it will be beneficial only for presymptomatic, high-risk patients needs to be determined. Like AD trials, not only careful selection of patients, but determination of optimal timing for treatment will be essential. As the understanding of PD pathogenesis and therapeutics evolves, it will become clear whether immunization targeting α-synuclein will modify disease progression.

The current risk-based criteria for screening for type 2 diabetes or prediabetes in youth have low sensitivity and specificity for detecting these disorders, and therefore “may miss high-risk youth who should be targeted for diabetes prevention,” according to the investigators of a cross-sectional analysis of youth in the 1999-2016 National Health and Nutrition Examination Survey (NHANES) database.

Belyjmishka/Getty Images

Regardless of whether or not youth meet screening eligibility, they say, hemoglobin A1c appears to be a “specific and useful test” for detecting high-risk youth.

Those with prediabetic levels of A1c or fasting plasma glucose (FPG) – A1c especially – had a high burden of other cardiometabolic risk factors that could benefit from lifestyle interventions to prevent diabetes and cardiovascular risk in adulthood, wrote Amelia S. Wallace and coinvestigators at the Johns Hopkins Bloomberg School of Public Health, Baltimore. The report is in Pediatrics.Their epidemiologic study had two aims: To assess the performance of the American Diabetes Association guidelines for screening in youth, and to evaluate how well various clinical definitions of diabetes and prediabetes identify U.S. youth at high cardiometabolic risk.

The 2018 ADA guidelines recommend screening for type 2 diabetes and prediabetes in all asymptomatic youth ages 10 years and older who are overweight or obese and who have at least one risk factor for diabetes: nonwhite race, family history of type 2 diabetes, maternal gestational diabetes, or signs of insulin resistance or conditions associated with insulin resistance (Diabetes Care. 2018:41[suppl 1:S13-S37]).

Approximately one-quarter of U.S. youth were found to be eligible for screening under the current ADA criteria, but there were few cases of confirmed diabetes (A1c greater than or equal to 6.5% and fasting plasma glucose greater than or equal to 126 mg/dL) that had gone undiagnosed (less than 0.5%), said Ms. Wallace and her associates.

Considering all hyperglycemia (undiagnosed diabetes or prediabetes) in the NHANES youth population, the sensitivity and specificity of the ADA criteria for detecting A1c-defined hyperglycemia (greater than or equal to 5.7%) were 56% and 76%, respectively, and the sensitivity and specificity for detecting FBG-defined hyperglycemia (greater than or equal to 100 mg/dL) were 36% and 77%.

The prevalence of any hyperglycemia was higher in youth who met ADA screening criteria than in those who didn’t, but there were also “a substantial number of youth with hyperglycemia in the non–screening eligible population,” they wrote. “In fact, the absolute number of youth with elevated FPG was larger in the non–screening eligible population, and the majority (88.5%) of these youth were of normal weight.”

Across all youth (irrespective of screening eligibility), both FPG and A1c-defined hyperglycemia effectively identified children and adolescents who had a high burden of cardiometabolic risk (obesity, metabolic syndrome, and hypercholesterolemia). Using a confirmatory definition of elevations in both FPG and A1c “provided the highest discrimination for cardiometabolic risk,” Ms. Wallace and her associates said.

But in comparing the single tests, risk factor associations with hyperglycemia were consistently stronger with A1c-defined hyperglycemia (odds ratios of 2.6-4.1) than FBG-defined hyperglycemia (ORs of 1.5-3.0). A1c-defined hyperglycemia “identifies a smaller, but higher-risk, population than FPG-defined hyperglycemia,” they said.

In an accompanying commentary, Tamara S. Hannon, MD, MS, of the division of pediatric endocrinology and diabetology at Indiana University in Indianapolis, said that more effective algorithms to determine who should have laboratory testing “could be useful.” Still, “for youth with obesity and multiple risk factors for developing type 2 diabetes, the principal challenge is how to effectively prevent or delay this disease for them and future generations.”

Pediatricians, she said, should screen for prediabetes and type 2 diabetes “according to professional recommendations with simple clinical tests, such as A1c. Screening and education about prediabetes alone can lead to better rates of follow-up for obesity,” she noted (Pediatrics. August 2020. doi: 10.1542/peds.2020-010272).

Sheela N. Magge, MD, MSCE, who directs the division of pediatric endocrinology and diabetes at John Hopkins University, Baltimore, and was asked to comment on the study, similarly said that the findings should not discourage use of the ADA guidelines.

While the guidelines may not have optimal sensitivity and specificity, “neither HbA1c nor fasting glucose are perfect screening tools for prediabetes and likely give us different mechanistic information,” she said. (The ADA guidelines also allow the use of a 2-hour oral glucose tolerance test, but this is not often used by pediatricians, she noted.)

The measurements are “only tools used to identify children who have prediabetes and are therefore at increased risk for type 2 diabetes,” said Dr. Magge, the Lawson Wilkins Endowed Chair of Pediatric Endocrinology at the university. “These children then need to be managed and followed to try to prevent worsening glycemia.”

Both she and Dr. Hannon stressed that youth with type 2 diabetes have more rapidly progressive disease compared with adults.

Microvascular complications are seen even at diagnosis, Dr. Magge said, and “youth may face serious complications such as cardiovascular disease decades earlier than previous generations.”

Dr. Hannon also noted in her commentary that oral diabetes medications often fail in youth with type 2 diabetes, leading to insulin therapy early on.

The prevalence of youth-onset type 2 diabetes has increased because of rising rates of pediatric overweight and obesity, Dr. Magge emphasized. In her experience, the diabetes risk factors that guide the ADA’s screening approach “are so common in overweight and obese youth that they all have at least one.”

The NHANES data did not contain information on all the variables that make up the current diabetes screening criteria in youth; there was no explicit information on history of maternal gestational diabetes and family history of type 2 diabetes, for instance, or the presence of acanthosis nigricans or polycystic ovarian syndrome – conditions associated with insulin resistance. The investigators said it’s likely, therefore, that the study underestimated the number of U.S. youth who would be eligible for diabetes screening.

And, as Dr. Magge said, “it is difficult to determine which risk factors [in the ADA guidelines] were less predictive.”

The NHANES analysis covered 14,119 youth in the 1999-2016 NHANES surveys, which consisted of interviews and standardized physical exams, including laboratory tests, in home and at a mobile examination center. Analyses involving any fasting lab tests were limited to a random subsample of participants aged 12-19 years without diagnosed diabetes who were asked to fast the night before; 6,225 youth properly followed instructions and were included in this subsample.

The surveys are conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention. The study authors and the editorial author indicated that they have no relevant financial disclosures or conflicts of interest. Dr. Magge also said she has no relevant disclosures.

SOURCE: Wallace AS et al. Pediatrics. August 2020. doi: 10.1542/peds.2020-0265.

The current risk-based criteria for screening for type 2 diabetes or prediabetes in youth have low sensitivity and specificity for detecting these disorders, and therefore “may miss high-risk youth who should be targeted for diabetes prevention,” according to the investigators of a cross-sectional analysis of youth in the 1999-2016 National Health and Nutrition Examination Survey (NHANES) database.

Belyjmishka/Getty Images

Regardless of whether or not youth meet screening eligibility, they say, hemoglobin A1c appears to be a “specific and useful test” for detecting high-risk youth.

Those with prediabetic levels of A1c or fasting plasma glucose (FPG) – A1c especially – had a high burden of other cardiometabolic risk factors that could benefit from lifestyle interventions to prevent diabetes and cardiovascular risk in adulthood, wrote Amelia S. Wallace and coinvestigators at the Johns Hopkins Bloomberg School of Public Health, Baltimore. The report is in Pediatrics.Their epidemiologic study had two aims: To assess the performance of the American Diabetes Association guidelines for screening in youth, and to evaluate how well various clinical definitions of diabetes and prediabetes identify U.S. youth at high cardiometabolic risk.

The 2018 ADA guidelines recommend screening for type 2 diabetes and prediabetes in all asymptomatic youth ages 10 years and older who are overweight or obese and who have at least one risk factor for diabetes: nonwhite race, family history of type 2 diabetes, maternal gestational diabetes, or signs of insulin resistance or conditions associated with insulin resistance (Diabetes Care. 2018:41[suppl 1:S13-S37]).

Approximately one-quarter of U.S. youth were found to be eligible for screening under the current ADA criteria, but there were few cases of confirmed diabetes (A1c greater than or equal to 6.5% and fasting plasma glucose greater than or equal to 126 mg/dL) that had gone undiagnosed (less than 0.5%), said Ms. Wallace and her associates.

Considering all hyperglycemia (undiagnosed diabetes or prediabetes) in the NHANES youth population, the sensitivity and specificity of the ADA criteria for detecting A1c-defined hyperglycemia (greater than or equal to 5.7%) were 56% and 76%, respectively, and the sensitivity and specificity for detecting FBG-defined hyperglycemia (greater than or equal to 100 mg/dL) were 36% and 77%.

The prevalence of any hyperglycemia was higher in youth who met ADA screening criteria than in those who didn’t, but there were also “a substantial number of youth with hyperglycemia in the non–screening eligible population,” they wrote. “In fact, the absolute number of youth with elevated FPG was larger in the non–screening eligible population, and the majority (88.5%) of these youth were of normal weight.”

Across all youth (irrespective of screening eligibility), both FPG and A1c-defined hyperglycemia effectively identified children and adolescents who had a high burden of cardiometabolic risk (obesity, metabolic syndrome, and hypercholesterolemia). Using a confirmatory definition of elevations in both FPG and A1c “provided the highest discrimination for cardiometabolic risk,” Ms. Wallace and her associates said.

But in comparing the single tests, risk factor associations with hyperglycemia were consistently stronger with A1c-defined hyperglycemia (odds ratios of 2.6-4.1) than FBG-defined hyperglycemia (ORs of 1.5-3.0). A1c-defined hyperglycemia “identifies a smaller, but higher-risk, population than FPG-defined hyperglycemia,” they said.

In an accompanying commentary, Tamara S. Hannon, MD, MS, of the division of pediatric endocrinology and diabetology at Indiana University in Indianapolis, said that more effective algorithms to determine who should have laboratory testing “could be useful.” Still, “for youth with obesity and multiple risk factors for developing type 2 diabetes, the principal challenge is how to effectively prevent or delay this disease for them and future generations.”

Pediatricians, she said, should screen for prediabetes and type 2 diabetes “according to professional recommendations with simple clinical tests, such as A1c. Screening and education about prediabetes alone can lead to better rates of follow-up for obesity,” she noted (Pediatrics. August 2020. doi: 10.1542/peds.2020-010272).

Sheela N. Magge, MD, MSCE, who directs the division of pediatric endocrinology and diabetes at John Hopkins University, Baltimore, and was asked to comment on the study, similarly said that the findings should not discourage use of the ADA guidelines.

While the guidelines may not have optimal sensitivity and specificity, “neither HbA1c nor fasting glucose are perfect screening tools for prediabetes and likely give us different mechanistic information,” she said. (The ADA guidelines also allow the use of a 2-hour oral glucose tolerance test, but this is not often used by pediatricians, she noted.)

The measurements are “only tools used to identify children who have prediabetes and are therefore at increased risk for type 2 diabetes,” said Dr. Magge, the Lawson Wilkins Endowed Chair of Pediatric Endocrinology at the university. “These children then need to be managed and followed to try to prevent worsening glycemia.”

Both she and Dr. Hannon stressed that youth with type 2 diabetes have more rapidly progressive disease compared with adults.

Microvascular complications are seen even at diagnosis, Dr. Magge said, and “youth may face serious complications such as cardiovascular disease decades earlier than previous generations.”

Dr. Hannon also noted in her commentary that oral diabetes medications often fail in youth with type 2 diabetes, leading to insulin therapy early on.

The prevalence of youth-onset type 2 diabetes has increased because of rising rates of pediatric overweight and obesity, Dr. Magge emphasized. In her experience, the diabetes risk factors that guide the ADA’s screening approach “are so common in overweight and obese youth that they all have at least one.”

The NHANES data did not contain information on all the variables that make up the current diabetes screening criteria in youth; there was no explicit information on history of maternal gestational diabetes and family history of type 2 diabetes, for instance, or the presence of acanthosis nigricans or polycystic ovarian syndrome – conditions associated with insulin resistance. The investigators said it’s likely, therefore, that the study underestimated the number of U.S. youth who would be eligible for diabetes screening.

And, as Dr. Magge said, “it is difficult to determine which risk factors [in the ADA guidelines] were less predictive.”

The NHANES analysis covered 14,119 youth in the 1999-2016 NHANES surveys, which consisted of interviews and standardized physical exams, including laboratory tests, in home and at a mobile examination center. Analyses involving any fasting lab tests were limited to a random subsample of participants aged 12-19 years without diagnosed diabetes who were asked to fast the night before; 6,225 youth properly followed instructions and were included in this subsample.

The surveys are conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention. The study authors and the editorial author indicated that they have no relevant financial disclosures or conflicts of interest. Dr. Magge also said she has no relevant disclosures.

SOURCE: Wallace AS et al. Pediatrics. August 2020. doi: 10.1542/peds.2020-0265.

The current risk-based criteria for screening for type 2 diabetes or prediabetes in youth have low sensitivity and specificity for detecting these disorders, and therefore “may miss high-risk youth who should be targeted for diabetes prevention,” according to the investigators of a cross-sectional analysis of youth in the 1999-2016 National Health and Nutrition Examination Survey (NHANES) database.

Belyjmishka/Getty Images

Regardless of whether or not youth meet screening eligibility, they say, hemoglobin A1c appears to be a “specific and useful test” for detecting high-risk youth.

Those with prediabetic levels of A1c or fasting plasma glucose (FPG) – A1c especially – had a high burden of other cardiometabolic risk factors that could benefit from lifestyle interventions to prevent diabetes and cardiovascular risk in adulthood, wrote Amelia S. Wallace and coinvestigators at the Johns Hopkins Bloomberg School of Public Health, Baltimore. The report is in Pediatrics.Their epidemiologic study had two aims: To assess the performance of the American Diabetes Association guidelines for screening in youth, and to evaluate how well various clinical definitions of diabetes and prediabetes identify U.S. youth at high cardiometabolic risk.

The 2018 ADA guidelines recommend screening for type 2 diabetes and prediabetes in all asymptomatic youth ages 10 years and older who are overweight or obese and who have at least one risk factor for diabetes: nonwhite race, family history of type 2 diabetes, maternal gestational diabetes, or signs of insulin resistance or conditions associated with insulin resistance (Diabetes Care. 2018:41[suppl 1:S13-S37]).

Approximately one-quarter of U.S. youth were found to be eligible for screening under the current ADA criteria, but there were few cases of confirmed diabetes (A1c greater than or equal to 6.5% and fasting plasma glucose greater than or equal to 126 mg/dL) that had gone undiagnosed (less than 0.5%), said Ms. Wallace and her associates.

Considering all hyperglycemia (undiagnosed diabetes or prediabetes) in the NHANES youth population, the sensitivity and specificity of the ADA criteria for detecting A1c-defined hyperglycemia (greater than or equal to 5.7%) were 56% and 76%, respectively, and the sensitivity and specificity for detecting FBG-defined hyperglycemia (greater than or equal to 100 mg/dL) were 36% and 77%.

The prevalence of any hyperglycemia was higher in youth who met ADA screening criteria than in those who didn’t, but there were also “a substantial number of youth with hyperglycemia in the non–screening eligible population,” they wrote. “In fact, the absolute number of youth with elevated FPG was larger in the non–screening eligible population, and the majority (88.5%) of these youth were of normal weight.”

Across all youth (irrespective of screening eligibility), both FPG and A1c-defined hyperglycemia effectively identified children and adolescents who had a high burden of cardiometabolic risk (obesity, metabolic syndrome, and hypercholesterolemia). Using a confirmatory definition of elevations in both FPG and A1c “provided the highest discrimination for cardiometabolic risk,” Ms. Wallace and her associates said.

But in comparing the single tests, risk factor associations with hyperglycemia were consistently stronger with A1c-defined hyperglycemia (odds ratios of 2.6-4.1) than FBG-defined hyperglycemia (ORs of 1.5-3.0). A1c-defined hyperglycemia “identifies a smaller, but higher-risk, population than FPG-defined hyperglycemia,” they said.

In an accompanying commentary, Tamara S. Hannon, MD, MS, of the division of pediatric endocrinology and diabetology at Indiana University in Indianapolis, said that more effective algorithms to determine who should have laboratory testing “could be useful.” Still, “for youth with obesity and multiple risk factors for developing type 2 diabetes, the principal challenge is how to effectively prevent or delay this disease for them and future generations.”

Pediatricians, she said, should screen for prediabetes and type 2 diabetes “according to professional recommendations with simple clinical tests, such as A1c. Screening and education about prediabetes alone can lead to better rates of follow-up for obesity,” she noted (Pediatrics. August 2020. doi: 10.1542/peds.2020-010272).

Sheela N. Magge, MD, MSCE, who directs the division of pediatric endocrinology and diabetes at John Hopkins University, Baltimore, and was asked to comment on the study, similarly said that the findings should not discourage use of the ADA guidelines.

While the guidelines may not have optimal sensitivity and specificity, “neither HbA1c nor fasting glucose are perfect screening tools for prediabetes and likely give us different mechanistic information,” she said. (The ADA guidelines also allow the use of a 2-hour oral glucose tolerance test, but this is not often used by pediatricians, she noted.)

The measurements are “only tools used to identify children who have prediabetes and are therefore at increased risk for type 2 diabetes,” said Dr. Magge, the Lawson Wilkins Endowed Chair of Pediatric Endocrinology at the university. “These children then need to be managed and followed to try to prevent worsening glycemia.”

Both she and Dr. Hannon stressed that youth with type 2 diabetes have more rapidly progressive disease compared with adults.

Microvascular complications are seen even at diagnosis, Dr. Magge said, and “youth may face serious complications such as cardiovascular disease decades earlier than previous generations.”

Dr. Hannon also noted in her commentary that oral diabetes medications often fail in youth with type 2 diabetes, leading to insulin therapy early on.

The prevalence of youth-onset type 2 diabetes has increased because of rising rates of pediatric overweight and obesity, Dr. Magge emphasized. In her experience, the diabetes risk factors that guide the ADA’s screening approach “are so common in overweight and obese youth that they all have at least one.”

The NHANES data did not contain information on all the variables that make up the current diabetes screening criteria in youth; there was no explicit information on history of maternal gestational diabetes and family history of type 2 diabetes, for instance, or the presence of acanthosis nigricans or polycystic ovarian syndrome – conditions associated with insulin resistance. The investigators said it’s likely, therefore, that the study underestimated the number of U.S. youth who would be eligible for diabetes screening.

And, as Dr. Magge said, “it is difficult to determine which risk factors [in the ADA guidelines] were less predictive.”

The NHANES analysis covered 14,119 youth in the 1999-2016 NHANES surveys, which consisted of interviews and standardized physical exams, including laboratory tests, in home and at a mobile examination center. Analyses involving any fasting lab tests were limited to a random subsample of participants aged 12-19 years without diagnosed diabetes who were asked to fast the night before; 6,225 youth properly followed instructions and were included in this subsample.

The surveys are conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention. The study authors and the editorial author indicated that they have no relevant financial disclosures or conflicts of interest. Dr. Magge also said she has no relevant disclosures.

SOURCE: Wallace AS et al. Pediatrics. August 2020. doi: 10.1542/peds.2020-0265.

Health care systems are faced with the challenge of meeting increasing patient care demands with finite resources.¹ Advocating for additional capital—specifically, human resources—requires compelling data that accurately capture workload credit. When workload is not captured accurately, clinicians may be tasked with providing care to a high volume of patients without appropriate resource allocation. This understaffing can delay care delivery and increase the risk of diagnostic and treatment errors.² Furthermore, workers in understaffed medical facilities are more likely to experience burnout, which leads to high workforce turnover.

Computer based documentation (CBD) is used often in medical practices to track patient care and clinical workload. However, improperly designed and implemented CBD systems can contribute to cumbersome documentation tasks and inaccurate or incomplete data capture.³ Conversely, CBD can be a useful tool to capture workload credit and can subsequently facilitate justification for medical staff allocation to meet patient care demands. This article uses our experience with US Department of Veterans Affairs (VA) national sleep medicine programs to illustrate the impact of CBD procedures on health care workload assessment and allocation. Specifically, we examine how appropriate workload capture facilitates growth and improves the efficiency of health care programs.

The VA is the largest integrated health care system in the US, serving 9 million veterans at 1,255 facilities, including 170 VA Medical Centers (VAMCs).⁴ As veterans’ demands for VA medical services have outpaced available resources, there have been several media reports of lapses in timely care delivery.^5-7 These lapses have been due, in part, to insufficient workforce resource allocation within the Veterans Health Administration (VHA) facilities. A 2012 audit of physician staffing levels conducted by the VA Inspector General concluded that the VA did not have an effective staffing methodology to ensure appropriate staffing levels for specialty care services.⁸ The lack of staffing plans and productivity standards limits the ability of medical facility officials to make informed business decisions regarding the appropriate number of specialty physicians required to meet patient care needs.⁸ In 2017, the Government Accountability Office (GAO) issued a report to Congress that stated the “VA’s productivity metrics and efficiency models do not provide complete and accurate information, they may misrepresent the true level of productivity and efficiency across VAMCs and limit the VA’s ability to determine the extent to which its resources are being used effectively.”⁹ To understand how and why many VA medical facilities remain understaffed, and therefore struggle to provide health care to veterans in a timely fashion, a description of VA CBD procedures is provided.

Background

VA Directive 1082 on Patient Care Data requires the capture of all outpatient and inpatient billable encounter data.¹⁰ Accurate capture of workload informs budget allocation models and is necessary for health care provider (HCP) productivity metrics. These data points help identify staff shortages relative to the generated workload. The Veterans Equitable Resource Allocation (VERA) model is used to allocate general purpose funds to the Veterans Integrated Service Networks (VISNs) regional network of VHA facilities. The underlying data components of the VERA model rely on comprehensive data systems that track and analyze the many management information systems used in VHA. Historically, at least 90% of the funds allocated by the VERA model have been attributed directly to patient care. All workload that is appropriately documented is accounted for in the VERA patient classification process, which is the official data source for funding patient care in VHA.

VA medical facilities use Stop Codes (formerly known as Decision Support System Identifiers) to identify workload for all outpatient encounters and inpatient professional services. Each code is composed of a 6-character descriptor that includes a primary Stop Code and a credit (secondary) Stop Code. Primary Stop Codes—the first 3 numbers in the sequence—designate the main clinical group responsible for patient care, such as sleep medicine or neurology. Secondary Stop Codes—the last 3 numbers in the sequence—further define the primary workgroup, such as the type of services provided (eg, telehealth) or the type of HCP (eg, nurse practitioner). These codes help ensure that workload and generated revenue are allocated or credited to the proper specialty care service.¹¹ An example of how changes or inaccuracies in Stop Code reporting can affect VHA clinical workload assessment and resource allocation is provided by the VHA sleep medicine program.

The prevalence of sleep disorders—particularly apnea and insomnia—among US military service members and veterans has increased dramatically over the past 2 decades and continues to rise.^12-14 Consequently, demand for sleep care services at VHA facilities also has increased substantially (Figure 1). Unfortunately, this demand has outpaced the VHA’s staffing models, sometimes resulting in long wait times for appointments.¹⁵ In fact, sleep medicine remains one of the most backlogged services in the VHA, despite significant improvements in program efficiency achieved by incorporating telehealth modalities.¹⁶ Untreated sleep disorders are associated with increased risk of depression, anxiety, impaired neurocognitive functions, cardiovascular disease, motor vehicle accidents, and premature death.^17-23

A major contributor to understaffing of VHA sleep medicine programs is the CBD system’s historical inability to accurately track sleep resources and demand for sleep care services. For many years, Stop Codes attributed sleep workload credit primarily to pulmonary medicine, neurology, and internal medicine workgroups. Within these workgroups, few individuals contributed to sleep care, but the entire workgroup received credit for these services, masking the workload of sleep care providers. Additional barriers to accurate sleep medicine workload capture within the VHA included (1) inability to centrally identify personnel, including physicians, as providers of sleep care; (2) limited and variable understanding among VA sleep physicians of the importance of proper encounter form completion (the mechanism by which the cost of a service is calculated); and (3) a lack of awareness that encounter closure is directly linked to productivity measures such as relative value units (RVUs) that support sleep medicine programs and the salaries of those who provide care.

Methods

The critical role of accurate CBD in health care administration is illustrated by the proper use of Stop Codes as a foundational step in tracking services provided to justify adequate resource allocation within VA. A complete redesign of tracking sleep service documentation was initiated in 2014 and resulted in national changes to sleep medicine Stop Codes. The Stop Code initiative was the first step of several to improve CBD for VA sleep services.

Primary Stop Code 349 designates sleep medicine encounters in VA facilities (Table). However, before changes were implemented in fiscal year (FY) 2015, Stop Codes for VHA sleep care did not differentiate between specific services provided, such as laboratory-based sleep testing, at-home sleep testing, education/training sessions, follow-up appointments, equipment consults, telephone or video consults, or administrative tasks. In early FY 2015, several changes were made to Stop Codes used for VHA sleep medicine services nationwide to capture the breadth of services that were being provided; services that had previously been performed but were not documented. A new standardized coding methodology was established for continuous positive airway pressure (CPAP) clinics (349/116 or 349/117); telephone consults for sleep care (324/349); and store and forward sleep telehealth encounters (349/694, 349/695, or 349/696).

In the VA, store-and-forward telehealth refers to asynchronous telemedicine involving the acquisition and storing of clinical information (eg, data, image, sound, or video) that another site or clinician reviews later for evaluation and interpretation. In sleep medicine, data uploaded from home sleep apnea test units or CPAP devices are examples of this asynchronous telehealth model. The goal of these changes in VA Stop Codes was to accurately assess the volume of sleep care delivered and the demand for sleep care (consult volumes); enable planning for resource allocation and utilization appropriately; provide veterans with consistent access to sleep services across the country; and facilitate reductions in wait times for sleep care appointments. Results of these changes were immediate and dramatic in terms of data capture and reporting.

Results

Figure 1 illustrates an increase in patient encounters in VA sleep clinics by 24,197 (19.6%) in the first quarter of Stop Code change implementation (FY 2015, quarter 2) compared with those of the previous quarter. VHA sleep clinic patient encounters increased in subsequent quarters of FY 2015 by 29,910 (20.2%) and 11,206 (6.3%) respectively. By the end of FY 2015, reported sleep clinic encounters increased by 190,803 compared with the those at the end of FY 2014, an increase of 42.7%.

Figures 2, 3, and 4 show the additional effects of sleep Stop Code changes that were implemented in FY 2015 for CPAP clinics, telephone encounters, and store-and-forward telehealth encounters, respectively. The large increases in reported sleep patient encounters between FY 2014 and FY 2016 reflect changes in CBD and are not entirely due to actual changes in clinical workloads. These results indicate that workloads in many VHA sleep medicine clinics were grossly underreported or misallocated to other specialty services prior to the changes implemented in FY 2015. This discrepancy in care delivery vs workload capture is a contributing factor to the understaffing that continues to challenge VHA sleep programs. However, the improved accuracy of workload reporting that resulted from Stop Code modifications has resulted in only a small proportional increase in VHA clinical resources allocated to provide adequate services and care for veterans with sleep disorders.

In response to the substantial and increasing demand for sleep services by veterans, the VA Office of Rural Health (ORH) funded an enterprise-wide initiative (EWI) to develop and implement a national TeleSleep Program.¹⁶ The goal of this program is to improve the health and well-being of rural veterans by increasing their access to sleep care and services.

Discussion

Inaccuracies in CBD procedures can adversely affect health care workload assessment and allocation, contributing to ongoing challenges faced by sleep medicine clinics and other VHA programs that have limited staff yet strive to provide timely and high-quality care to veterans. “Not only does inaccurate coding contribute to miscalculations in staffing and resource allocation, it can also contribute to inaccuracies in overall measures of VA healthcare efficiency,” the GAO reported to Congress.⁹ The GAO went on to recommend that the VA should ensure the accuracy of underlying staffing and workload data. VHA sleep medicine programs have made efforts to educate HCPs and administrators on the importance of accurate CBD as a tool for accurate data capture that is necessary to facilitate improvements in health care availability and delivery.

In 2018, the VA Sleep Program Office released an updated set of Stop Code changes, including expansion of telehealth codes and improved designation of laboratory and home sleep testing services. These changes are anticipated to result in accurate documentation of VA sleep clinic workload and services, especially as the VA TeleSleep EWI to reach rural veterans expands.¹⁶ In light of the improved accuracy of reporting of delivered sleep services due to changes in Stop Codes over the past 4 years, VHA sleep medicine providers continue to advocate for allocation of resources commensurate with their clinical workload. An appropriate administrative response to the significant clinical workload performed by disproportionately few providers should include the authorization of increased resources and personnel for sleep medicine as well as providing the tools needed to further streamline workflow efficiency (eg, artificial intelligence, machine learning, and population health management).

Conclusions

Despite the barriers faced by many large integrated health care systems, VHA sleep medicine leadership continues to implement changes in CBD protocols that improve the accuracy of clinical workload tracking and reporting. Ultimately, these changes will support proposals for increased resources necessary to improve the quality and availability of sleep care for veterans. This example from VA illustrates the importance of accurate workload capture and its role in informing administrators of health care systems as they strive to meet the needs of patients. Although some VA sleep medicine programs continue to face challenges imposed by systemwide limitations, the ORH TeleSleep Program is a major initiative that improves veterans’ access to care by disseminating and implementing effective telehealth technologies and strategies.¹⁶

Acknowledgments

This work was supported by a VA Office of Rural Health Enterprise-Wide Initiative.

Health care systems are faced with the challenge of meeting increasing patient care demands with finite resources.¹ Advocating for additional capital—specifically, human resources—requires compelling data that accurately capture workload credit. When workload is not captured accurately, clinicians may be tasked with providing care to a high volume of patients without appropriate resource allocation. This understaffing can delay care delivery and increase the risk of diagnostic and treatment errors.² Furthermore, workers in understaffed medical facilities are more likely to experience burnout, which leads to high workforce turnover.

Computer based documentation (CBD) is used often in medical practices to track patient care and clinical workload. However, improperly designed and implemented CBD systems can contribute to cumbersome documentation tasks and inaccurate or incomplete data capture.³ Conversely, CBD can be a useful tool to capture workload credit and can subsequently facilitate justification for medical staff allocation to meet patient care demands. This article uses our experience with US Department of Veterans Affairs (VA) national sleep medicine programs to illustrate the impact of CBD procedures on health care workload assessment and allocation. Specifically, we examine how appropriate workload capture facilitates growth and improves the efficiency of health care programs.

The VA is the largest integrated health care system in the US, serving 9 million veterans at 1,255 facilities, including 170 VA Medical Centers (VAMCs).⁴ As veterans’ demands for VA medical services have outpaced available resources, there have been several media reports of lapses in timely care delivery.^5-7 These lapses have been due, in part, to insufficient workforce resource allocation within the Veterans Health Administration (VHA) facilities. A 2012 audit of physician staffing levels conducted by the VA Inspector General concluded that the VA did not have an effective staffing methodology to ensure appropriate staffing levels for specialty care services.⁸ The lack of staffing plans and productivity standards limits the ability of medical facility officials to make informed business decisions regarding the appropriate number of specialty physicians required to meet patient care needs.⁸ In 2017, the Government Accountability Office (GAO) issued a report to Congress that stated the “VA’s productivity metrics and efficiency models do not provide complete and accurate information, they may misrepresent the true level of productivity and efficiency across VAMCs and limit the VA’s ability to determine the extent to which its resources are being used effectively.”⁹ To understand how and why many VA medical facilities remain understaffed, and therefore struggle to provide health care to veterans in a timely fashion, a description of VA CBD procedures is provided.

Background

VA Directive 1082 on Patient Care Data requires the capture of all outpatient and inpatient billable encounter data.¹⁰ Accurate capture of workload informs budget allocation models and is necessary for health care provider (HCP) productivity metrics. These data points help identify staff shortages relative to the generated workload. The Veterans Equitable Resource Allocation (VERA) model is used to allocate general purpose funds to the Veterans Integrated Service Networks (VISNs) regional network of VHA facilities. The underlying data components of the VERA model rely on comprehensive data systems that track and analyze the many management information systems used in VHA. Historically, at least 90% of the funds allocated by the VERA model have been attributed directly to patient care. All workload that is appropriately documented is accounted for in the VERA patient classification process, which is the official data source for funding patient care in VHA.

VA medical facilities use Stop Codes (formerly known as Decision Support System Identifiers) to identify workload for all outpatient encounters and inpatient professional services. Each code is composed of a 6-character descriptor that includes a primary Stop Code and a credit (secondary) Stop Code. Primary Stop Codes—the first 3 numbers in the sequence—designate the main clinical group responsible for patient care, such as sleep medicine or neurology. Secondary Stop Codes—the last 3 numbers in the sequence—further define the primary workgroup, such as the type of services provided (eg, telehealth) or the type of HCP (eg, nurse practitioner). These codes help ensure that workload and generated revenue are allocated or credited to the proper specialty care service.¹¹ An example of how changes or inaccuracies in Stop Code reporting can affect VHA clinical workload assessment and resource allocation is provided by the VHA sleep medicine program.

The prevalence of sleep disorders—particularly apnea and insomnia—among US military service members and veterans has increased dramatically over the past 2 decades and continues to rise.^12-14 Consequently, demand for sleep care services at VHA facilities also has increased substantially (Figure 1). Unfortunately, this demand has outpaced the VHA’s staffing models, sometimes resulting in long wait times for appointments.¹⁵ In fact, sleep medicine remains one of the most backlogged services in the VHA, despite significant improvements in program efficiency achieved by incorporating telehealth modalities.¹⁶ Untreated sleep disorders are associated with increased risk of depression, anxiety, impaired neurocognitive functions, cardiovascular disease, motor vehicle accidents, and premature death.^17-23

A major contributor to understaffing of VHA sleep medicine programs is the CBD system’s historical inability to accurately track sleep resources and demand for sleep care services. For many years, Stop Codes attributed sleep workload credit primarily to pulmonary medicine, neurology, and internal medicine workgroups. Within these workgroups, few individuals contributed to sleep care, but the entire workgroup received credit for these services, masking the workload of sleep care providers. Additional barriers to accurate sleep medicine workload capture within the VHA included (1) inability to centrally identify personnel, including physicians, as providers of sleep care; (2) limited and variable understanding among VA sleep physicians of the importance of proper encounter form completion (the mechanism by which the cost of a service is calculated); and (3) a lack of awareness that encounter closure is directly linked to productivity measures such as relative value units (RVUs) that support sleep medicine programs and the salaries of those who provide care.

Methods

The critical role of accurate CBD in health care administration is illustrated by the proper use of Stop Codes as a foundational step in tracking services provided to justify adequate resource allocation within VA. A complete redesign of tracking sleep service documentation was initiated in 2014 and resulted in national changes to sleep medicine Stop Codes. The Stop Code initiative was the first step of several to improve CBD for VA sleep services.

Primary Stop Code 349 designates sleep medicine encounters in VA facilities (Table). However, before changes were implemented in fiscal year (FY) 2015, Stop Codes for VHA sleep care did not differentiate between specific services provided, such as laboratory-based sleep testing, at-home sleep testing, education/training sessions, follow-up appointments, equipment consults, telephone or video consults, or administrative tasks. In early FY 2015, several changes were made to Stop Codes used for VHA sleep medicine services nationwide to capture the breadth of services that were being provided; services that had previously been performed but were not documented. A new standardized coding methodology was established for continuous positive airway pressure (CPAP) clinics (349/116 or 349/117); telephone consults for sleep care (324/349); and store and forward sleep telehealth encounters (349/694, 349/695, or 349/696).

In the VA, store-and-forward telehealth refers to asynchronous telemedicine involving the acquisition and storing of clinical information (eg, data, image, sound, or video) that another site or clinician reviews later for evaluation and interpretation. In sleep medicine, data uploaded from home sleep apnea test units or CPAP devices are examples of this asynchronous telehealth model. The goal of these changes in VA Stop Codes was to accurately assess the volume of sleep care delivered and the demand for sleep care (consult volumes); enable planning for resource allocation and utilization appropriately; provide veterans with consistent access to sleep services across the country; and facilitate reductions in wait times for sleep care appointments. Results of these changes were immediate and dramatic in terms of data capture and reporting.

Results

Figure 1 illustrates an increase in patient encounters in VA sleep clinics by 24,197 (19.6%) in the first quarter of Stop Code change implementation (FY 2015, quarter 2) compared with those of the previous quarter. VHA sleep clinic patient encounters increased in subsequent quarters of FY 2015 by 29,910 (20.2%) and 11,206 (6.3%) respectively. By the end of FY 2015, reported sleep clinic encounters increased by 190,803 compared with the those at the end of FY 2014, an increase of 42.7%.

Figures 2, 3, and 4 show the additional effects of sleep Stop Code changes that were implemented in FY 2015 for CPAP clinics, telephone encounters, and store-and-forward telehealth encounters, respectively. The large increases in reported sleep patient encounters between FY 2014 and FY 2016 reflect changes in CBD and are not entirely due to actual changes in clinical workloads. These results indicate that workloads in many VHA sleep medicine clinics were grossly underreported or misallocated to other specialty services prior to the changes implemented in FY 2015. This discrepancy in care delivery vs workload capture is a contributing factor to the understaffing that continues to challenge VHA sleep programs. However, the improved accuracy of workload reporting that resulted from Stop Code modifications has resulted in only a small proportional increase in VHA clinical resources allocated to provide adequate services and care for veterans with sleep disorders.

In response to the substantial and increasing demand for sleep services by veterans, the VA Office of Rural Health (ORH) funded an enterprise-wide initiative (EWI) to develop and implement a national TeleSleep Program.¹⁶ The goal of this program is to improve the health and well-being of rural veterans by increasing their access to sleep care and services.

Discussion

Inaccuracies in CBD procedures can adversely affect health care workload assessment and allocation, contributing to ongoing challenges faced by sleep medicine clinics and other VHA programs that have limited staff yet strive to provide timely and high-quality care to veterans. “Not only does inaccurate coding contribute to miscalculations in staffing and resource allocation, it can also contribute to inaccuracies in overall measures of VA healthcare efficiency,” the GAO reported to Congress.⁹ The GAO went on to recommend that the VA should ensure the accuracy of underlying staffing and workload data. VHA sleep medicine programs have made efforts to educate HCPs and administrators on the importance of accurate CBD as a tool for accurate data capture that is necessary to facilitate improvements in health care availability and delivery.

In 2018, the VA Sleep Program Office released an updated set of Stop Code changes, including expansion of telehealth codes and improved designation of laboratory and home sleep testing services. These changes are anticipated to result in accurate documentation of VA sleep clinic workload and services, especially as the VA TeleSleep EWI to reach rural veterans expands.¹⁶ In light of the improved accuracy of reporting of delivered sleep services due to changes in Stop Codes over the past 4 years, VHA sleep medicine providers continue to advocate for allocation of resources commensurate with their clinical workload. An appropriate administrative response to the significant clinical workload performed by disproportionately few providers should include the authorization of increased resources and personnel for sleep medicine as well as providing the tools needed to further streamline workflow efficiency (eg, artificial intelligence, machine learning, and population health management).

Conclusions

Despite the barriers faced by many large integrated health care systems, VHA sleep medicine leadership continues to implement changes in CBD protocols that improve the accuracy of clinical workload tracking and reporting. Ultimately, these changes will support proposals for increased resources necessary to improve the quality and availability of sleep care for veterans. This example from VA illustrates the importance of accurate workload capture and its role in informing administrators of health care systems as they strive to meet the needs of patients. Although some VA sleep medicine programs continue to face challenges imposed by systemwide limitations, the ORH TeleSleep Program is a major initiative that improves veterans’ access to care by disseminating and implementing effective telehealth technologies and strategies.¹⁶

Acknowledgments

This work was supported by a VA Office of Rural Health Enterprise-Wide Initiative.

Health care systems are faced with the challenge of meeting increasing patient care demands with finite resources.¹ Advocating for additional capital—specifically, human resources—requires compelling data that accurately capture workload credit. When workload is not captured accurately, clinicians may be tasked with providing care to a high volume of patients without appropriate resource allocation. This understaffing can delay care delivery and increase the risk of diagnostic and treatment errors.² Furthermore, workers in understaffed medical facilities are more likely to experience burnout, which leads to high workforce turnover.

Computer based documentation (CBD) is used often in medical practices to track patient care and clinical workload. However, improperly designed and implemented CBD systems can contribute to cumbersome documentation tasks and inaccurate or incomplete data capture.³ Conversely, CBD can be a useful tool to capture workload credit and can subsequently facilitate justification for medical staff allocation to meet patient care demands. This article uses our experience with US Department of Veterans Affairs (VA) national sleep medicine programs to illustrate the impact of CBD procedures on health care workload assessment and allocation. Specifically, we examine how appropriate workload capture facilitates growth and improves the efficiency of health care programs.

The VA is the largest integrated health care system in the US, serving 9 million veterans at 1,255 facilities, including 170 VA Medical Centers (VAMCs).⁴ As veterans’ demands for VA medical services have outpaced available resources, there have been several media reports of lapses in timely care delivery.^5-7 These lapses have been due, in part, to insufficient workforce resource allocation within the Veterans Health Administration (VHA) facilities. A 2012 audit of physician staffing levels conducted by the VA Inspector General concluded that the VA did not have an effective staffing methodology to ensure appropriate staffing levels for specialty care services.⁸ The lack of staffing plans and productivity standards limits the ability of medical facility officials to make informed business decisions regarding the appropriate number of specialty physicians required to meet patient care needs.⁸ In 2017, the Government Accountability Office (GAO) issued a report to Congress that stated the “VA’s productivity metrics and efficiency models do not provide complete and accurate information, they may misrepresent the true level of productivity and efficiency across VAMCs and limit the VA’s ability to determine the extent to which its resources are being used effectively.”⁹ To understand how and why many VA medical facilities remain understaffed, and therefore struggle to provide health care to veterans in a timely fashion, a description of VA CBD procedures is provided.

Background

VA Directive 1082 on Patient Care Data requires the capture of all outpatient and inpatient billable encounter data.¹⁰ Accurate capture of workload informs budget allocation models and is necessary for health care provider (HCP) productivity metrics. These data points help identify staff shortages relative to the generated workload. The Veterans Equitable Resource Allocation (VERA) model is used to allocate general purpose funds to the Veterans Integrated Service Networks (VISNs) regional network of VHA facilities. The underlying data components of the VERA model rely on comprehensive data systems that track and analyze the many management information systems used in VHA. Historically, at least 90% of the funds allocated by the VERA model have been attributed directly to patient care. All workload that is appropriately documented is accounted for in the VERA patient classification process, which is the official data source for funding patient care in VHA.

VA medical facilities use Stop Codes (formerly known as Decision Support System Identifiers) to identify workload for all outpatient encounters and inpatient professional services. Each code is composed of a 6-character descriptor that includes a primary Stop Code and a credit (secondary) Stop Code. Primary Stop Codes—the first 3 numbers in the sequence—designate the main clinical group responsible for patient care, such as sleep medicine or neurology. Secondary Stop Codes—the last 3 numbers in the sequence—further define the primary workgroup, such as the type of services provided (eg, telehealth) or the type of HCP (eg, nurse practitioner). These codes help ensure that workload and generated revenue are allocated or credited to the proper specialty care service.¹¹ An example of how changes or inaccuracies in Stop Code reporting can affect VHA clinical workload assessment and resource allocation is provided by the VHA sleep medicine program.

The prevalence of sleep disorders—particularly apnea and insomnia—among US military service members and veterans has increased dramatically over the past 2 decades and continues to rise.^12-14 Consequently, demand for sleep care services at VHA facilities also has increased substantially (Figure 1). Unfortunately, this demand has outpaced the VHA’s staffing models, sometimes resulting in long wait times for appointments.¹⁵ In fact, sleep medicine remains one of the most backlogged services in the VHA, despite significant improvements in program efficiency achieved by incorporating telehealth modalities.¹⁶ Untreated sleep disorders are associated with increased risk of depression, anxiety, impaired neurocognitive functions, cardiovascular disease, motor vehicle accidents, and premature death.^17-23

A major contributor to understaffing of VHA sleep medicine programs is the CBD system’s historical inability to accurately track sleep resources and demand for sleep care services. For many years, Stop Codes attributed sleep workload credit primarily to pulmonary medicine, neurology, and internal medicine workgroups. Within these workgroups, few individuals contributed to sleep care, but the entire workgroup received credit for these services, masking the workload of sleep care providers. Additional barriers to accurate sleep medicine workload capture within the VHA included (1) inability to centrally identify personnel, including physicians, as providers of sleep care; (2) limited and variable understanding among VA sleep physicians of the importance of proper encounter form completion (the mechanism by which the cost of a service is calculated); and (3) a lack of awareness that encounter closure is directly linked to productivity measures such as relative value units (RVUs) that support sleep medicine programs and the salaries of those who provide care.

Methods

The critical role of accurate CBD in health care administration is illustrated by the proper use of Stop Codes as a foundational step in tracking services provided to justify adequate resource allocation within VA. A complete redesign of tracking sleep service documentation was initiated in 2014 and resulted in national changes to sleep medicine Stop Codes. The Stop Code initiative was the first step of several to improve CBD for VA sleep services.

Primary Stop Code 349 designates sleep medicine encounters in VA facilities (Table). However, before changes were implemented in fiscal year (FY) 2015, Stop Codes for VHA sleep care did not differentiate between specific services provided, such as laboratory-based sleep testing, at-home sleep testing, education/training sessions, follow-up appointments, equipment consults, telephone or video consults, or administrative tasks. In early FY 2015, several changes were made to Stop Codes used for VHA sleep medicine services nationwide to capture the breadth of services that were being provided; services that had previously been performed but were not documented. A new standardized coding methodology was established for continuous positive airway pressure (CPAP) clinics (349/116 or 349/117); telephone consults for sleep care (324/349); and store and forward sleep telehealth encounters (349/694, 349/695, or 349/696).

In the VA, store-and-forward telehealth refers to asynchronous telemedicine involving the acquisition and storing of clinical information (eg, data, image, sound, or video) that another site or clinician reviews later for evaluation and interpretation. In sleep medicine, data uploaded from home sleep apnea test units or CPAP devices are examples of this asynchronous telehealth model. The goal of these changes in VA Stop Codes was to accurately assess the volume of sleep care delivered and the demand for sleep care (consult volumes); enable planning for resource allocation and utilization appropriately; provide veterans with consistent access to sleep services across the country; and facilitate reductions in wait times for sleep care appointments. Results of these changes were immediate and dramatic in terms of data capture and reporting.

Results

Figure 1 illustrates an increase in patient encounters in VA sleep clinics by 24,197 (19.6%) in the first quarter of Stop Code change implementation (FY 2015, quarter 2) compared with those of the previous quarter. VHA sleep clinic patient encounters increased in subsequent quarters of FY 2015 by 29,910 (20.2%) and 11,206 (6.3%) respectively. By the end of FY 2015, reported sleep clinic encounters increased by 190,803 compared with the those at the end of FY 2014, an increase of 42.7%.

Figures 2, 3, and 4 show the additional effects of sleep Stop Code changes that were implemented in FY 2015 for CPAP clinics, telephone encounters, and store-and-forward telehealth encounters, respectively. The large increases in reported sleep patient encounters between FY 2014 and FY 2016 reflect changes in CBD and are not entirely due to actual changes in clinical workloads. These results indicate that workloads in many VHA sleep medicine clinics were grossly underreported or misallocated to other specialty services prior to the changes implemented in FY 2015. This discrepancy in care delivery vs workload capture is a contributing factor to the understaffing that continues to challenge VHA sleep programs. However, the improved accuracy of workload reporting that resulted from Stop Code modifications has resulted in only a small proportional increase in VHA clinical resources allocated to provide adequate services and care for veterans with sleep disorders.

In response to the substantial and increasing demand for sleep services by veterans, the VA Office of Rural Health (ORH) funded an enterprise-wide initiative (EWI) to develop and implement a national TeleSleep Program.¹⁶ The goal of this program is to improve the health and well-being of rural veterans by increasing their access to sleep care and services.

Discussion

Inaccuracies in CBD procedures can adversely affect health care workload assessment and allocation, contributing to ongoing challenges faced by sleep medicine clinics and other VHA programs that have limited staff yet strive to provide timely and high-quality care to veterans. “Not only does inaccurate coding contribute to miscalculations in staffing and resource allocation, it can also contribute to inaccuracies in overall measures of VA healthcare efficiency,” the GAO reported to Congress.⁹ The GAO went on to recommend that the VA should ensure the accuracy of underlying staffing and workload data. VHA sleep medicine programs have made efforts to educate HCPs and administrators on the importance of accurate CBD as a tool for accurate data capture that is necessary to facilitate improvements in health care availability and delivery.

In 2018, the VA Sleep Program Office released an updated set of Stop Code changes, including expansion of telehealth codes and improved designation of laboratory and home sleep testing services. These changes are anticipated to result in accurate documentation of VA sleep clinic workload and services, especially as the VA TeleSleep EWI to reach rural veterans expands.¹⁶ In light of the improved accuracy of reporting of delivered sleep services due to changes in Stop Codes over the past 4 years, VHA sleep medicine providers continue to advocate for allocation of resources commensurate with their clinical workload. An appropriate administrative response to the significant clinical workload performed by disproportionately few providers should include the authorization of increased resources and personnel for sleep medicine as well as providing the tools needed to further streamline workflow efficiency (eg, artificial intelligence, machine learning, and population health management).

Conclusions

Despite the barriers faced by many large integrated health care systems, VHA sleep medicine leadership continues to implement changes in CBD protocols that improve the accuracy of clinical workload tracking and reporting. Ultimately, these changes will support proposals for increased resources necessary to improve the quality and availability of sleep care for veterans. This example from VA illustrates the importance of accurate workload capture and its role in informing administrators of health care systems as they strive to meet the needs of patients. Although some VA sleep medicine programs continue to face challenges imposed by systemwide limitations, the ORH TeleSleep Program is a major initiative that improves veterans’ access to care by disseminating and implementing effective telehealth technologies and strategies.¹⁶

Acknowledgments

This work was supported by a VA Office of Rural Health Enterprise-Wide Initiative.

The US Department of Veterans Affairs (VA) established a formal Amputation System of Care (ASoC) in 2008 with the goal of enhancing the quality and consistency of amputation rehabilitation care for veterans with limb loss.^1,2 Throughout its history, the VA has placed a high priority on the care that is provided to veterans with limb amputation.^1,3 Amputations have medical, physical, social, and psychological ramifications for the veteran and his or her family. Therefore, management of veterans with limb loss requires a comprehensive, coordinated, transdisciplinary program of services throughout the continuum of care. This includes offering the latest practices in medical interventions, artificial limbs, assistive technologies, and rehabilitation strategies to restore function and thereby optimize quality of life.

Amputation System of Care

The ASoC is an integrated system within the Veterans Health Administration (VHA) that provides specialized expertise in amputation rehabilitation incorporating the latest practices in medical management, rehabilitation therapies, artificial limbs, and assistive technologies. The system facilitates patient-centered, gender-sensitive, lifelong care and care coordination across the entire health continuum from acute inpatient hospitalization through a spectrum of inpatient, residential, and outpatient rehabilitation care settings. Through the provision of quality rehabilitation and prosthetic limb care, the ASoC strives to minimize disability and enable the highest level of social, vocational, and recreational success for veterans with an amputation.^1-3

The policy and procedures for the ASoC have been detailed in prior VA Handbooks and in the ASoC Directive.¹ This article highlights the background, population served, and organizational structure of the ASoC by detailing the outcomes and accomplishments of this systems-based approach to longitudinal amputation care between 2009 and 2019. Four core areas of activities and accomplishments are highlighted: (1) learning organization creation; (2) trust in VA care; (3) system modernization; and (4) customer service. This analysis and description of the VA amputation care program serves as a model of amputation care that can be used in the civilian sector. There also is potential for the ASoC to serve as a care model example for other populations within the VA.

Organizational Structure

The ASoC is an integrated, national health care delivery system in which each VA medical center (VAMC) has a specific designation that reflects the level of expertise and accessibility across the system based on an individual veteran’s needs and the specific capabilities of each VAMC.^1-3 The organizational structure for the ASoC is similar to the Polytrauma System of Care in that facilities are divided into 4 tiers.^1,4

For the ASoC, the 4 tiers are Regional Amputation Centers (RAC) at 7 VAMCs, Polytrauma Amputation Network Sites (PANS) at 18 VAMCs, Amputation Clinic Teams (ACT) at 106 VAMCs, and Amputation Points of Contact (APoC) at 22 VAMCs. The RAC locations provide the highest level of specialized expertise in clinical care and prosthetic limb technology and have rehabilitation capabilities to manage the most complicated cases. Like the RAC facilities, PANS provide a full range of clinical and ancillary services to veterans within their catchment area and serve as referral locations for veterans with needs that are more complex. ACT sites have a core amputation specialty team that provides regular follow-up and address ongoing care needs. ACT sites may or may not have full ancillary services, such as surgical subspecialties or an in-house prosthetics laboratory. APoC facilities have at least 1 person on staff who serves as the point of contact for consultation, assessment, and referral of a veteran with an amputation to a facility capable of providing the level of services required.¹

The VA also places a high priority on both primary and secondary amputation prevention. The Preventing Amputations in Veterans Everywhere (PAVE) program and the ASoC coordinate efforts in order to address the prevention of an initial amputation, the rehabilitation of veterans who have had an amputation, and the prevention of a second amputation in those with an amputation.^1,5

Population Served

The ASoC serves veterans with limb loss regardless of the etiology. This includes care of individuals with complex limb trauma and those with other injuries or disease processes resulting in a high likelihood of requiring a limb amputation. In 2019, the VA provided care to 96,519 veterans with amputation, and about half (46,214) had at least 1 major limb amputation, which is defined as an amputation at or proximal to the wrist or ankle.⁶ The majority of veterans with amputation treated within the VA have limb loss resulting from disease processes, such as diabetes mellitus (DM) and peripheral vascular disease (PVD). Amputations caused by these diseases generally occur in the older veteran population and are associated with comorbidities, such as cardiovascular disease, hypertension, and end-stage renal disease. Veterans with amputation due to trauma, including conflict-related injuries, are commonly younger at the time of their amputation. Although the number of conflict-related amputations is small compared with the number of amputations associated with disease processes, both groups require high-quality, comprehensive, lifelong care.

Between 2009 and 2019, the number of veterans with limb loss receiving care in the VA increased 34%.⁶ With advances in vascular surgery and limb-sparing procedures, minor amputations are more common than major limb amputations and more below-knee rather than above-knee amputations have been noted over the same time. However, the high prevalence of DM in the overall veteran population places about 1.8 million veterans at risk for amputation, and it is anticipated that the volume of limb loss in the veteran population will continue to grow and possibly accelerate.⁵

Performance Metrics

Over the past 10 years, the ASoC has focused on ensuring that an amputation specialty care team addresses the needs of veterans with amputation. Between 2009 and 2019, the VA amputation specialty clinics saw a 49% annual increase in the number of unique veterans treated and a 64% annual increase in the number of total clinic encounters (Figure 1).⁶ This growth is attributed to the larger amputation population receiving enhanced access to the specialty team providing consistent, comprehensive, lifelong care.

During this same period, the amputation specialty clinic encounter to unique ratio (a measure of how frequently patients return to the clinic each year) rose from 1.8 in 2009 to 2.3 in 2019 for both the total amputation population and for those with major limb amputation. When looking more specifically at the RAC facilities, the encounter to unique ratio increased from 1.5 to 3.0 over the same time, reflecting the added benefit of having dedicated resources for the amputation specialty program.⁶

Comparing the percentage of veterans with amputation who are seen in the VA for any service with those who also are seen in the amputation specialty clinic in the same year is a performance metric that reflects the penetration of amputation specialty services across the system. Between 2009 and 2019, this increased from 2.9 to 12.7% for the overall amputation population and from 4.8 to 26% for those with major limb amputation (Figure 2). This metric improved to a greater extent in RAC facilities; 44% of veterans with major limb amputation seen at a RAC were also seen in the amputation specialty clinic in 2019.⁶

System Hallmarks

One of the primary hallmarks of the ASoC is the interdisciplinary team approach addressing all aspects of management across the continuum of care (Table). The core team consists of a physician, therapist, and prosthetist, and may include a variety of other disciplines based on a veteran’s individual needs. This model promotes veteran-centric care. Comprehensive management of veterans with limb loss includes addressing medical considerations such as residual limb skin health to the prescription of artificial limbs and the provision of therapy services for prosthetic limb gait training.^1,2

Lifelong care for veterans living with limb loss is another hallmark of the ASoC. The provision of care coordination across the continuum of care from acute hospitalization following an amputation to long-term follow-up in the outpatient setting for veteran’s lifespan is essential. Care coordination is provided across the system of care, which assures that a veteran with limb loss can obtain the required services through consultation or referral to a RAC or PANS as needed. Care coordination for the ASoC is facilitated by amputation rehabilitation coordinators at each of the RAC and PANS designated VAMCs.

Integration of services and resource collaboration are additional key aspects of the ASoC (Figure 3). In order to be successful, care of the veteran facing potential amputation or living with the challenges postamputation must be well-integrated into the broader care of the individual. Many veterans who undergo amputation have significant medical comorbidities, including a high prevalence of DM and peripheral vascular disease. Management of these conditions in collaboration with primary care and other medical specialties promotes the achievement of rehabilitation goals. Integration of surgical services and amputation prevention strategies is critical. Another essential element of the system is maintaining amputation specialty care team contact with all veterans with limb loss on at least an annual basis. A clinical practice guideline published in 2017 on lower Limb amputation rehabilitation emphasizes this need for an annual contact and includes a management and referral algorithm to assist primary care providers in the management of veterans with amputation (Figure 4).⁷

Collaboration with external partners has been an important element in the system of care development. The VA has partnered extensively with the US Department of Defense (DoD) to transition service members with amputation from the military health care system to the VA. The VA and DoD also have collaborated through the development and provision of joint provider trainings, clinical practice guidelines, incentive funding programs, and patient education materials. Congress authorized the Extremity Trauma and Amputation Center of Excellence (EACE) in 2009 with the mission to serve as the joint DoD and VA lead element focused on the mitigation, treatment, and rehabilitation of traumatic extremity injuries and amputations. The EACE has several lines of effort, including clinical affairs, research, and global outreach focused on building partnerships and fostering collaboration to optimize quality of life for those with extremity trauma and amputation. The Amputee Coalition, the largest nonprofit consumer-based amputee advocacy organization in the US, has been an important strategic partner for the dissemination of guideline recommendations and patient education as well as the development and provision of peer support services.

Methods

The ASoC created a learning organization to develop and maintain a knowledgeable and highly skilled clinical workforce through the identification of best practices related to amputation rehabilitation and the use of innovative education delivery models. During the past 10 years, the ASoC conducted 9 national, live health care provider training events in conjunction with the DoD. In conjunction with the EACE, the ASoC holds 6 national Grand Rounds sessions each year. Dissemination of information and trainings across both the VA and DoD has been facilitated through a national listserv referred to as the Federal Amputation Interest Group (FAIG), which has > 800 members. Since 2009, the VA, in collaboration with the DoD, has produced 3 clinical practice guidelines (CPGs) related to amputation care. The Lower Limb Amputation CPG was published in 2007 and updated in 2017, and a CPG and associated clinician resources focused on upper extremity amputation were published in 2014.^7,8 In addition to these formal, comprehensive, and evidence-driven guidelines, the ASoC has developed other clinical support documents covering a range of topics from prosthesis prescription candidacy determination to osseointegration. In conjunction with the EACE, The ASoC also has published guidance for clinical implementation of new technologies such as the Mobius Bionics LUKE arm and Dynamic Response Ankle-Foot Orthoses.

The ASoC strives to improve the psychosocial welfare of veterans with amputation and enhance trust in VA amputation care services through sharing results on the quality and timeliness of care. The Commission on Accreditation for Rehabilitation Facilities (CARF) provides an international, independent, peer-reviewed system of accreditation that is widely recognized by federal agencies, state governments, major insurers, and professional organizations.^1,2 CARF offers amputation specialty accreditation for inpatient and outpatient programs that signifies the attainment of a distinguished level of expertise and the provision of a comprehensive spectrum of services related to amputation care and rehabilitation. During its development, the ASoC established the expectation that each of the RAC and PANS designated VAMCs would attain and maintain CARF amputation specialty accreditation. The ASoC has achieved 100% success on this metric.

In addition, the ASoC has completed many other initiatives focused on enhancing trust in VA amputation care services. These include assuring compliance with implementation of the Mission Act as it relates to the provision of amputation care and prosthetic limb delivery so that any services provided in the community are well integrated and at the direction of the amputation specialty team. The ASoC has maintained a strong relationship with the Amputee Coalition to provide veterans with high-quality patient education materials as well as integrated peer support services.

ASoC virtual and face-to-face training events incorporate suicide prevention training for providers. Special focus has been placed on care provision for Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn veterans with conflict-related multiple limb amputations. Although relatively small, this cohort is recognized as a unique and important population due to their unique care needs and increased risk for secondary complications. In 2019, 83% of these individuals were contacted to assure their amputation care needs were being adequately addressed.

Discussion

Over the past 10 years, the ASoC has built a modern, high-performance network of care to best serve veterans with amputation. Maturation of the system has included the addition of 3 new PANS locations to improve access to services as well as to better support geographic regions near large DoD military treatment facilities. The number of ACT designated VAMCs also has grown from 101 to 106 locations. The regional organization of sites has been modified to enhance the availability of referral and consultative services across the system. In addition, the ASoC has supported the development of an upper extremity amputation specialty program for consultation or referral to a highly specialized team of providers well versed in the significant technology advances that have taken place with upper extremity prostheses.⁹

One of the key components to high-performance network development is attaining a clear picture of the clinical demands and service delivery needs of the population served. The Amputee Data Repository was developed with the support of the VHA Support Service Center (VSSC) in order to better understand and track the population of veterans with amputation.⁶ The development and implementation of the Amputee Data Repository took place over several years, and the product was officially released into publication in 2015. The overall goals of this resource are to provide a data system for the ASoC to identify clinical care volumes and patterns of treatment; better understand the demographics of the veteran amputee population; assess the effectiveness of new treatment strategies; and utilize data analysis outcomes to influence clinical practice. The acquisition and analysis of this information will provide justification for the modification of clinical practice and will enhance the quality of care for all veterans with amputation.

Although the ASoC focuses primarily on the provision of clinical services, the system has been leveraged to support research activities and the advancement of artificial limb technologies. For example, ASoC providers and investigators supported the clinical research required to test and optimize the development of the DEKA arm. These research efforts resulted in the US Food and Drug Administration approval and commercialization of this device. Once the device became commercially available as the LUKE arm, the ASoC developed a clinical implementation strategy that assured availability and appropriate prescription and training with the new technology. The VA also has supported research and program development in osseointegration with further investigations and clinical implementation being planned.

Telehealth

The goal of the ASoC is to provide timely access and greater choice to specialty amputation rehabilitation services for veterans as determined by their clinical needs. One key strategy used to achieve this goal has been the expansion of virtual communication tools to enhance access to clinical expertise. Telehealth (Virtual Care) amputation services afford the opportunity to provide specialized clinical expertise to veterans who otherwise may not have access to this level of service or consultation.^1,2 For others, virtual care services reduce the need for travel. The ASoC has leveraged these services effectively to enhance specialty amputation care for veterans in rural areas. Over time, the scope of virtual care services has expanded to provide virtual peer support services as well as care in the veteran’s home.

Another unique example is the use of virtual care to see veterans when they are being provided services by a community prosthetist. This service improves the timeliness of care and reduces the travel burden for the veteran. Between 2009 and 2019, total virtual care encounters to provide amputation-related services grew from 44 encounters to 3,905 encounters (Figure 5). In 2019, 13.8% of veterans seen in a VA outpatient amputation specialty clinic had at least 1 virtual encounter in the same year.⁶

In addition to the expansion of virtual care and building capacity through increasing the number of amputation specialty clinics and providers, the ASoC has used a host of other strategies to improve care access. The development of provider expertise in amputation care has been achieved through the methods of extensive provider training. Implementation of Patient Self-Referral Direct Scheduling allows veterans to access the outpatient amputation specialty clinic without a referral and without having to be seen by their primary care provider. This initiative provides easier and more timely access to amputation specialty services while reducing burden on primary care services. The amputation outpatient specialty clinic was one of a few specialty programs to be an early adopter of national online scheduling. The implementation of this service is still ongoing, but this program gives veterans greater control over scheduling, canceling, and rescheduling appointments.

Conclusions

During the 10 years following its implementation, the VA ASoC has successfully enhanced the quality and consistency of care and rehabilitation services provided to veterans with limb loss through the provision of highly specialized services in the areas of medical care, rehabilitation services, and prosthetic technology. This mission has been accomplished through prioritization and implementation of key strategic initiatives in learning organization creation, trust in VA care, development of a modern, high-performance network, and customer service. Collaborative partnerships both internally within the VA and externally with key stakeholders has facilitated this development, and these will need to be enhanced for future success. Evolving trends in amputation surgery, limb transplantation, artificial limb control and suspension strategies as well as advances in assistive technology also will need to be integrated into best practices and program development.

The US Department of Veterans Affairs (VA) established a formal Amputation System of Care (ASoC) in 2008 with the goal of enhancing the quality and consistency of amputation rehabilitation care for veterans with limb loss.^1,2 Throughout its history, the VA has placed a high priority on the care that is provided to veterans with limb amputation.^1,3 Amputations have medical, physical, social, and psychological ramifications for the veteran and his or her family. Therefore, management of veterans with limb loss requires a comprehensive, coordinated, transdisciplinary program of services throughout the continuum of care. This includes offering the latest practices in medical interventions, artificial limbs, assistive technologies, and rehabilitation strategies to restore function and thereby optimize quality of life.

Amputation System of Care

The ASoC is an integrated system within the Veterans Health Administration (VHA) that provides specialized expertise in amputation rehabilitation incorporating the latest practices in medical management, rehabilitation therapies, artificial limbs, and assistive technologies. The system facilitates patient-centered, gender-sensitive, lifelong care and care coordination across the entire health continuum from acute inpatient hospitalization through a spectrum of inpatient, residential, and outpatient rehabilitation care settings. Through the provision of quality rehabilitation and prosthetic limb care, the ASoC strives to minimize disability and enable the highest level of social, vocational, and recreational success for veterans with an amputation.^1-3

The policy and procedures for the ASoC have been detailed in prior VA Handbooks and in the ASoC Directive.¹ This article highlights the background, population served, and organizational structure of the ASoC by detailing the outcomes and accomplishments of this systems-based approach to longitudinal amputation care between 2009 and 2019. Four core areas of activities and accomplishments are highlighted: (1) learning organization creation; (2) trust in VA care; (3) system modernization; and (4) customer service. This analysis and description of the VA amputation care program serves as a model of amputation care that can be used in the civilian sector. There also is potential for the ASoC to serve as a care model example for other populations within the VA.

Organizational Structure

The ASoC is an integrated, national health care delivery system in which each VA medical center (VAMC) has a specific designation that reflects the level of expertise and accessibility across the system based on an individual veteran’s needs and the specific capabilities of each VAMC.^1-3 The organizational structure for the ASoC is similar to the Polytrauma System of Care in that facilities are divided into 4 tiers.^1,4

For the ASoC, the 4 tiers are Regional Amputation Centers (RAC) at 7 VAMCs, Polytrauma Amputation Network Sites (PANS) at 18 VAMCs, Amputation Clinic Teams (ACT) at 106 VAMCs, and Amputation Points of Contact (APoC) at 22 VAMCs. The RAC locations provide the highest level of specialized expertise in clinical care and prosthetic limb technology and have rehabilitation capabilities to manage the most complicated cases. Like the RAC facilities, PANS provide a full range of clinical and ancillary services to veterans within their catchment area and serve as referral locations for veterans with needs that are more complex. ACT sites have a core amputation specialty team that provides regular follow-up and address ongoing care needs. ACT sites may or may not have full ancillary services, such as surgical subspecialties or an in-house prosthetics laboratory. APoC facilities have at least 1 person on staff who serves as the point of contact for consultation, assessment, and referral of a veteran with an amputation to a facility capable of providing the level of services required.¹

The VA also places a high priority on both primary and secondary amputation prevention. The Preventing Amputations in Veterans Everywhere (PAVE) program and the ASoC coordinate efforts in order to address the prevention of an initial amputation, the rehabilitation of veterans who have had an amputation, and the prevention of a second amputation in those with an amputation.^1,5

Population Served

The ASoC serves veterans with limb loss regardless of the etiology. This includes care of individuals with complex limb trauma and those with other injuries or disease processes resulting in a high likelihood of requiring a limb amputation. In 2019, the VA provided care to 96,519 veterans with amputation, and about half (46,214) had at least 1 major limb amputation, which is defined as an amputation at or proximal to the wrist or ankle.⁶ The majority of veterans with amputation treated within the VA have limb loss resulting from disease processes, such as diabetes mellitus (DM) and peripheral vascular disease (PVD). Amputations caused by these diseases generally occur in the older veteran population and are associated with comorbidities, such as cardiovascular disease, hypertension, and end-stage renal disease. Veterans with amputation due to trauma, including conflict-related injuries, are commonly younger at the time of their amputation. Although the number of conflict-related amputations is small compared with the number of amputations associated with disease processes, both groups require high-quality, comprehensive, lifelong care.

Between 2009 and 2019, the number of veterans with limb loss receiving care in the VA increased 34%.⁶ With advances in vascular surgery and limb-sparing procedures, minor amputations are more common than major limb amputations and more below-knee rather than above-knee amputations have been noted over the same time. However, the high prevalence of DM in the overall veteran population places about 1.8 million veterans at risk for amputation, and it is anticipated that the volume of limb loss in the veteran population will continue to grow and possibly accelerate.⁵

Performance Metrics

Over the past 10 years, the ASoC has focused on ensuring that an amputation specialty care team addresses the needs of veterans with amputation. Between 2009 and 2019, the VA amputation specialty clinics saw a 49% annual increase in the number of unique veterans treated and a 64% annual increase in the number of total clinic encounters (Figure 1).⁶ This growth is attributed to the larger amputation population receiving enhanced access to the specialty team providing consistent, comprehensive, lifelong care.

During this same period, the amputation specialty clinic encounter to unique ratio (a measure of how frequently patients return to the clinic each year) rose from 1.8 in 2009 to 2.3 in 2019 for both the total amputation population and for those with major limb amputation. When looking more specifically at the RAC facilities, the encounter to unique ratio increased from 1.5 to 3.0 over the same time, reflecting the added benefit of having dedicated resources for the amputation specialty program.⁶

Comparing the percentage of veterans with amputation who are seen in the VA for any service with those who also are seen in the amputation specialty clinic in the same year is a performance metric that reflects the penetration of amputation specialty services across the system. Between 2009 and 2019, this increased from 2.9 to 12.7% for the overall amputation population and from 4.8 to 26% for those with major limb amputation (Figure 2). This metric improved to a greater extent in RAC facilities; 44% of veterans with major limb amputation seen at a RAC were also seen in the amputation specialty clinic in 2019.⁶

System Hallmarks

One of the primary hallmarks of the ASoC is the interdisciplinary team approach addressing all aspects of management across the continuum of care (Table). The core team consists of a physician, therapist, and prosthetist, and may include a variety of other disciplines based on a veteran’s individual needs. This model promotes veteran-centric care. Comprehensive management of veterans with limb loss includes addressing medical considerations such as residual limb skin health to the prescription of artificial limbs and the provision of therapy services for prosthetic limb gait training.^1,2

Lifelong care for veterans living with limb loss is another hallmark of the ASoC. The provision of care coordination across the continuum of care from acute hospitalization following an amputation to long-term follow-up in the outpatient setting for veteran’s lifespan is essential. Care coordination is provided across the system of care, which assures that a veteran with limb loss can obtain the required services through consultation or referral to a RAC or PANS as needed. Care coordination for the ASoC is facilitated by amputation rehabilitation coordinators at each of the RAC and PANS designated VAMCs.

Integration of services and resource collaboration are additional key aspects of the ASoC (Figure 3). In order to be successful, care of the veteran facing potential amputation or living with the challenges postamputation must be well-integrated into the broader care of the individual. Many veterans who undergo amputation have significant medical comorbidities, including a high prevalence of DM and peripheral vascular disease. Management of these conditions in collaboration with primary care and other medical specialties promotes the achievement of rehabilitation goals. Integration of surgical services and amputation prevention strategies is critical. Another essential element of the system is maintaining amputation specialty care team contact with all veterans with limb loss on at least an annual basis. A clinical practice guideline published in 2017 on lower Limb amputation rehabilitation emphasizes this need for an annual contact and includes a management and referral algorithm to assist primary care providers in the management of veterans with amputation (Figure 4).⁷

Collaboration with external partners has been an important element in the system of care development. The VA has partnered extensively with the US Department of Defense (DoD) to transition service members with amputation from the military health care system to the VA. The VA and DoD also have collaborated through the development and provision of joint provider trainings, clinical practice guidelines, incentive funding programs, and patient education materials. Congress authorized the Extremity Trauma and Amputation Center of Excellence (EACE) in 2009 with the mission to serve as the joint DoD and VA lead element focused on the mitigation, treatment, and rehabilitation of traumatic extremity injuries and amputations. The EACE has several lines of effort, including clinical affairs, research, and global outreach focused on building partnerships and fostering collaboration to optimize quality of life for those with extremity trauma and amputation. The Amputee Coalition, the largest nonprofit consumer-based amputee advocacy organization in the US, has been an important strategic partner for the dissemination of guideline recommendations and patient education as well as the development and provision of peer support services.

Methods

The ASoC created a learning organization to develop and maintain a knowledgeable and highly skilled clinical workforce through the identification of best practices related to amputation rehabilitation and the use of innovative education delivery models. During the past 10 years, the ASoC conducted 9 national, live health care provider training events in conjunction with the DoD. In conjunction with the EACE, the ASoC holds 6 national Grand Rounds sessions each year. Dissemination of information and trainings across both the VA and DoD has been facilitated through a national listserv referred to as the Federal Amputation Interest Group (FAIG), which has > 800 members. Since 2009, the VA, in collaboration with the DoD, has produced 3 clinical practice guidelines (CPGs) related to amputation care. The Lower Limb Amputation CPG was published in 2007 and updated in 2017, and a CPG and associated clinician resources focused on upper extremity amputation were published in 2014.^7,8 In addition to these formal, comprehensive, and evidence-driven guidelines, the ASoC has developed other clinical support documents covering a range of topics from prosthesis prescription candidacy determination to osseointegration. In conjunction with the EACE, The ASoC also has published guidance for clinical implementation of new technologies such as the Mobius Bionics LUKE arm and Dynamic Response Ankle-Foot Orthoses.

The ASoC strives to improve the psychosocial welfare of veterans with amputation and enhance trust in VA amputation care services through sharing results on the quality and timeliness of care. The Commission on Accreditation for Rehabilitation Facilities (CARF) provides an international, independent, peer-reviewed system of accreditation that is widely recognized by federal agencies, state governments, major insurers, and professional organizations.^1,2 CARF offers amputation specialty accreditation for inpatient and outpatient programs that signifies the attainment of a distinguished level of expertise and the provision of a comprehensive spectrum of services related to amputation care and rehabilitation. During its development, the ASoC established the expectation that each of the RAC and PANS designated VAMCs would attain and maintain CARF amputation specialty accreditation. The ASoC has achieved 100% success on this metric.

In addition, the ASoC has completed many other initiatives focused on enhancing trust in VA amputation care services. These include assuring compliance with implementation of the Mission Act as it relates to the provision of amputation care and prosthetic limb delivery so that any services provided in the community are well integrated and at the direction of the amputation specialty team. The ASoC has maintained a strong relationship with the Amputee Coalition to provide veterans with high-quality patient education materials as well as integrated peer support services.

ASoC virtual and face-to-face training events incorporate suicide prevention training for providers. Special focus has been placed on care provision for Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn veterans with conflict-related multiple limb amputations. Although relatively small, this cohort is recognized as a unique and important population due to their unique care needs and increased risk for secondary complications. In 2019, 83% of these individuals were contacted to assure their amputation care needs were being adequately addressed.

Discussion

Over the past 10 years, the ASoC has built a modern, high-performance network of care to best serve veterans with amputation. Maturation of the system has included the addition of 3 new PANS locations to improve access to services as well as to better support geographic regions near large DoD military treatment facilities. The number of ACT designated VAMCs also has grown from 101 to 106 locations. The regional organization of sites has been modified to enhance the availability of referral and consultative services across the system. In addition, the ASoC has supported the development of an upper extremity amputation specialty program for consultation or referral to a highly specialized team of providers well versed in the significant technology advances that have taken place with upper extremity prostheses.⁹

One of the key components to high-performance network development is attaining a clear picture of the clinical demands and service delivery needs of the population served. The Amputee Data Repository was developed with the support of the VHA Support Service Center (VSSC) in order to better understand and track the population of veterans with amputation.⁶ The development and implementation of the Amputee Data Repository took place over several years, and the product was officially released into publication in 2015. The overall goals of this resource are to provide a data system for the ASoC to identify clinical care volumes and patterns of treatment; better understand the demographics of the veteran amputee population; assess the effectiveness of new treatment strategies; and utilize data analysis outcomes to influence clinical practice. The acquisition and analysis of this information will provide justification for the modification of clinical practice and will enhance the quality of care for all veterans with amputation.

Although the ASoC focuses primarily on the provision of clinical services, the system has been leveraged to support research activities and the advancement of artificial limb technologies. For example, ASoC providers and investigators supported the clinical research required to test and optimize the development of the DEKA arm. These research efforts resulted in the US Food and Drug Administration approval and commercialization of this device. Once the device became commercially available as the LUKE arm, the ASoC developed a clinical implementation strategy that assured availability and appropriate prescription and training with the new technology. The VA also has supported research and program development in osseointegration with further investigations and clinical implementation being planned.

Telehealth

The goal of the ASoC is to provide timely access and greater choice to specialty amputation rehabilitation services for veterans as determined by their clinical needs. One key strategy used to achieve this goal has been the expansion of virtual communication tools to enhance access to clinical expertise. Telehealth (Virtual Care) amputation services afford the opportunity to provide specialized clinical expertise to veterans who otherwise may not have access to this level of service or consultation.^1,2 For others, virtual care services reduce the need for travel. The ASoC has leveraged these services effectively to enhance specialty amputation care for veterans in rural areas. Over time, the scope of virtual care services has expanded to provide virtual peer support services as well as care in the veteran’s home.

Another unique example is the use of virtual care to see veterans when they are being provided services by a community prosthetist. This service improves the timeliness of care and reduces the travel burden for the veteran. Between 2009 and 2019, total virtual care encounters to provide amputation-related services grew from 44 encounters to 3,905 encounters (Figure 5). In 2019, 13.8% of veterans seen in a VA outpatient amputation specialty clinic had at least 1 virtual encounter in the same year.⁶

In addition to the expansion of virtual care and building capacity through increasing the number of amputation specialty clinics and providers, the ASoC has used a host of other strategies to improve care access. The development of provider expertise in amputation care has been achieved through the methods of extensive provider training. Implementation of Patient Self-Referral Direct Scheduling allows veterans to access the outpatient amputation specialty clinic without a referral and without having to be seen by their primary care provider. This initiative provides easier and more timely access to amputation specialty services while reducing burden on primary care services. The amputation outpatient specialty clinic was one of a few specialty programs to be an early adopter of national online scheduling. The implementation of this service is still ongoing, but this program gives veterans greater control over scheduling, canceling, and rescheduling appointments.

Conclusions

During the 10 years following its implementation, the VA ASoC has successfully enhanced the quality and consistency of care and rehabilitation services provided to veterans with limb loss through the provision of highly specialized services in the areas of medical care, rehabilitation services, and prosthetic technology. This mission has been accomplished through prioritization and implementation of key strategic initiatives in learning organization creation, trust in VA care, development of a modern, high-performance network, and customer service. Collaborative partnerships both internally within the VA and externally with key stakeholders has facilitated this development, and these will need to be enhanced for future success. Evolving trends in amputation surgery, limb transplantation, artificial limb control and suspension strategies as well as advances in assistive technology also will need to be integrated into best practices and program development.

The US Department of Veterans Affairs (VA) established a formal Amputation System of Care (ASoC) in 2008 with the goal of enhancing the quality and consistency of amputation rehabilitation care for veterans with limb loss.^1,2 Throughout its history, the VA has placed a high priority on the care that is provided to veterans with limb amputation.^1,3 Amputations have medical, physical, social, and psychological ramifications for the veteran and his or her family. Therefore, management of veterans with limb loss requires a comprehensive, coordinated, transdisciplinary program of services throughout the continuum of care. This includes offering the latest practices in medical interventions, artificial limbs, assistive technologies, and rehabilitation strategies to restore function and thereby optimize quality of life.

Amputation System of Care

The ASoC is an integrated system within the Veterans Health Administration (VHA) that provides specialized expertise in amputation rehabilitation incorporating the latest practices in medical management, rehabilitation therapies, artificial limbs, and assistive technologies. The system facilitates patient-centered, gender-sensitive, lifelong care and care coordination across the entire health continuum from acute inpatient hospitalization through a spectrum of inpatient, residential, and outpatient rehabilitation care settings. Through the provision of quality rehabilitation and prosthetic limb care, the ASoC strives to minimize disability and enable the highest level of social, vocational, and recreational success for veterans with an amputation.^1-3

The policy and procedures for the ASoC have been detailed in prior VA Handbooks and in the ASoC Directive.¹ This article highlights the background, population served, and organizational structure of the ASoC by detailing the outcomes and accomplishments of this systems-based approach to longitudinal amputation care between 2009 and 2019. Four core areas of activities and accomplishments are highlighted: (1) learning organization creation; (2) trust in VA care; (3) system modernization; and (4) customer service. This analysis and description of the VA amputation care program serves as a model of amputation care that can be used in the civilian sector. There also is potential for the ASoC to serve as a care model example for other populations within the VA.

Organizational Structure

The ASoC is an integrated, national health care delivery system in which each VA medical center (VAMC) has a specific designation that reflects the level of expertise and accessibility across the system based on an individual veteran’s needs and the specific capabilities of each VAMC.^1-3 The organizational structure for the ASoC is similar to the Polytrauma System of Care in that facilities are divided into 4 tiers.^1,4

For the ASoC, the 4 tiers are Regional Amputation Centers (RAC) at 7 VAMCs, Polytrauma Amputation Network Sites (PANS) at 18 VAMCs, Amputation Clinic Teams (ACT) at 106 VAMCs, and Amputation Points of Contact (APoC) at 22 VAMCs. The RAC locations provide the highest level of specialized expertise in clinical care and prosthetic limb technology and have rehabilitation capabilities to manage the most complicated cases. Like the RAC facilities, PANS provide a full range of clinical and ancillary services to veterans within their catchment area and serve as referral locations for veterans with needs that are more complex. ACT sites have a core amputation specialty team that provides regular follow-up and address ongoing care needs. ACT sites may or may not have full ancillary services, such as surgical subspecialties or an in-house prosthetics laboratory. APoC facilities have at least 1 person on staff who serves as the point of contact for consultation, assessment, and referral of a veteran with an amputation to a facility capable of providing the level of services required.¹

The VA also places a high priority on both primary and secondary amputation prevention. The Preventing Amputations in Veterans Everywhere (PAVE) program and the ASoC coordinate efforts in order to address the prevention of an initial amputation, the rehabilitation of veterans who have had an amputation, and the prevention of a second amputation in those with an amputation.^1,5

Population Served

The ASoC serves veterans with limb loss regardless of the etiology. This includes care of individuals with complex limb trauma and those with other injuries or disease processes resulting in a high likelihood of requiring a limb amputation. In 2019, the VA provided care to 96,519 veterans with amputation, and about half (46,214) had at least 1 major limb amputation, which is defined as an amputation at or proximal to the wrist or ankle.⁶ The majority of veterans with amputation treated within the VA have limb loss resulting from disease processes, such as diabetes mellitus (DM) and peripheral vascular disease (PVD). Amputations caused by these diseases generally occur in the older veteran population and are associated with comorbidities, such as cardiovascular disease, hypertension, and end-stage renal disease. Veterans with amputation due to trauma, including conflict-related injuries, are commonly younger at the time of their amputation. Although the number of conflict-related amputations is small compared with the number of amputations associated with disease processes, both groups require high-quality, comprehensive, lifelong care.

Between 2009 and 2019, the number of veterans with limb loss receiving care in the VA increased 34%.⁶ With advances in vascular surgery and limb-sparing procedures, minor amputations are more common than major limb amputations and more below-knee rather than above-knee amputations have been noted over the same time. However, the high prevalence of DM in the overall veteran population places about 1.8 million veterans at risk for amputation, and it is anticipated that the volume of limb loss in the veteran population will continue to grow and possibly accelerate.⁵

Performance Metrics

Over the past 10 years, the ASoC has focused on ensuring that an amputation specialty care team addresses the needs of veterans with amputation. Between 2009 and 2019, the VA amputation specialty clinics saw a 49% annual increase in the number of unique veterans treated and a 64% annual increase in the number of total clinic encounters (Figure 1).⁶ This growth is attributed to the larger amputation population receiving enhanced access to the specialty team providing consistent, comprehensive, lifelong care.

During this same period, the amputation specialty clinic encounter to unique ratio (a measure of how frequently patients return to the clinic each year) rose from 1.8 in 2009 to 2.3 in 2019 for both the total amputation population and for those with major limb amputation. When looking more specifically at the RAC facilities, the encounter to unique ratio increased from 1.5 to 3.0 over the same time, reflecting the added benefit of having dedicated resources for the amputation specialty program.⁶

Comparing the percentage of veterans with amputation who are seen in the VA for any service with those who also are seen in the amputation specialty clinic in the same year is a performance metric that reflects the penetration of amputation specialty services across the system. Between 2009 and 2019, this increased from 2.9 to 12.7% for the overall amputation population and from 4.8 to 26% for those with major limb amputation (Figure 2). This metric improved to a greater extent in RAC facilities; 44% of veterans with major limb amputation seen at a RAC were also seen in the amputation specialty clinic in 2019.⁶

System Hallmarks

One of the primary hallmarks of the ASoC is the interdisciplinary team approach addressing all aspects of management across the continuum of care (Table). The core team consists of a physician, therapist, and prosthetist, and may include a variety of other disciplines based on a veteran’s individual needs. This model promotes veteran-centric care. Comprehensive management of veterans with limb loss includes addressing medical considerations such as residual limb skin health to the prescription of artificial limbs and the provision of therapy services for prosthetic limb gait training.^1,2

Lifelong care for veterans living with limb loss is another hallmark of the ASoC. The provision of care coordination across the continuum of care from acute hospitalization following an amputation to long-term follow-up in the outpatient setting for veteran’s lifespan is essential. Care coordination is provided across the system of care, which assures that a veteran with limb loss can obtain the required services through consultation or referral to a RAC or PANS as needed. Care coordination for the ASoC is facilitated by amputation rehabilitation coordinators at each of the RAC and PANS designated VAMCs.

Integration of services and resource collaboration are additional key aspects of the ASoC (Figure 3). In order to be successful, care of the veteran facing potential amputation or living with the challenges postamputation must be well-integrated into the broader care of the individual. Many veterans who undergo amputation have significant medical comorbidities, including a high prevalence of DM and peripheral vascular disease. Management of these conditions in collaboration with primary care and other medical specialties promotes the achievement of rehabilitation goals. Integration of surgical services and amputation prevention strategies is critical. Another essential element of the system is maintaining amputation specialty care team contact with all veterans with limb loss on at least an annual basis. A clinical practice guideline published in 2017 on lower Limb amputation rehabilitation emphasizes this need for an annual contact and includes a management and referral algorithm to assist primary care providers in the management of veterans with amputation (Figure 4).⁷

Collaboration with external partners has been an important element in the system of care development. The VA has partnered extensively with the US Department of Defense (DoD) to transition service members with amputation from the military health care system to the VA. The VA and DoD also have collaborated through the development and provision of joint provider trainings, clinical practice guidelines, incentive funding programs, and patient education materials. Congress authorized the Extremity Trauma and Amputation Center of Excellence (EACE) in 2009 with the mission to serve as the joint DoD and VA lead element focused on the mitigation, treatment, and rehabilitation of traumatic extremity injuries and amputations. The EACE has several lines of effort, including clinical affairs, research, and global outreach focused on building partnerships and fostering collaboration to optimize quality of life for those with extremity trauma and amputation. The Amputee Coalition, the largest nonprofit consumer-based amputee advocacy organization in the US, has been an important strategic partner for the dissemination of guideline recommendations and patient education as well as the development and provision of peer support services.

Methods

The ASoC created a learning organization to develop and maintain a knowledgeable and highly skilled clinical workforce through the identification of best practices related to amputation rehabilitation and the use of innovative education delivery models. During the past 10 years, the ASoC conducted 9 national, live health care provider training events in conjunction with the DoD. In conjunction with the EACE, the ASoC holds 6 national Grand Rounds sessions each year. Dissemination of information and trainings across both the VA and DoD has been facilitated through a national listserv referred to as the Federal Amputation Interest Group (FAIG), which has > 800 members. Since 2009, the VA, in collaboration with the DoD, has produced 3 clinical practice guidelines (CPGs) related to amputation care. The Lower Limb Amputation CPG was published in 2007 and updated in 2017, and a CPG and associated clinician resources focused on upper extremity amputation were published in 2014.^7,8 In addition to these formal, comprehensive, and evidence-driven guidelines, the ASoC has developed other clinical support documents covering a range of topics from prosthesis prescription candidacy determination to osseointegration. In conjunction with the EACE, The ASoC also has published guidance for clinical implementation of new technologies such as the Mobius Bionics LUKE arm and Dynamic Response Ankle-Foot Orthoses.

The ASoC strives to improve the psychosocial welfare of veterans with amputation and enhance trust in VA amputation care services through sharing results on the quality and timeliness of care. The Commission on Accreditation for Rehabilitation Facilities (CARF) provides an international, independent, peer-reviewed system of accreditation that is widely recognized by federal agencies, state governments, major insurers, and professional organizations.^1,2 CARF offers amputation specialty accreditation for inpatient and outpatient programs that signifies the attainment of a distinguished level of expertise and the provision of a comprehensive spectrum of services related to amputation care and rehabilitation. During its development, the ASoC established the expectation that each of the RAC and PANS designated VAMCs would attain and maintain CARF amputation specialty accreditation. The ASoC has achieved 100% success on this metric.

In addition, the ASoC has completed many other initiatives focused on enhancing trust in VA amputation care services. These include assuring compliance with implementation of the Mission Act as it relates to the provision of amputation care and prosthetic limb delivery so that any services provided in the community are well integrated and at the direction of the amputation specialty team. The ASoC has maintained a strong relationship with the Amputee Coalition to provide veterans with high-quality patient education materials as well as integrated peer support services.

ASoC virtual and face-to-face training events incorporate suicide prevention training for providers. Special focus has been placed on care provision for Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn veterans with conflict-related multiple limb amputations. Although relatively small, this cohort is recognized as a unique and important population due to their unique care needs and increased risk for secondary complications. In 2019, 83% of these individuals were contacted to assure their amputation care needs were being adequately addressed.

Discussion

Over the past 10 years, the ASoC has built a modern, high-performance network of care to best serve veterans with amputation. Maturation of the system has included the addition of 3 new PANS locations to improve access to services as well as to better support geographic regions near large DoD military treatment facilities. The number of ACT designated VAMCs also has grown from 101 to 106 locations. The regional organization of sites has been modified to enhance the availability of referral and consultative services across the system. In addition, the ASoC has supported the development of an upper extremity amputation specialty program for consultation or referral to a highly specialized team of providers well versed in the significant technology advances that have taken place with upper extremity prostheses.⁹

One of the key components to high-performance network development is attaining a clear picture of the clinical demands and service delivery needs of the population served. The Amputee Data Repository was developed with the support of the VHA Support Service Center (VSSC) in order to better understand and track the population of veterans with amputation.⁶ The development and implementation of the Amputee Data Repository took place over several years, and the product was officially released into publication in 2015. The overall goals of this resource are to provide a data system for the ASoC to identify clinical care volumes and patterns of treatment; better understand the demographics of the veteran amputee population; assess the effectiveness of new treatment strategies; and utilize data analysis outcomes to influence clinical practice. The acquisition and analysis of this information will provide justification for the modification of clinical practice and will enhance the quality of care for all veterans with amputation.

Although the ASoC focuses primarily on the provision of clinical services, the system has been leveraged to support research activities and the advancement of artificial limb technologies. For example, ASoC providers and investigators supported the clinical research required to test and optimize the development of the DEKA arm. These research efforts resulted in the US Food and Drug Administration approval and commercialization of this device. Once the device became commercially available as the LUKE arm, the ASoC developed a clinical implementation strategy that assured availability and appropriate prescription and training with the new technology. The VA also has supported research and program development in osseointegration with further investigations and clinical implementation being planned.

Telehealth

The goal of the ASoC is to provide timely access and greater choice to specialty amputation rehabilitation services for veterans as determined by their clinical needs. One key strategy used to achieve this goal has been the expansion of virtual communication tools to enhance access to clinical expertise. Telehealth (Virtual Care) amputation services afford the opportunity to provide specialized clinical expertise to veterans who otherwise may not have access to this level of service or consultation.^1,2 For others, virtual care services reduce the need for travel. The ASoC has leveraged these services effectively to enhance specialty amputation care for veterans in rural areas. Over time, the scope of virtual care services has expanded to provide virtual peer support services as well as care in the veteran’s home.

Another unique example is the use of virtual care to see veterans when they are being provided services by a community prosthetist. This service improves the timeliness of care and reduces the travel burden for the veteran. Between 2009 and 2019, total virtual care encounters to provide amputation-related services grew from 44 encounters to 3,905 encounters (Figure 5). In 2019, 13.8% of veterans seen in a VA outpatient amputation specialty clinic had at least 1 virtual encounter in the same year.⁶

In addition to the expansion of virtual care and building capacity through increasing the number of amputation specialty clinics and providers, the ASoC has used a host of other strategies to improve care access. The development of provider expertise in amputation care has been achieved through the methods of extensive provider training. Implementation of Patient Self-Referral Direct Scheduling allows veterans to access the outpatient amputation specialty clinic without a referral and without having to be seen by their primary care provider. This initiative provides easier and more timely access to amputation specialty services while reducing burden on primary care services. The amputation outpatient specialty clinic was one of a few specialty programs to be an early adopter of national online scheduling. The implementation of this service is still ongoing, but this program gives veterans greater control over scheduling, canceling, and rescheduling appointments.

Conclusions

During the 10 years following its implementation, the VA ASoC has successfully enhanced the quality and consistency of care and rehabilitation services provided to veterans with limb loss through the provision of highly specialized services in the areas of medical care, rehabilitation services, and prosthetic technology. This mission has been accomplished through prioritization and implementation of key strategic initiatives in learning organization creation, trust in VA care, development of a modern, high-performance network, and customer service. Collaborative partnerships both internally within the VA and externally with key stakeholders has facilitated this development, and these will need to be enhanced for future success. Evolving trends in amputation surgery, limb transplantation, artificial limb control and suspension strategies as well as advances in assistive technology also will need to be integrated into best practices and program development.

In late 2019 a new pandemic started in Wuhan, China, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to its similarities with the virus responsible for the SARS outbreak of 2003. The disease manifestations are named coronavirus disease 2019 (COVID-19).¹

Pseudothrombocytopenia, or platelet clumping, visualized on the peripheral blood smear, is a common cause for artificial thrombocytopenia laboratory reporting and is frequently attributed to laboratory artifact. In this case presentation, a critically ill patient with COVID-19 developed pan-pseudothrombocytopenia (ethylenediaminetetraacetic acid [EDTA], sodium citrate, and heparin tubes) just prior to his death from a ST-segment elevation myocardial infarction (STEMI) in the setting of therapeutic anticoagulation during a prolonged hospitalization. This case raises the possibility that pseudothrombocytopenia in the setting of COVID-19 critical illness may represent an ominous feature of COVID-19-associated coagulopathy (CAC). Furthermore, it prompts the question whether pseudothrombocytopenia in this setting is representative of increased platelet aggregation activity in vivo.

Case Presentation

A 50-year-old African American man who was diagnosed with COVID-19 3 days prior to admission presented to the emergency department of the W.G. (Bill) Hefner VA Medical Center in Salisbury, North Carolina, with worsening dyspnea and fever. His primary chronic medical problems included obesity (body mass index, 33), type 2 diabetes mellitus (hemoglobin A_1c 2 months prior of 6.6%), migraine headaches, and obstructive sleep apnea. Shortly after presentation, his respiratory status declined, requiring intubation. He was admitted to the medical intensive care unit for further management.

Notable findings at admission included > 20 mcg/mL FEU D-dimer (normal range, 0-0.56 mcg/mL FEU), 20.4 mg/dL C-reactive protein (normal range, < 1 mg/dL), 30 mm/h erythrocyte sedimentation rate (normal range, 0-25 mm/h), and 3.56 ng/mL procalcitonin (normal range, 0.05-1.99 ng/mL). Patient’s hemoglobin and platelet counts were normal. Empiric antimicrobial therapy was initiated with ceftriaxone (2 g IV daily) and doxycycline (100 mg IV twice daily) due to concern of superimposed infection in the setting of an elevated procalcitonin.

A heparin infusion was initiated (5,000 U IV bolus followed by continuous infusion with goal partial thromboplastin time [PTT] of 1.5x the upper limit of normal) on admission to treat CAC. Renal function worsened requiring intermittent renal replacement therapy on day 3. His lactate dehydrogenase was elevated to 1,188 U/L (normal range: 100-240 U/L) and ferritin was elevated to 2,603 ng/mL (normal range: 25-350 ng/mL) (Table). Initial neuromuscular blockade and prone positioning maneuvers were instituted to optimize oxygenation based on the latest literature for respiratory distress in the COVID-19 management.²

Intermittent norepinephrine infusion (5 mcg/min with a 2 mcg/min titration every 5 minutes as needed to maintain mean arterial pressure of > 65 mm Hg) was required for hemodynamic support throughout the patient’s course. Several therapies for COVID-19 were considered and were a reflection of the rapidly evolving literature during the care of patients with this disease. The patient originally received hydroxychloroquine (200 mg by mouth twice daily) in accordance with the US Department of Veterans Affairs (VA) institutional protocol between day 2 and day 4; however, hydroxychloroquine was stopped due to concerns of QTc prolongation. The patient also received 1 unit of convalescent plasma on day 6 after being enrolled in the expanded access program.³ The patient was not a candidate for remdesivir due to his unstable renal function and need for vasopressors. Finally, interleukin-6 inhibitors also were considered; however, the risk of superimposed infection precluded its use.

On day 7 antimicrobial therapy was transitioned to linezolid (600 mg IV twice daily) due to the persistence of fever and a portable chest radiograph revealing diffuse infiltrates throughout the bilateral lungs, worse compared with prior radiograph on day 5, suggesting a worsening of pneumonia. On day 12, the patient was transitioned to cefepime (1 gram IV daily) to broaden antimicrobial coverage and was continued thereafter. Blood cultures were negative throughout his hospitalization.

Given his worsening clinical scenario there was a question about whether or not the patient was still shedding virus for prognostic and therapeutic implications. Therefore, his SARS-CoV-2 test by polymerase chain reaction nasopharyngeal was positive again on day 18. On day 20, the patient developed leukocytosis, his fever persisted, and a portable chest radiograph revealed extensive bilateral pulmonary opacities with focal worsening in left lower base. Due to this constellation of findings, a vancomycin IV (1,500 mg once) was started for empirical treatment of hospital-acquired pneumonia. Sputum samples obtained on day 20 revealed Staphylococcus aureus on subsequent days.

From a hematologic perspective, on day 9 due to challenges to maintain a therapeutic level of anticoagulation with heparin infusion thought to be related to antithrombin deficiency, anticoagulation was changed to argatroban infusion (0.5 mcg/kg/min targeting a PTT of 70-105 seconds) for ongoing management of CAC. Although D-dimer was > 20 mcg/mL FEU on admission and on days 4 and 5, D-dimer trended down to 12.5 mcg/mL FEU on day 16.

Throughout the patient’s hospital stay, no significant bleeding was seen. Hemoglobin was 15.2 g/dL on admission, but anemia developed with a nadir of 6.5 g/dL, warranting transfusion of red blood cells on day 22. Platelet count was 165,000 per microliter on admission and remained within normal limits until platelet clumping was noted on day 15 laboratory collection.

Hematology was consulted on day 20 to obtain an accurate platelet count. A peripheral blood smear from a sodium citrate containing tube was remarkable for prominent platelet clumping, particularly at the periphery of the slide (Figure 1). Platelet clumping was reproduced in samples containing EDTA and heparin. Other features of the peripheral blood smear included the presence of echinocytes with rare schistocytes. To investigate for presence of disseminated intravascular coagulation on day 22, fibrinogen was found to be mildly elevated at 538 mg/dL (normal range: 243-517 mg/dL) and a D-dimer value of 11.96 mcg/mL FEU.

On day 22, the patient’s ventilator requirements escalated to requiring 100% FiO₂ and 10 cm H₂0 of positive end-expiratory pressure with mean arterial pressures in the 50 to 60 mm Hg range. Within 30 minutes an electrocardiogram (EKG) obtained revealed a STEMI (Figure 2). Troponin was measured at 0.65 ng/mL (normal range: 0.02-0.06 ng/mL). Just after an EKG was performed, the patient developed a ventricular fibrillation arrest and was unable to obtain return of spontaneous circulation. The patient was pronounced dead. The family declined an autopsy.

Discussion

Pseudothrombocytopenia, or platelet clumping (agglutination), is estimated to be present in up to 2% of hospitalized patients.⁴ Pseudothrombocytopenia was found to be the root cause of thrombocytopenia hematology consultations in up to 4% of hospitalized patients.⁵ The etiology is commonly ascribed to EDTA inducing a conformational change in the GpIIb-IIIa platelet complex, rendering it susceptible to binding of autoantibodies, which cause subsequent platelet agglutination.⁶ In most cases (83%), the use of a non-EDTA anticoagulant, such as sodium citrate, resolves the platelet agglutination and allows for accurate platelet count reporting.⁴ Pseudothrombocytopenia in most cases is considered an in vitro finding without clinical relevance.⁷ However, in this patient’s case, his pan-pseudothrombocytopenia was temporally associated with an arterial occlusive event (STEMI) leading to his demise despite therapeutic anticoagulation in the setting of CAC. This temporal association raises the possibility that pseudothrombocytopenia seen on the peripheral blood smear is an accurate representation of in vivo activity.

Pseudothrombocytopenia has been associated with sepsis from bacterial and viral causes as well as autoimmune and medication effect.^4,8-10 Li and colleagues reported transient EDTA-dependent pseudothrombocytopenia in a patient with COVID-19 infection; however, platelet clumping resolved with use of a citrate tube, and the EDTA-dependent pseudothrombocytopenia phenomenon resolved with patient recovery.¹¹ The frequency of COVID-19-related pseudothrombocytopenia is currently unknown.

Although the understanding of COVID-19-associated CAC continues to evolve, it seems that initial reports support the idea that hemostatic dysfunction tends to more thrombosis than to bleeding.¹² Rather than overt disseminated intravascular coagulation with reduced fibrinogen and bleeding, CAC is more closely associated with blood clotting, as demonstrated by autopsy studies revealing microvascular thrombosis in the lungs.¹³ The D-dimer test has been identified as the most useful biomarker by the International Society of Thrombosis and Hemostasis to screen for CAC and stratify patients who warrant admission or closer monitoring.¹² Other identified features of CAC include prolonged prothrombin time and thrombocytopenia.¹²

There have been varying clinical approaches to CAC management. A retrospective review found that prophylactic heparin doses were associated with improved mortality in those with elevated D-dimer > 3.0 mg/L.¹⁴ There continues to be a diversity of varying clinical approaches with many medical centers advocating for an intensified prophylactic twice daily low molecular-weight heparin compared with others advocating for full therapeutic dose anticoagulation for patients with elevated D-dimer.¹⁵ This patient was treated aggressively with full-dose anticoagulation, and despite his having a down-trend in D-dimer, he suffered a lethal arterial thrombosis in the form of a STEMI.

Varatharajah and Rajah believe that CAC is more closely aligned with endotheliopathy-associated vascular microthrombotic disease (EA-VMTD).¹⁶ EA-VMTD involves a disequilibrium state between insufficient ADAMTS13 enzyme and excessive exocytosis of ultralarge von Willebrand factor (ULvWF) multimers from endothelial cells affected by COVID-19. This theory endorses that ULvWF multimers cause platelet adhesion and subsequent rapid platelet activation, causing platelet aggregation and formation of microthrombi.¹⁷ As these platelet aggregates grow to a certain point, they can no longer remain adhered to ULvWF, causing these platelet aggregates to be released into the circulation and causing thrombotic sequelae.¹⁶ Therefore, a plausible explanation for the patient’s pan-pseudothrombocytopenia may be the detection of these circulating platelet aggregates, which, in turn, was the same process leading to his STEMI. Interestingly, this patient’s fatal arterial event occurred in the presence of therapeutic anticoagulation, raising the question of whether other therapeutic interventions to treat CAC, such as further antithrombotic therapy (eg, aspirin, clopidogrel) or novel strategies would be of benefit.

Conclusions

This patient’s case highlights the presence of pan-pseudothrombocytopenia despite the use of a sodium citrate and heparin containing tube in a COVID-19 infection with multiorgan dysfunction. This developed 1 week prior to the patient suffering a STEMI despite therapeutic anticoagulation. Although the exact nature of CAC remains to be worked out, it is possible that platelet agglutination/clumping seen on the peripheral blood smear is representative of in vivo activity and serves as a harbinger for worsening thrombosis. The frequency of such phenomenon and efficacy of further interventions has yet to be explored.

In late 2019 a new pandemic started in Wuhan, China, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to its similarities with the virus responsible for the SARS outbreak of 2003. The disease manifestations are named coronavirus disease 2019 (COVID-19).¹

Pseudothrombocytopenia, or platelet clumping, visualized on the peripheral blood smear, is a common cause for artificial thrombocytopenia laboratory reporting and is frequently attributed to laboratory artifact. In this case presentation, a critically ill patient with COVID-19 developed pan-pseudothrombocytopenia (ethylenediaminetetraacetic acid [EDTA], sodium citrate, and heparin tubes) just prior to his death from a ST-segment elevation myocardial infarction (STEMI) in the setting of therapeutic anticoagulation during a prolonged hospitalization. This case raises the possibility that pseudothrombocytopenia in the setting of COVID-19 critical illness may represent an ominous feature of COVID-19-associated coagulopathy (CAC). Furthermore, it prompts the question whether pseudothrombocytopenia in this setting is representative of increased platelet aggregation activity in vivo.

Case Presentation

A 50-year-old African American man who was diagnosed with COVID-19 3 days prior to admission presented to the emergency department of the W.G. (Bill) Hefner VA Medical Center in Salisbury, North Carolina, with worsening dyspnea and fever. His primary chronic medical problems included obesity (body mass index, 33), type 2 diabetes mellitus (hemoglobin A_1c 2 months prior of 6.6%), migraine headaches, and obstructive sleep apnea. Shortly after presentation, his respiratory status declined, requiring intubation. He was admitted to the medical intensive care unit for further management.

Notable findings at admission included > 20 mcg/mL FEU D-dimer (normal range, 0-0.56 mcg/mL FEU), 20.4 mg/dL C-reactive protein (normal range, < 1 mg/dL), 30 mm/h erythrocyte sedimentation rate (normal range, 0-25 mm/h), and 3.56 ng/mL procalcitonin (normal range, 0.05-1.99 ng/mL). Patient’s hemoglobin and platelet counts were normal. Empiric antimicrobial therapy was initiated with ceftriaxone (2 g IV daily) and doxycycline (100 mg IV twice daily) due to concern of superimposed infection in the setting of an elevated procalcitonin.

A heparin infusion was initiated (5,000 U IV bolus followed by continuous infusion with goal partial thromboplastin time [PTT] of 1.5x the upper limit of normal) on admission to treat CAC. Renal function worsened requiring intermittent renal replacement therapy on day 3. His lactate dehydrogenase was elevated to 1,188 U/L (normal range: 100-240 U/L) and ferritin was elevated to 2,603 ng/mL (normal range: 25-350 ng/mL) (Table). Initial neuromuscular blockade and prone positioning maneuvers were instituted to optimize oxygenation based on the latest literature for respiratory distress in the COVID-19 management.²

Intermittent norepinephrine infusion (5 mcg/min with a 2 mcg/min titration every 5 minutes as needed to maintain mean arterial pressure of > 65 mm Hg) was required for hemodynamic support throughout the patient’s course. Several therapies for COVID-19 were considered and were a reflection of the rapidly evolving literature during the care of patients with this disease. The patient originally received hydroxychloroquine (200 mg by mouth twice daily) in accordance with the US Department of Veterans Affairs (VA) institutional protocol between day 2 and day 4; however, hydroxychloroquine was stopped due to concerns of QTc prolongation. The patient also received 1 unit of convalescent plasma on day 6 after being enrolled in the expanded access program.³ The patient was not a candidate for remdesivir due to his unstable renal function and need for vasopressors. Finally, interleukin-6 inhibitors also were considered; however, the risk of superimposed infection precluded its use.

On day 7 antimicrobial therapy was transitioned to linezolid (600 mg IV twice daily) due to the persistence of fever and a portable chest radiograph revealing diffuse infiltrates throughout the bilateral lungs, worse compared with prior radiograph on day 5, suggesting a worsening of pneumonia. On day 12, the patient was transitioned to cefepime (1 gram IV daily) to broaden antimicrobial coverage and was continued thereafter. Blood cultures were negative throughout his hospitalization.

Given his worsening clinical scenario there was a question about whether or not the patient was still shedding virus for prognostic and therapeutic implications. Therefore, his SARS-CoV-2 test by polymerase chain reaction nasopharyngeal was positive again on day 18. On day 20, the patient developed leukocytosis, his fever persisted, and a portable chest radiograph revealed extensive bilateral pulmonary opacities with focal worsening in left lower base. Due to this constellation of findings, a vancomycin IV (1,500 mg once) was started for empirical treatment of hospital-acquired pneumonia. Sputum samples obtained on day 20 revealed Staphylococcus aureus on subsequent days.

From a hematologic perspective, on day 9 due to challenges to maintain a therapeutic level of anticoagulation with heparin infusion thought to be related to antithrombin deficiency, anticoagulation was changed to argatroban infusion (0.5 mcg/kg/min targeting a PTT of 70-105 seconds) for ongoing management of CAC. Although D-dimer was > 20 mcg/mL FEU on admission and on days 4 and 5, D-dimer trended down to 12.5 mcg/mL FEU on day 16.

Throughout the patient’s hospital stay, no significant bleeding was seen. Hemoglobin was 15.2 g/dL on admission, but anemia developed with a nadir of 6.5 g/dL, warranting transfusion of red blood cells on day 22. Platelet count was 165,000 per microliter on admission and remained within normal limits until platelet clumping was noted on day 15 laboratory collection.

Hematology was consulted on day 20 to obtain an accurate platelet count. A peripheral blood smear from a sodium citrate containing tube was remarkable for prominent platelet clumping, particularly at the periphery of the slide (Figure 1). Platelet clumping was reproduced in samples containing EDTA and heparin. Other features of the peripheral blood smear included the presence of echinocytes with rare schistocytes. To investigate for presence of disseminated intravascular coagulation on day 22, fibrinogen was found to be mildly elevated at 538 mg/dL (normal range: 243-517 mg/dL) and a D-dimer value of 11.96 mcg/mL FEU.

On day 22, the patient’s ventilator requirements escalated to requiring 100% FiO₂ and 10 cm H₂0 of positive end-expiratory pressure with mean arterial pressures in the 50 to 60 mm Hg range. Within 30 minutes an electrocardiogram (EKG) obtained revealed a STEMI (Figure 2). Troponin was measured at 0.65 ng/mL (normal range: 0.02-0.06 ng/mL). Just after an EKG was performed, the patient developed a ventricular fibrillation arrest and was unable to obtain return of spontaneous circulation. The patient was pronounced dead. The family declined an autopsy.

Discussion

Pseudothrombocytopenia, or platelet clumping (agglutination), is estimated to be present in up to 2% of hospitalized patients.⁴ Pseudothrombocytopenia was found to be the root cause of thrombocytopenia hematology consultations in up to 4% of hospitalized patients.⁵ The etiology is commonly ascribed to EDTA inducing a conformational change in the GpIIb-IIIa platelet complex, rendering it susceptible to binding of autoantibodies, which cause subsequent platelet agglutination.⁶ In most cases (83%), the use of a non-EDTA anticoagulant, such as sodium citrate, resolves the platelet agglutination and allows for accurate platelet count reporting.⁴ Pseudothrombocytopenia in most cases is considered an in vitro finding without clinical relevance.⁷ However, in this patient’s case, his pan-pseudothrombocytopenia was temporally associated with an arterial occlusive event (STEMI) leading to his demise despite therapeutic anticoagulation in the setting of CAC. This temporal association raises the possibility that pseudothrombocytopenia seen on the peripheral blood smear is an accurate representation of in vivo activity.

Pseudothrombocytopenia has been associated with sepsis from bacterial and viral causes as well as autoimmune and medication effect.^4,8-10 Li and colleagues reported transient EDTA-dependent pseudothrombocytopenia in a patient with COVID-19 infection; however, platelet clumping resolved with use of a citrate tube, and the EDTA-dependent pseudothrombocytopenia phenomenon resolved with patient recovery.¹¹ The frequency of COVID-19-related pseudothrombocytopenia is currently unknown.

Although the understanding of COVID-19-associated CAC continues to evolve, it seems that initial reports support the idea that hemostatic dysfunction tends to more thrombosis than to bleeding.¹² Rather than overt disseminated intravascular coagulation with reduced fibrinogen and bleeding, CAC is more closely associated with blood clotting, as demonstrated by autopsy studies revealing microvascular thrombosis in the lungs.¹³ The D-dimer test has been identified as the most useful biomarker by the International Society of Thrombosis and Hemostasis to screen for CAC and stratify patients who warrant admission or closer monitoring.¹² Other identified features of CAC include prolonged prothrombin time and thrombocytopenia.¹²

There have been varying clinical approaches to CAC management. A retrospective review found that prophylactic heparin doses were associated with improved mortality in those with elevated D-dimer > 3.0 mg/L.¹⁴ There continues to be a diversity of varying clinical approaches with many medical centers advocating for an intensified prophylactic twice daily low molecular-weight heparin compared with others advocating for full therapeutic dose anticoagulation for patients with elevated D-dimer.¹⁵ This patient was treated aggressively with full-dose anticoagulation, and despite his having a down-trend in D-dimer, he suffered a lethal arterial thrombosis in the form of a STEMI.

Varatharajah and Rajah believe that CAC is more closely aligned with endotheliopathy-associated vascular microthrombotic disease (EA-VMTD).¹⁶ EA-VMTD involves a disequilibrium state between insufficient ADAMTS13 enzyme and excessive exocytosis of ultralarge von Willebrand factor (ULvWF) multimers from endothelial cells affected by COVID-19. This theory endorses that ULvWF multimers cause platelet adhesion and subsequent rapid platelet activation, causing platelet aggregation and formation of microthrombi.¹⁷ As these platelet aggregates grow to a certain point, they can no longer remain adhered to ULvWF, causing these platelet aggregates to be released into the circulation and causing thrombotic sequelae.¹⁶ Therefore, a plausible explanation for the patient’s pan-pseudothrombocytopenia may be the detection of these circulating platelet aggregates, which, in turn, was the same process leading to his STEMI. Interestingly, this patient’s fatal arterial event occurred in the presence of therapeutic anticoagulation, raising the question of whether other therapeutic interventions to treat CAC, such as further antithrombotic therapy (eg, aspirin, clopidogrel) or novel strategies would be of benefit.

Conclusions

This patient’s case highlights the presence of pan-pseudothrombocytopenia despite the use of a sodium citrate and heparin containing tube in a COVID-19 infection with multiorgan dysfunction. This developed 1 week prior to the patient suffering a STEMI despite therapeutic anticoagulation. Although the exact nature of CAC remains to be worked out, it is possible that platelet agglutination/clumping seen on the peripheral blood smear is representative of in vivo activity and serves as a harbinger for worsening thrombosis. The frequency of such phenomenon and efficacy of further interventions has yet to be explored.

In late 2019 a new pandemic started in Wuhan, China, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to its similarities with the virus responsible for the SARS outbreak of 2003. The disease manifestations are named coronavirus disease 2019 (COVID-19).¹

Pseudothrombocytopenia, or platelet clumping, visualized on the peripheral blood smear, is a common cause for artificial thrombocytopenia laboratory reporting and is frequently attributed to laboratory artifact. In this case presentation, a critically ill patient with COVID-19 developed pan-pseudothrombocytopenia (ethylenediaminetetraacetic acid [EDTA], sodium citrate, and heparin tubes) just prior to his death from a ST-segment elevation myocardial infarction (STEMI) in the setting of therapeutic anticoagulation during a prolonged hospitalization. This case raises the possibility that pseudothrombocytopenia in the setting of COVID-19 critical illness may represent an ominous feature of COVID-19-associated coagulopathy (CAC). Furthermore, it prompts the question whether pseudothrombocytopenia in this setting is representative of increased platelet aggregation activity in vivo.

Case Presentation

A 50-year-old African American man who was diagnosed with COVID-19 3 days prior to admission presented to the emergency department of the W.G. (Bill) Hefner VA Medical Center in Salisbury, North Carolina, with worsening dyspnea and fever. His primary chronic medical problems included obesity (body mass index, 33), type 2 diabetes mellitus (hemoglobin A_1c 2 months prior of 6.6%), migraine headaches, and obstructive sleep apnea. Shortly after presentation, his respiratory status declined, requiring intubation. He was admitted to the medical intensive care unit for further management.

Notable findings at admission included > 20 mcg/mL FEU D-dimer (normal range, 0-0.56 mcg/mL FEU), 20.4 mg/dL C-reactive protein (normal range, < 1 mg/dL), 30 mm/h erythrocyte sedimentation rate (normal range, 0-25 mm/h), and 3.56 ng/mL procalcitonin (normal range, 0.05-1.99 ng/mL). Patient’s hemoglobin and platelet counts were normal. Empiric antimicrobial therapy was initiated with ceftriaxone (2 g IV daily) and doxycycline (100 mg IV twice daily) due to concern of superimposed infection in the setting of an elevated procalcitonin.

A heparin infusion was initiated (5,000 U IV bolus followed by continuous infusion with goal partial thromboplastin time [PTT] of 1.5x the upper limit of normal) on admission to treat CAC. Renal function worsened requiring intermittent renal replacement therapy on day 3. His lactate dehydrogenase was elevated to 1,188 U/L (normal range: 100-240 U/L) and ferritin was elevated to 2,603 ng/mL (normal range: 25-350 ng/mL) (Table). Initial neuromuscular blockade and prone positioning maneuvers were instituted to optimize oxygenation based on the latest literature for respiratory distress in the COVID-19 management.²

Intermittent norepinephrine infusion (5 mcg/min with a 2 mcg/min titration every 5 minutes as needed to maintain mean arterial pressure of > 65 mm Hg) was required for hemodynamic support throughout the patient’s course. Several therapies for COVID-19 were considered and were a reflection of the rapidly evolving literature during the care of patients with this disease. The patient originally received hydroxychloroquine (200 mg by mouth twice daily) in accordance with the US Department of Veterans Affairs (VA) institutional protocol between day 2 and day 4; however, hydroxychloroquine was stopped due to concerns of QTc prolongation. The patient also received 1 unit of convalescent plasma on day 6 after being enrolled in the expanded access program.³ The patient was not a candidate for remdesivir due to his unstable renal function and need for vasopressors. Finally, interleukin-6 inhibitors also were considered; however, the risk of superimposed infection precluded its use.

On day 7 antimicrobial therapy was transitioned to linezolid (600 mg IV twice daily) due to the persistence of fever and a portable chest radiograph revealing diffuse infiltrates throughout the bilateral lungs, worse compared with prior radiograph on day 5, suggesting a worsening of pneumonia. On day 12, the patient was transitioned to cefepime (1 gram IV daily) to broaden antimicrobial coverage and was continued thereafter. Blood cultures were negative throughout his hospitalization.

Given his worsening clinical scenario there was a question about whether or not the patient was still shedding virus for prognostic and therapeutic implications. Therefore, his SARS-CoV-2 test by polymerase chain reaction nasopharyngeal was positive again on day 18. On day 20, the patient developed leukocytosis, his fever persisted, and a portable chest radiograph revealed extensive bilateral pulmonary opacities with focal worsening in left lower base. Due to this constellation of findings, a vancomycin IV (1,500 mg once) was started for empirical treatment of hospital-acquired pneumonia. Sputum samples obtained on day 20 revealed Staphylococcus aureus on subsequent days.

From a hematologic perspective, on day 9 due to challenges to maintain a therapeutic level of anticoagulation with heparin infusion thought to be related to antithrombin deficiency, anticoagulation was changed to argatroban infusion (0.5 mcg/kg/min targeting a PTT of 70-105 seconds) for ongoing management of CAC. Although D-dimer was > 20 mcg/mL FEU on admission and on days 4 and 5, D-dimer trended down to 12.5 mcg/mL FEU on day 16.

Throughout the patient’s hospital stay, no significant bleeding was seen. Hemoglobin was 15.2 g/dL on admission, but anemia developed with a nadir of 6.5 g/dL, warranting transfusion of red blood cells on day 22. Platelet count was 165,000 per microliter on admission and remained within normal limits until platelet clumping was noted on day 15 laboratory collection.

Hematology was consulted on day 20 to obtain an accurate platelet count. A peripheral blood smear from a sodium citrate containing tube was remarkable for prominent platelet clumping, particularly at the periphery of the slide (Figure 1). Platelet clumping was reproduced in samples containing EDTA and heparin. Other features of the peripheral blood smear included the presence of echinocytes with rare schistocytes. To investigate for presence of disseminated intravascular coagulation on day 22, fibrinogen was found to be mildly elevated at 538 mg/dL (normal range: 243-517 mg/dL) and a D-dimer value of 11.96 mcg/mL FEU.

On day 22, the patient’s ventilator requirements escalated to requiring 100% FiO₂ and 10 cm H₂0 of positive end-expiratory pressure with mean arterial pressures in the 50 to 60 mm Hg range. Within 30 minutes an electrocardiogram (EKG) obtained revealed a STEMI (Figure 2). Troponin was measured at 0.65 ng/mL (normal range: 0.02-0.06 ng/mL). Just after an EKG was performed, the patient developed a ventricular fibrillation arrest and was unable to obtain return of spontaneous circulation. The patient was pronounced dead. The family declined an autopsy.

Discussion

Pseudothrombocytopenia, or platelet clumping (agglutination), is estimated to be present in up to 2% of hospitalized patients.⁴ Pseudothrombocytopenia was found to be the root cause of thrombocytopenia hematology consultations in up to 4% of hospitalized patients.⁵ The etiology is commonly ascribed to EDTA inducing a conformational change in the GpIIb-IIIa platelet complex, rendering it susceptible to binding of autoantibodies, which cause subsequent platelet agglutination.⁶ In most cases (83%), the use of a non-EDTA anticoagulant, such as sodium citrate, resolves the platelet agglutination and allows for accurate platelet count reporting.⁴ Pseudothrombocytopenia in most cases is considered an in vitro finding without clinical relevance.⁷ However, in this patient’s case, his pan-pseudothrombocytopenia was temporally associated with an arterial occlusive event (STEMI) leading to his demise despite therapeutic anticoagulation in the setting of CAC. This temporal association raises the possibility that pseudothrombocytopenia seen on the peripheral blood smear is an accurate representation of in vivo activity.

Pseudothrombocytopenia has been associated with sepsis from bacterial and viral causes as well as autoimmune and medication effect.^4,8-10 Li and colleagues reported transient EDTA-dependent pseudothrombocytopenia in a patient with COVID-19 infection; however, platelet clumping resolved with use of a citrate tube, and the EDTA-dependent pseudothrombocytopenia phenomenon resolved with patient recovery.¹¹ The frequency of COVID-19-related pseudothrombocytopenia is currently unknown.

Although the understanding of COVID-19-associated CAC continues to evolve, it seems that initial reports support the idea that hemostatic dysfunction tends to more thrombosis than to bleeding.¹² Rather than overt disseminated intravascular coagulation with reduced fibrinogen and bleeding, CAC is more closely associated with blood clotting, as demonstrated by autopsy studies revealing microvascular thrombosis in the lungs.¹³ The D-dimer test has been identified as the most useful biomarker by the International Society of Thrombosis and Hemostasis to screen for CAC and stratify patients who warrant admission or closer monitoring.¹² Other identified features of CAC include prolonged prothrombin time and thrombocytopenia.¹²

There have been varying clinical approaches to CAC management. A retrospective review found that prophylactic heparin doses were associated with improved mortality in those with elevated D-dimer > 3.0 mg/L.¹⁴ There continues to be a diversity of varying clinical approaches with many medical centers advocating for an intensified prophylactic twice daily low molecular-weight heparin compared with others advocating for full therapeutic dose anticoagulation for patients with elevated D-dimer.¹⁵ This patient was treated aggressively with full-dose anticoagulation, and despite his having a down-trend in D-dimer, he suffered a lethal arterial thrombosis in the form of a STEMI.

Varatharajah and Rajah believe that CAC is more closely aligned with endotheliopathy-associated vascular microthrombotic disease (EA-VMTD).¹⁶ EA-VMTD involves a disequilibrium state between insufficient ADAMTS13 enzyme and excessive exocytosis of ultralarge von Willebrand factor (ULvWF) multimers from endothelial cells affected by COVID-19. This theory endorses that ULvWF multimers cause platelet adhesion and subsequent rapid platelet activation, causing platelet aggregation and formation of microthrombi.¹⁷ As these platelet aggregates grow to a certain point, they can no longer remain adhered to ULvWF, causing these platelet aggregates to be released into the circulation and causing thrombotic sequelae.¹⁶ Therefore, a plausible explanation for the patient’s pan-pseudothrombocytopenia may be the detection of these circulating platelet aggregates, which, in turn, was the same process leading to his STEMI. Interestingly, this patient’s fatal arterial event occurred in the presence of therapeutic anticoagulation, raising the question of whether other therapeutic interventions to treat CAC, such as further antithrombotic therapy (eg, aspirin, clopidogrel) or novel strategies would be of benefit.

Conclusions

This patient’s case highlights the presence of pan-pseudothrombocytopenia despite the use of a sodium citrate and heparin containing tube in a COVID-19 infection with multiorgan dysfunction. This developed 1 week prior to the patient suffering a STEMI despite therapeutic anticoagulation. Although the exact nature of CAC remains to be worked out, it is possible that platelet agglutination/clumping seen on the peripheral blood smear is representative of in vivo activity and serves as a harbinger for worsening thrombosis. The frequency of such phenomenon and efficacy of further interventions has yet to be explored.