Article

Hypoglycemia and weight gain are well-known adverse effects that can result from insulin and sulfonylureas in patients with type 2 diabetes mellitus (T2DM).^1,2 Insulin and sulfonylurea medications can cause additional weight gain in patients who are overweight or obese, which can increase the burden of diabetes therapy with added medications, raise the risk of hypoglycemia complications, and raise atherosclerotic cardiovascular disease risk factors.³ Although increasing the insulin or sulfonylurea dose is an option health care practitioners or pharmacists have, this approach can increase the risk of hypoglycemia, especially in older adults, such as the veteran population, which could lead to complications, such as falls.²

Previous studies focusing on hypoglycemic events in patients with T2DM showed that glucagon-like peptide-1 (GLP-1) agonist monotherapy has a low incidence of a hypoglycemic events. However, when a GLP-1 agonist is combined with insulin or sulfonylureas, patients have an increased chance of a hypoglycemic event.^3-8 According to the prescribing information for semaglutide, 1.6% to 3.8% of patients on a GLP-1 agonist monotherapy reported a documented symptomatic hypoglycemic event (blood glucose ≤ 70 mg/dL), based on semaglutide dosing. ⁹ Patients on combination therapy of a GLP-1 agonist and basal insulin and a GLP-1 agonist and a sulfonylurea reported a documented symptomatic hypoglycemic event ranging from 16.7% to 29.8% and 17.3% to 24.4%, respectively.⁹ The incidences of hypoglycemia thus dramatically increase with combination therapy of a GLP-1 agonist plus insulin or a sulfonylurea.

When adding a GLP-1 agonist to insulin or a sulfonylurea, clinicians must be mindful of the increased risk of hypoglycemia. Per the warnings and precautions in the prescribing information of GLP-1 agonists, concomitant use with insulin or a sulfonylurea may increase the risk of hypoglycemia, and reducing the dose of insulin or a sulfonylurea may be necessary.^9-11 According to the American College of Cardiology guidelines, when starting a GLP-1 agonist, the insulin dose should be decreased by about 20% in patients with a well-controlled hemoglobin A_1c (HbA_1c).¹²

This study aimed to determine the percentage of patients who required dose reductions or discontinuations of insulin and sulfonylureas with the addition of a GLP-1 agonist. Understanding necessary dose reductions or discontinuations of these concomitant diabetes agents can assist pharmacists in preventing hypoglycemia and minimizing weight gain.

Methods

This clinical review was a single-center, retrospective chart review of patients prescribed a GLP-1 agonist while on insulin or a sulfonylurea between January 1, 2019, and September 30, 2022, at the Wilkes-Barre Veterans Affairs Medical Center (WBVAMC) in Pennsylvania and managed in a pharmacist-led patient aligned care team (PACT) clinic. It was determined by the US Department of Veterans Affairs Office of Research and Development that an institutional review board or other review committee approval was not needed for this nonresearch Veterans Health Administration quality assurance and improvement project. Patients aged ≥ 18 years were included in this study. Patients were excluded if they were not on insulin or a sulfonylurea when starting a GLP-1 agonist, started a GLP-1 agonist outside of the retrospective chart review dates, or were prescribed a GLP-1 agonist by anyone other than a pharmacist in their PACT clinic. This included if a GLP-1 agonist was prescribed by a primary care physician, endocrinologist, or someone outside the VA system.

The primary study outcomes were to determine the percentage of patients with a dose reduction of insulin or sulfonylurea and discontinuation of insulin or a sulfonylurea at intervals of 0 (baseline), 3, 6, and 12 months. Secondary outcomes included changes in HbA_1c and body weight measured at the same intervals of 0 (baseline), 3, 6, and 12 months.
Data were collected using the VA Computerized Patient Record System (CPRS) and stored in a locked spreadsheet. Descriptive statistics were used to analyze the data. Patient data included the number of patients on insulin or a sulfonylurea when initiating a GLP-1 agonist, the percentage of patients started on a certain GLP-1 agonist (dulaglutide, liraglutide, exenatide, and semaglutide), and the percentage of patients with a baseline HbA_1c of < 8%, 8% to 10%, and > 10%. The GLP-1 agonist formulary was adjusted during the time of this retrospective chart review. Patients who were not on semaglutide were switched over if they were on another GLP-1 agonist as semaglutide became the preferred GLP-1 agonist.

Patients were considered to have a dose reduction or discontinuation of insulin or a sulfonylurea if the dose or medication they were on decreased or was discontinued permanently within 12 months of starting a GLP-1 agonist. For example, if a patient who was administering 10 units of insulin daily was decreased to 8 but later increased back to 10, this was not counted as a dose reduction. If a patient discontinued insulin or a sulfonylurea and then restarted it within 12 months of initiating a GLP-1 agonist, this was not counted as a discontinuation.

This retrospective review included 136 patients; 96 patients taking insulin and 54 taking a sulfonylurea when they started a GLP-1 agonist. Fourteen patients were on both. Criteria for use, which are clinical criteria to determine if a patient is eligible for the use of a given medication, are used within the VA. The inclusion criteria for a patient initiating a GLP-1 agonist is that the patient must have atherosclerotic cardiovascular disease or chronic kidney disease with the patient receiving metformin (unless unable to use metformin) and empagliflozin (unless unable to use empagliflozin).

The baseline mean age and weight for the patient population in this retrospective chart review was 70.7 years and 238.2 lb, respectively. Ninety-six patients (70.6%) were started on semaglutide, 27 (19.9%) on dulaglutide, 12 (8.8%) on liraglutide, and 1 (0.7%) on exenatide. The mean HbA_1c when patients initiated a GLP-1 agonist was 8.6%. When starting a GLP-1 agonist, 34 patients (25.0%) had an HbA_1c < 8%, 89 (65.4%) had an HbA_1c between 8% to 10%, and 13 (9.6%) had an HbA_1c > 10% (Table).

For the primary results, 25 patients (26.0%) had a dose reduction of insulin when they started a GLP-1 agonist, and 55 patients (57.3%) had at least 1 insulin dose reduction within the year follow-up. Seven patients (13.0%) had a dose reduction of a sulfonylurea when they started a GLP-1 agonist, and 16 patients (29.6%) had at least 1 dose reduction of a sulfonylurea within the year follow-up. Six patients (6.3%) discontinued insulin use when they initially started a GLP-1 agonist, and 14 patients (14.6%) discontinued insulin use within the year follow-up. Eleven patients (20.4%) discontinued sulfonylurea use when they initially started a GLP-1 agonist, and 21 patients (38.9%) discontinued sulfonylurea use within the year follow-up (Figure).

Fourteen patients were on both insulin and a sulfonylurea. Two patients (14.3%) had a dose reduction of insulin when they started a GLP-1 agonist, and 5 (35.7%) had ≥ 1 insulin dose reduction within the year follow-up. Three patients (21.4%) had a dose reduction of a sulfonylurea when they started a GLP-1 agonist, and 6 (42.9%) had ≥ 1 dose reduction of a sulfonylurea within the year follow-up. Seven patients (50.0%) discontinued sulfonylurea and 3 (21.4%) discontinued insulin at any time throughout the year. The majority of the discontinuations were at the initial start of GLP-1 agonist therapy.

The mean HbA_1c for patients on GLP-1 agonist was 8.6% at baseline, 8.0% at 0 to 3 months, 7.6% at 3 to 6 months, and 7.5% at 12 months. Patients experienced a mean HbA_1c reduction of 1.1%. The mean weight when a GLP-1 agonist was started was 238.2 lb, 236.0 lb at 0 to 3 months, 223.8 lb at 3 to 6 months, and 224.3 lb after 12 months. Study participants lost a mean weight of 13.9 lb while on a GLP-1 agonist.

Discussion

While this study did not examine why there were dose reductions or discontinuations, we can hypothesize that insulin or sulfonylureas were reduced or discontinued due to a myriad of reasons, such as prophylactic dosing per guidelines, patients having a hypoglycemic event, or pharmacists anticipating potential low blood glucose trends. Also, there could have been numerous reasons GLP-1 agonists were started in patients on insulin or a sulfonylurea, such as HbA_1c not being within goal range, cardiovascular benefits (reduce risk of stroke, heart attack, and death), weight loss, and renal protection, such as preventing albuminuria.^13,14

This retrospective chart review found a large proportion of patients had a dose reduction of insulin (57.3%) or sulfonylurea (29.6%). The percentage of patients with a dose reduction was potentially underestimated as patients were not counted if they discontinued insulin or sulfonylurea. Concomitant use of GLP-1 agonists with insulin or a sulfonylurea may increase the risk of hypoglycemia and reducing the dose of insulin or a sulfonylurea may be necessary.^9-11 The dose reductions in this study show that pharmacists within pharmacy-led PACT clinics monitor for or attempt to prevent hypoglycemia, which aligns with the prescribing information of GLP-1 agonists. While increasing the insulin or sulfonylurea dose is an option for patients, this approach can increase the risk of hypoglycemia, especially in an older population, like this one with a mean age > 70 years. The large proportions of patients with dose reductions or insulin and sulfonylurea discontinuations suggest that pharmacists may need to take a more cautious approach when initiating a GLP-1 agonist to prevent adverse health outcomes related to low blood sugar for older adults, such as falls and fractures.

Insulin was discontinued in 20.4% of patients and sulfonylurea was discontinued in 38.9% of patients within 12 months after starting a GLP-1 agonist. When a patient was on both insulin and a sulfonylurea, the percentage of patients who discontinued insulin (21.4%) or a sulfonylurea (50.0%) was higher compared with patients just on insulin (14.6%) or a sulfonylurea (38.9%) alone. Patients on both insulin and a sulfonylurea may need closer monitoring due to a higher incidence of discontinuations when these diabetes agents are administered in combination.

Limitations

Several limitations of this study should be considered when evaluating the results. This review was comprised of a mostly older, male population, which results in a low generalizability to organizations other than VA medical centers. In addition, this study only evaluated patients on a GLP-1 agonist followed in a pharmacist-led PACT clinic. This study excluded patients who were prescribed a GLP-1 agonist by an endocrinologist or a pharmacist at one of the community-based outpatient clinics affiliated with WBVAMC, or a pharmacist or clinician outside the VA. The sole focus of this study was patients in a pharmacist-led VAMC clinic. Not all patient data may have been included in the study. If a patient did not have an appointment at baseline, 3, 6, and 12 months or did not obtain laboratory tests, HbA_1c and weights were not recorded. Data were collected during the COVID-19 pandemic and in-person appointments were potentially switched to phone or video appointments. There were many instances during this chart review where a weight was not recorded at each time interval. Also, this study did not consider any other diabetes medications the patient was taking. There were many instances where the patient was taking metformin and/or sodium-glucose cotransporter-2 (SGLT-2) inhibitors. These medications along with diet could have affected the weight results as metformin is weight neutral and SGLT-2 inhibitors promote weight loss.¹⁵ Lastly, this study did not evaluate the amount of insulin reduced, only if there was a dose reduction or discontinuation of insulin and/or a sulfonylurea.

Conclusions

Dose reductions and a discontinuation of insulin or a sulfonylurea with the addition of a GLP-1 agonist may be needed. Patients on both insulin and a sulfonylurea may need closer monitoring due to the higher incidences of discontinuations compared with patients on just 1 of these agents. Dose reductions or discontinuations of these diabetic agents can promote positive patient outcomes, such as preventing hypoglycemia, minimizing weight gain, increasing weight loss, and reducing HbA_1c levels.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Wilkes-Barre Veterans Affairs Medical Center in Pennsylvania.

Hypoglycemia and weight gain are well-known adverse effects that can result from insulin and sulfonylureas in patients with type 2 diabetes mellitus (T2DM).^1,2 Insulin and sulfonylurea medications can cause additional weight gain in patients who are overweight or obese, which can increase the burden of diabetes therapy with added medications, raise the risk of hypoglycemia complications, and raise atherosclerotic cardiovascular disease risk factors.³ Although increasing the insulin or sulfonylurea dose is an option health care practitioners or pharmacists have, this approach can increase the risk of hypoglycemia, especially in older adults, such as the veteran population, which could lead to complications, such as falls.²

Previous studies focusing on hypoglycemic events in patients with T2DM showed that glucagon-like peptide-1 (GLP-1) agonist monotherapy has a low incidence of a hypoglycemic events. However, when a GLP-1 agonist is combined with insulin or sulfonylureas, patients have an increased chance of a hypoglycemic event.^3-8 According to the prescribing information for semaglutide, 1.6% to 3.8% of patients on a GLP-1 agonist monotherapy reported a documented symptomatic hypoglycemic event (blood glucose ≤ 70 mg/dL), based on semaglutide dosing. ⁹ Patients on combination therapy of a GLP-1 agonist and basal insulin and a GLP-1 agonist and a sulfonylurea reported a documented symptomatic hypoglycemic event ranging from 16.7% to 29.8% and 17.3% to 24.4%, respectively.⁹ The incidences of hypoglycemia thus dramatically increase with combination therapy of a GLP-1 agonist plus insulin or a sulfonylurea.

When adding a GLP-1 agonist to insulin or a sulfonylurea, clinicians must be mindful of the increased risk of hypoglycemia. Per the warnings and precautions in the prescribing information of GLP-1 agonists, concomitant use with insulin or a sulfonylurea may increase the risk of hypoglycemia, and reducing the dose of insulin or a sulfonylurea may be necessary.^9-11 According to the American College of Cardiology guidelines, when starting a GLP-1 agonist, the insulin dose should be decreased by about 20% in patients with a well-controlled hemoglobin A_1c (HbA_1c).¹²

This study aimed to determine the percentage of patients who required dose reductions or discontinuations of insulin and sulfonylureas with the addition of a GLP-1 agonist. Understanding necessary dose reductions or discontinuations of these concomitant diabetes agents can assist pharmacists in preventing hypoglycemia and minimizing weight gain.

Methods

This clinical review was a single-center, retrospective chart review of patients prescribed a GLP-1 agonist while on insulin or a sulfonylurea between January 1, 2019, and September 30, 2022, at the Wilkes-Barre Veterans Affairs Medical Center (WBVAMC) in Pennsylvania and managed in a pharmacist-led patient aligned care team (PACT) clinic. It was determined by the US Department of Veterans Affairs Office of Research and Development that an institutional review board or other review committee approval was not needed for this nonresearch Veterans Health Administration quality assurance and improvement project. Patients aged ≥ 18 years were included in this study. Patients were excluded if they were not on insulin or a sulfonylurea when starting a GLP-1 agonist, started a GLP-1 agonist outside of the retrospective chart review dates, or were prescribed a GLP-1 agonist by anyone other than a pharmacist in their PACT clinic. This included if a GLP-1 agonist was prescribed by a primary care physician, endocrinologist, or someone outside the VA system.

The primary study outcomes were to determine the percentage of patients with a dose reduction of insulin or sulfonylurea and discontinuation of insulin or a sulfonylurea at intervals of 0 (baseline), 3, 6, and 12 months. Secondary outcomes included changes in HbA_1c and body weight measured at the same intervals of 0 (baseline), 3, 6, and 12 months.
Data were collected using the VA Computerized Patient Record System (CPRS) and stored in a locked spreadsheet. Descriptive statistics were used to analyze the data. Patient data included the number of patients on insulin or a sulfonylurea when initiating a GLP-1 agonist, the percentage of patients started on a certain GLP-1 agonist (dulaglutide, liraglutide, exenatide, and semaglutide), and the percentage of patients with a baseline HbA_1c of < 8%, 8% to 10%, and > 10%. The GLP-1 agonist formulary was adjusted during the time of this retrospective chart review. Patients who were not on semaglutide were switched over if they were on another GLP-1 agonist as semaglutide became the preferred GLP-1 agonist.

Patients were considered to have a dose reduction or discontinuation of insulin or a sulfonylurea if the dose or medication they were on decreased or was discontinued permanently within 12 months of starting a GLP-1 agonist. For example, if a patient who was administering 10 units of insulin daily was decreased to 8 but later increased back to 10, this was not counted as a dose reduction. If a patient discontinued insulin or a sulfonylurea and then restarted it within 12 months of initiating a GLP-1 agonist, this was not counted as a discontinuation.

This retrospective review included 136 patients; 96 patients taking insulin and 54 taking a sulfonylurea when they started a GLP-1 agonist. Fourteen patients were on both. Criteria for use, which are clinical criteria to determine if a patient is eligible for the use of a given medication, are used within the VA. The inclusion criteria for a patient initiating a GLP-1 agonist is that the patient must have atherosclerotic cardiovascular disease or chronic kidney disease with the patient receiving metformin (unless unable to use metformin) and empagliflozin (unless unable to use empagliflozin).

The baseline mean age and weight for the patient population in this retrospective chart review was 70.7 years and 238.2 lb, respectively. Ninety-six patients (70.6%) were started on semaglutide, 27 (19.9%) on dulaglutide, 12 (8.8%) on liraglutide, and 1 (0.7%) on exenatide. The mean HbA_1c when patients initiated a GLP-1 agonist was 8.6%. When starting a GLP-1 agonist, 34 patients (25.0%) had an HbA_1c < 8%, 89 (65.4%) had an HbA_1c between 8% to 10%, and 13 (9.6%) had an HbA_1c > 10% (Table).

For the primary results, 25 patients (26.0%) had a dose reduction of insulin when they started a GLP-1 agonist, and 55 patients (57.3%) had at least 1 insulin dose reduction within the year follow-up. Seven patients (13.0%) had a dose reduction of a sulfonylurea when they started a GLP-1 agonist, and 16 patients (29.6%) had at least 1 dose reduction of a sulfonylurea within the year follow-up. Six patients (6.3%) discontinued insulin use when they initially started a GLP-1 agonist, and 14 patients (14.6%) discontinued insulin use within the year follow-up. Eleven patients (20.4%) discontinued sulfonylurea use when they initially started a GLP-1 agonist, and 21 patients (38.9%) discontinued sulfonylurea use within the year follow-up (Figure).

Fourteen patients were on both insulin and a sulfonylurea. Two patients (14.3%) had a dose reduction of insulin when they started a GLP-1 agonist, and 5 (35.7%) had ≥ 1 insulin dose reduction within the year follow-up. Three patients (21.4%) had a dose reduction of a sulfonylurea when they started a GLP-1 agonist, and 6 (42.9%) had ≥ 1 dose reduction of a sulfonylurea within the year follow-up. Seven patients (50.0%) discontinued sulfonylurea and 3 (21.4%) discontinued insulin at any time throughout the year. The majority of the discontinuations were at the initial start of GLP-1 agonist therapy.

The mean HbA_1c for patients on GLP-1 agonist was 8.6% at baseline, 8.0% at 0 to 3 months, 7.6% at 3 to 6 months, and 7.5% at 12 months. Patients experienced a mean HbA_1c reduction of 1.1%. The mean weight when a GLP-1 agonist was started was 238.2 lb, 236.0 lb at 0 to 3 months, 223.8 lb at 3 to 6 months, and 224.3 lb after 12 months. Study participants lost a mean weight of 13.9 lb while on a GLP-1 agonist.

Discussion

While this study did not examine why there were dose reductions or discontinuations, we can hypothesize that insulin or sulfonylureas were reduced or discontinued due to a myriad of reasons, such as prophylactic dosing per guidelines, patients having a hypoglycemic event, or pharmacists anticipating potential low blood glucose trends. Also, there could have been numerous reasons GLP-1 agonists were started in patients on insulin or a sulfonylurea, such as HbA_1c not being within goal range, cardiovascular benefits (reduce risk of stroke, heart attack, and death), weight loss, and renal protection, such as preventing albuminuria.^13,14

This retrospective chart review found a large proportion of patients had a dose reduction of insulin (57.3%) or sulfonylurea (29.6%). The percentage of patients with a dose reduction was potentially underestimated as patients were not counted if they discontinued insulin or sulfonylurea. Concomitant use of GLP-1 agonists with insulin or a sulfonylurea may increase the risk of hypoglycemia and reducing the dose of insulin or a sulfonylurea may be necessary.^9-11 The dose reductions in this study show that pharmacists within pharmacy-led PACT clinics monitor for or attempt to prevent hypoglycemia, which aligns with the prescribing information of GLP-1 agonists. While increasing the insulin or sulfonylurea dose is an option for patients, this approach can increase the risk of hypoglycemia, especially in an older population, like this one with a mean age > 70 years. The large proportions of patients with dose reductions or insulin and sulfonylurea discontinuations suggest that pharmacists may need to take a more cautious approach when initiating a GLP-1 agonist to prevent adverse health outcomes related to low blood sugar for older adults, such as falls and fractures.

Insulin was discontinued in 20.4% of patients and sulfonylurea was discontinued in 38.9% of patients within 12 months after starting a GLP-1 agonist. When a patient was on both insulin and a sulfonylurea, the percentage of patients who discontinued insulin (21.4%) or a sulfonylurea (50.0%) was higher compared with patients just on insulin (14.6%) or a sulfonylurea (38.9%) alone. Patients on both insulin and a sulfonylurea may need closer monitoring due to a higher incidence of discontinuations when these diabetes agents are administered in combination.

Limitations

Several limitations of this study should be considered when evaluating the results. This review was comprised of a mostly older, male population, which results in a low generalizability to organizations other than VA medical centers. In addition, this study only evaluated patients on a GLP-1 agonist followed in a pharmacist-led PACT clinic. This study excluded patients who were prescribed a GLP-1 agonist by an endocrinologist or a pharmacist at one of the community-based outpatient clinics affiliated with WBVAMC, or a pharmacist or clinician outside the VA. The sole focus of this study was patients in a pharmacist-led VAMC clinic. Not all patient data may have been included in the study. If a patient did not have an appointment at baseline, 3, 6, and 12 months or did not obtain laboratory tests, HbA_1c and weights were not recorded. Data were collected during the COVID-19 pandemic and in-person appointments were potentially switched to phone or video appointments. There were many instances during this chart review where a weight was not recorded at each time interval. Also, this study did not consider any other diabetes medications the patient was taking. There were many instances where the patient was taking metformin and/or sodium-glucose cotransporter-2 (SGLT-2) inhibitors. These medications along with diet could have affected the weight results as metformin is weight neutral and SGLT-2 inhibitors promote weight loss.¹⁵ Lastly, this study did not evaluate the amount of insulin reduced, only if there was a dose reduction or discontinuation of insulin and/or a sulfonylurea.

Conclusions

Dose reductions and a discontinuation of insulin or a sulfonylurea with the addition of a GLP-1 agonist may be needed. Patients on both insulin and a sulfonylurea may need closer monitoring due to the higher incidences of discontinuations compared with patients on just 1 of these agents. Dose reductions or discontinuations of these diabetic agents can promote positive patient outcomes, such as preventing hypoglycemia, minimizing weight gain, increasing weight loss, and reducing HbA_1c levels.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Wilkes-Barre Veterans Affairs Medical Center in Pennsylvania.

Hypoglycemia and weight gain are well-known adverse effects that can result from insulin and sulfonylureas in patients with type 2 diabetes mellitus (T2DM).^1,2 Insulin and sulfonylurea medications can cause additional weight gain in patients who are overweight or obese, which can increase the burden of diabetes therapy with added medications, raise the risk of hypoglycemia complications, and raise atherosclerotic cardiovascular disease risk factors.³ Although increasing the insulin or sulfonylurea dose is an option health care practitioners or pharmacists have, this approach can increase the risk of hypoglycemia, especially in older adults, such as the veteran population, which could lead to complications, such as falls.²

Previous studies focusing on hypoglycemic events in patients with T2DM showed that glucagon-like peptide-1 (GLP-1) agonist monotherapy has a low incidence of a hypoglycemic events. However, when a GLP-1 agonist is combined with insulin or sulfonylureas, patients have an increased chance of a hypoglycemic event.^3-8 According to the prescribing information for semaglutide, 1.6% to 3.8% of patients on a GLP-1 agonist monotherapy reported a documented symptomatic hypoglycemic event (blood glucose ≤ 70 mg/dL), based on semaglutide dosing. ⁹ Patients on combination therapy of a GLP-1 agonist and basal insulin and a GLP-1 agonist and a sulfonylurea reported a documented symptomatic hypoglycemic event ranging from 16.7% to 29.8% and 17.3% to 24.4%, respectively.⁹ The incidences of hypoglycemia thus dramatically increase with combination therapy of a GLP-1 agonist plus insulin or a sulfonylurea.

When adding a GLP-1 agonist to insulin or a sulfonylurea, clinicians must be mindful of the increased risk of hypoglycemia. Per the warnings and precautions in the prescribing information of GLP-1 agonists, concomitant use with insulin or a sulfonylurea may increase the risk of hypoglycemia, and reducing the dose of insulin or a sulfonylurea may be necessary.^9-11 According to the American College of Cardiology guidelines, when starting a GLP-1 agonist, the insulin dose should be decreased by about 20% in patients with a well-controlled hemoglobin A_1c (HbA_1c).¹²

This study aimed to determine the percentage of patients who required dose reductions or discontinuations of insulin and sulfonylureas with the addition of a GLP-1 agonist. Understanding necessary dose reductions or discontinuations of these concomitant diabetes agents can assist pharmacists in preventing hypoglycemia and minimizing weight gain.

Methods

This clinical review was a single-center, retrospective chart review of patients prescribed a GLP-1 agonist while on insulin or a sulfonylurea between January 1, 2019, and September 30, 2022, at the Wilkes-Barre Veterans Affairs Medical Center (WBVAMC) in Pennsylvania and managed in a pharmacist-led patient aligned care team (PACT) clinic. It was determined by the US Department of Veterans Affairs Office of Research and Development that an institutional review board or other review committee approval was not needed for this nonresearch Veterans Health Administration quality assurance and improvement project. Patients aged ≥ 18 years were included in this study. Patients were excluded if they were not on insulin or a sulfonylurea when starting a GLP-1 agonist, started a GLP-1 agonist outside of the retrospective chart review dates, or were prescribed a GLP-1 agonist by anyone other than a pharmacist in their PACT clinic. This included if a GLP-1 agonist was prescribed by a primary care physician, endocrinologist, or someone outside the VA system.

The primary study outcomes were to determine the percentage of patients with a dose reduction of insulin or sulfonylurea and discontinuation of insulin or a sulfonylurea at intervals of 0 (baseline), 3, 6, and 12 months. Secondary outcomes included changes in HbA_1c and body weight measured at the same intervals of 0 (baseline), 3, 6, and 12 months.
Data were collected using the VA Computerized Patient Record System (CPRS) and stored in a locked spreadsheet. Descriptive statistics were used to analyze the data. Patient data included the number of patients on insulin or a sulfonylurea when initiating a GLP-1 agonist, the percentage of patients started on a certain GLP-1 agonist (dulaglutide, liraglutide, exenatide, and semaglutide), and the percentage of patients with a baseline HbA_1c of < 8%, 8% to 10%, and > 10%. The GLP-1 agonist formulary was adjusted during the time of this retrospective chart review. Patients who were not on semaglutide were switched over if they were on another GLP-1 agonist as semaglutide became the preferred GLP-1 agonist.

Patients were considered to have a dose reduction or discontinuation of insulin or a sulfonylurea if the dose or medication they were on decreased or was discontinued permanently within 12 months of starting a GLP-1 agonist. For example, if a patient who was administering 10 units of insulin daily was decreased to 8 but later increased back to 10, this was not counted as a dose reduction. If a patient discontinued insulin or a sulfonylurea and then restarted it within 12 months of initiating a GLP-1 agonist, this was not counted as a discontinuation.

This retrospective review included 136 patients; 96 patients taking insulin and 54 taking a sulfonylurea when they started a GLP-1 agonist. Fourteen patients were on both. Criteria for use, which are clinical criteria to determine if a patient is eligible for the use of a given medication, are used within the VA. The inclusion criteria for a patient initiating a GLP-1 agonist is that the patient must have atherosclerotic cardiovascular disease or chronic kidney disease with the patient receiving metformin (unless unable to use metformin) and empagliflozin (unless unable to use empagliflozin).

The baseline mean age and weight for the patient population in this retrospective chart review was 70.7 years and 238.2 lb, respectively. Ninety-six patients (70.6%) were started on semaglutide, 27 (19.9%) on dulaglutide, 12 (8.8%) on liraglutide, and 1 (0.7%) on exenatide. The mean HbA_1c when patients initiated a GLP-1 agonist was 8.6%. When starting a GLP-1 agonist, 34 patients (25.0%) had an HbA_1c < 8%, 89 (65.4%) had an HbA_1c between 8% to 10%, and 13 (9.6%) had an HbA_1c > 10% (Table).

For the primary results, 25 patients (26.0%) had a dose reduction of insulin when they started a GLP-1 agonist, and 55 patients (57.3%) had at least 1 insulin dose reduction within the year follow-up. Seven patients (13.0%) had a dose reduction of a sulfonylurea when they started a GLP-1 agonist, and 16 patients (29.6%) had at least 1 dose reduction of a sulfonylurea within the year follow-up. Six patients (6.3%) discontinued insulin use when they initially started a GLP-1 agonist, and 14 patients (14.6%) discontinued insulin use within the year follow-up. Eleven patients (20.4%) discontinued sulfonylurea use when they initially started a GLP-1 agonist, and 21 patients (38.9%) discontinued sulfonylurea use within the year follow-up (Figure).

Fourteen patients were on both insulin and a sulfonylurea. Two patients (14.3%) had a dose reduction of insulin when they started a GLP-1 agonist, and 5 (35.7%) had ≥ 1 insulin dose reduction within the year follow-up. Three patients (21.4%) had a dose reduction of a sulfonylurea when they started a GLP-1 agonist, and 6 (42.9%) had ≥ 1 dose reduction of a sulfonylurea within the year follow-up. Seven patients (50.0%) discontinued sulfonylurea and 3 (21.4%) discontinued insulin at any time throughout the year. The majority of the discontinuations were at the initial start of GLP-1 agonist therapy.

The mean HbA_1c for patients on GLP-1 agonist was 8.6% at baseline, 8.0% at 0 to 3 months, 7.6% at 3 to 6 months, and 7.5% at 12 months. Patients experienced a mean HbA_1c reduction of 1.1%. The mean weight when a GLP-1 agonist was started was 238.2 lb, 236.0 lb at 0 to 3 months, 223.8 lb at 3 to 6 months, and 224.3 lb after 12 months. Study participants lost a mean weight of 13.9 lb while on a GLP-1 agonist.

Discussion

While this study did not examine why there were dose reductions or discontinuations, we can hypothesize that insulin or sulfonylureas were reduced or discontinued due to a myriad of reasons, such as prophylactic dosing per guidelines, patients having a hypoglycemic event, or pharmacists anticipating potential low blood glucose trends. Also, there could have been numerous reasons GLP-1 agonists were started in patients on insulin or a sulfonylurea, such as HbA_1c not being within goal range, cardiovascular benefits (reduce risk of stroke, heart attack, and death), weight loss, and renal protection, such as preventing albuminuria.^13,14

This retrospective chart review found a large proportion of patients had a dose reduction of insulin (57.3%) or sulfonylurea (29.6%). The percentage of patients with a dose reduction was potentially underestimated as patients were not counted if they discontinued insulin or sulfonylurea. Concomitant use of GLP-1 agonists with insulin or a sulfonylurea may increase the risk of hypoglycemia and reducing the dose of insulin or a sulfonylurea may be necessary.^9-11 The dose reductions in this study show that pharmacists within pharmacy-led PACT clinics monitor for or attempt to prevent hypoglycemia, which aligns with the prescribing information of GLP-1 agonists. While increasing the insulin or sulfonylurea dose is an option for patients, this approach can increase the risk of hypoglycemia, especially in an older population, like this one with a mean age > 70 years. The large proportions of patients with dose reductions or insulin and sulfonylurea discontinuations suggest that pharmacists may need to take a more cautious approach when initiating a GLP-1 agonist to prevent adverse health outcomes related to low blood sugar for older adults, such as falls and fractures.

Insulin was discontinued in 20.4% of patients and sulfonylurea was discontinued in 38.9% of patients within 12 months after starting a GLP-1 agonist. When a patient was on both insulin and a sulfonylurea, the percentage of patients who discontinued insulin (21.4%) or a sulfonylurea (50.0%) was higher compared with patients just on insulin (14.6%) or a sulfonylurea (38.9%) alone. Patients on both insulin and a sulfonylurea may need closer monitoring due to a higher incidence of discontinuations when these diabetes agents are administered in combination.

Limitations

Several limitations of this study should be considered when evaluating the results. This review was comprised of a mostly older, male population, which results in a low generalizability to organizations other than VA medical centers. In addition, this study only evaluated patients on a GLP-1 agonist followed in a pharmacist-led PACT clinic. This study excluded patients who were prescribed a GLP-1 agonist by an endocrinologist or a pharmacist at one of the community-based outpatient clinics affiliated with WBVAMC, or a pharmacist or clinician outside the VA. The sole focus of this study was patients in a pharmacist-led VAMC clinic. Not all patient data may have been included in the study. If a patient did not have an appointment at baseline, 3, 6, and 12 months or did not obtain laboratory tests, HbA_1c and weights were not recorded. Data were collected during the COVID-19 pandemic and in-person appointments were potentially switched to phone or video appointments. There were many instances during this chart review where a weight was not recorded at each time interval. Also, this study did not consider any other diabetes medications the patient was taking. There were many instances where the patient was taking metformin and/or sodium-glucose cotransporter-2 (SGLT-2) inhibitors. These medications along with diet could have affected the weight results as metformin is weight neutral and SGLT-2 inhibitors promote weight loss.¹⁵ Lastly, this study did not evaluate the amount of insulin reduced, only if there was a dose reduction or discontinuation of insulin and/or a sulfonylurea.

Conclusions

Dose reductions and a discontinuation of insulin or a sulfonylurea with the addition of a GLP-1 agonist may be needed. Patients on both insulin and a sulfonylurea may need closer monitoring due to the higher incidences of discontinuations compared with patients on just 1 of these agents. Dose reductions or discontinuations of these diabetic agents can promote positive patient outcomes, such as preventing hypoglycemia, minimizing weight gain, increasing weight loss, and reducing HbA_1c levels.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Wilkes-Barre Veterans Affairs Medical Center in Pennsylvania.

Competency in paracentesis is an important procedural skill for medical practitioners caring for patients with decompensated liver cirrhosis. Paracentesis is performed to drain ascitic fluid for both diagnosis and/or therapeutic purposes.¹ While this procedure can be performed without the use of ultrasound, it is preferable to use ultrasound to identify an area of fluid that is away from dangerous anatomy including bowel loops, the liver, and spleen. After prepping the area, lidocaine is administered locally. A catheter is then inserted until fluid begins flowing freely. The catheter is connected to a suction canister or collection kit, and the patient is monitored until the flow ceases. Samples can be sent for analysis to determine the etiology of ascites, identify concerns for infection, and more.

Paracentesis is a very common procedure. Barsuk and colleagues noted that between 2010 and 2012, 97,577 procedures were performed across 120 academic medical centers and 290 affiliated hospitals.² Patients undergo paracentesis in a variety of settings including the emergency department, inpatient hospitalizations, and clinics. Some patients may require only 1 paracentesis procedure while others may require it regularly.

Due to the rising need for paracentesis in the Central Texas Veterans Affairs Hospital (CTVAH) in Temple, a paracentesis clinic was started in February 2018. The goal of the paracentesis clinic was multifocal—to reduce hospital admissions, improve access to regularly scheduled procedures, decrease wait times, and increase patient satisfaction.³ Through the CTVAH affiliation with the Texas A&M internal medicine residency program, the paracentesis clinic started involving and training residents on this procedure. Up to 3 residents are on weekly rotation and can perform up to 6 paracentesis procedures in a week. The purpose of this article was to evaluate resident competency in paracentesis after completion of the paracentesis clinic.

Methods

The paracentesis clinic schedules up to 3 patients on Tuesdays and Thursdays between 8 am and noon. All the necessary equipment is readily available and includes the paracentesis kit, lidocaine, sterile gloves, ultrasound, and albumin if needed. Because this procedure is performed at the hospital, direct access to the emergency department is available. Residents are scheduled weekly. Up to 2 residents are scheduled for the paracentesis clinic during their dedicated clinic week. They are expected to practice obtaining consent, performing the procedure, and documenting the encounter under staff supervision. Additionally, 1 or 2 residents participate in the paracentesis clinic as part of an ultrasound elective twice per year. In this elective, they practice ultrasound skills using a simulation and translate that information in the paracentesis clinic while identifying anatomy and performing the paracentesis procedure under staff supervision.

A survey was sent via email to all categorical internal medicine residents across all 3 program years at the time of data collection. Competency for paracentesis sign-off was defined as completing and logging 5 procedures supervised by a competent physician who confirmed that all portions of the procedure were performed correctly. Residents were also asked to answer questions on a scale from 1 to 10, with 1 representing no confidence and 10 representing strong confidence to practice independently (Table).

We also evaluated the number of procedures performed by internal medicine residents 3 years before the clinic was started in 2015 up to the completion of 2022. The numbers were obtained by examining procedural log data for each year for all internal medicine residents.

Results

Thirty-three residents completed the survey: 10 first-year internal medicine residents (PGY1), 12 second-year residents (PGY2), and 11 third-year residents (PGY3). The mean participation was 4.8 paracentesis sessions per person for the duration of the study. The range of paracentesis procedures performed varied based on PGY year: PGY1s performed 1 to > 10 procedures, PGY2s performed 2 to > 10 procedures, and PGY3s performed 5 to > 10 procedures. Thirty-six percent of residents completed > 10 procedures in the paracentesis clinic; 82% of PGY3s had completed > 10 procedures by December of their third year. Twenty-six residents (79%) were credentialed to perform paracentesis procedures independently after performing > 5 procedures, and 7 residents were not yet cleared for procedural independence.

In the survey, residents rated their comfort with performing paracentesis procedures independently at a mean of 7.9. The mean comfort reported by PGY1s was 7.2, PGY2s was 7.3, and PGY3s was 9.3. Residents also rated their opinion on whether or not the paracentesis clinic adequately prepared them for paracentesis procedural independence; the mean was 8.9 across all residents.

The total number of procedures performed by residents at CTVAH also increased. Starting in 2015, 3 years before the clinic was started, 38 procedures were performed by internal medicine residents, followed by 72 procedures in 2016; 76 in 2017; 58 in 2018; 94 in 2019; 88 in 2020; 136 in 2021; and 188 in 2022.

Paracentesis is a simple but invasive procedure to relieve ascites, often relieving patients’ symptoms, preventing hospital admission, and increasing patient satisfaction.⁴ The CTVAH does not have the capacity to perform outpatient paracentesis effectively in its emergency or radiology departments. Furthermore, the use of the emergency or radiology departments for routine paracentesis may not be feasible due to the acuity of care being provided, as these procedures can be time consuming and can draw away critical resources and time from patients that need emergent care. The paracentesis clinic was then formed to provide veterans access to the procedural care they need, while also preparing residents to ably and confidently perform the procedure independently.

Based on our study, most residents were cleared to independently perform paracentesis procedures across all 3 years, with 79% of residents having completed the required 5 supervised procedures to independently practice. A study assessing unsupervised practice standards showed that paracentesis skill declines as soon as 3 months after training. However, retraining was shown to potentially interrupt this skill decline.⁵ Studies have shown that procedure-driven electives or services significantly improved paracentesis certification rates and total logged procedures, with minimal funding or scheduling changes required.⁶ Our clinic showed a significant increase in the number of procedures logged starting with the minimum of 38 procedures in 2015 and ending with 188 procedures logged at the end of 2022.

By allowing residents to routinely return to the paracentesis clinic across all 3 years, residents were more likely to feel comfortable independently performing the procedure, with residents reporting a mean comfort score of 7.9. The spaced repetition and ability to work with the clinic during elective time allows regular opportunities to undergo supervised training in a controlled environment and created scheduled retraining opportunities. Future studies should evaluate residents prior to each paracentesis clinic to ascertain if skill decline is occurring at a slower rate.

The inpatient effect of the clinic is also multifocal. Pham and colleagues showed that integrating paracentesis into timely training can reduce paracentesis delay and delays in care.⁷ By increasing the volume of procedures each resident performs and creating a sense of confidence amongst residents, the clinic increases the number of residents able and willing to perform inpatient procedures, thus reducing the number of unnecessary consultations and hospital resources. One of the reasons the paracentesis clinic was started was to allow patients to have scheduled times to remove fluid from their abdomen, thus cutting down on emergency department procedures and unnecessary admissions. Additionally, the benefits of early paracentesis procedural performance by residents and internal medicine physicians have been demonstrated in the literature. A study by Gaetano and colleagues noted that patients undergoing early paracentesis had reduced mortality of 5.5% vs 7.5% in those undergoing late paracentesis.⁸ This study also showed the in-hospital mortality rate was decreased with paracentesis (6.3%) vs without paracentesis (8.9%).⁸ By offering residents a chance to participate in the clinic, we have shown that regular opportunities to perform paracentesis may increase the number of physicians capable of independently practicing, improve procedural competency, and improve patient access to this procedure.

Limitations

Our study was not free of bias and has potential weaknesses. The survey was sent to all current residents who have participated in the paracentesis clinic, but not every resident filled out the survey (55% of all residents across 3 years completed the survey, 68.7% who had done clinic that year completed the survey). There is a possibility that those not signed off avoided doing the survey, but we are unable to confirm this. The survey also depended on resident recall of the number of paracenteses completed or looking at their procedure log. It is possible that some procedures were not documented, changing the true number. Additionally, rating comfortability with procedures is subjective, which may also create a source of potential weakness. Future projects should include a baseline survey for residents, followed by a repeat survey a year later to show changes from baseline competency.

Conclusions

A dedicated paracentesis clinic with internal medicine resident involvement may increase resident paracentesis procedural independence, the number of procedures available and performed, and procedural comfort level.

Competency in paracentesis is an important procedural skill for medical practitioners caring for patients with decompensated liver cirrhosis. Paracentesis is performed to drain ascitic fluid for both diagnosis and/or therapeutic purposes.¹ While this procedure can be performed without the use of ultrasound, it is preferable to use ultrasound to identify an area of fluid that is away from dangerous anatomy including bowel loops, the liver, and spleen. After prepping the area, lidocaine is administered locally. A catheter is then inserted until fluid begins flowing freely. The catheter is connected to a suction canister or collection kit, and the patient is monitored until the flow ceases. Samples can be sent for analysis to determine the etiology of ascites, identify concerns for infection, and more.

Paracentesis is a very common procedure. Barsuk and colleagues noted that between 2010 and 2012, 97,577 procedures were performed across 120 academic medical centers and 290 affiliated hospitals.² Patients undergo paracentesis in a variety of settings including the emergency department, inpatient hospitalizations, and clinics. Some patients may require only 1 paracentesis procedure while others may require it regularly.

Due to the rising need for paracentesis in the Central Texas Veterans Affairs Hospital (CTVAH) in Temple, a paracentesis clinic was started in February 2018. The goal of the paracentesis clinic was multifocal—to reduce hospital admissions, improve access to regularly scheduled procedures, decrease wait times, and increase patient satisfaction.³ Through the CTVAH affiliation with the Texas A&M internal medicine residency program, the paracentesis clinic started involving and training residents on this procedure. Up to 3 residents are on weekly rotation and can perform up to 6 paracentesis procedures in a week. The purpose of this article was to evaluate resident competency in paracentesis after completion of the paracentesis clinic.

Methods

The paracentesis clinic schedules up to 3 patients on Tuesdays and Thursdays between 8 am and noon. All the necessary equipment is readily available and includes the paracentesis kit, lidocaine, sterile gloves, ultrasound, and albumin if needed. Because this procedure is performed at the hospital, direct access to the emergency department is available. Residents are scheduled weekly. Up to 2 residents are scheduled for the paracentesis clinic during their dedicated clinic week. They are expected to practice obtaining consent, performing the procedure, and documenting the encounter under staff supervision. Additionally, 1 or 2 residents participate in the paracentesis clinic as part of an ultrasound elective twice per year. In this elective, they practice ultrasound skills using a simulation and translate that information in the paracentesis clinic while identifying anatomy and performing the paracentesis procedure under staff supervision.

A survey was sent via email to all categorical internal medicine residents across all 3 program years at the time of data collection. Competency for paracentesis sign-off was defined as completing and logging 5 procedures supervised by a competent physician who confirmed that all portions of the procedure were performed correctly. Residents were also asked to answer questions on a scale from 1 to 10, with 1 representing no confidence and 10 representing strong confidence to practice independently (Table).

We also evaluated the number of procedures performed by internal medicine residents 3 years before the clinic was started in 2015 up to the completion of 2022. The numbers were obtained by examining procedural log data for each year for all internal medicine residents.

Results

Thirty-three residents completed the survey: 10 first-year internal medicine residents (PGY1), 12 second-year residents (PGY2), and 11 third-year residents (PGY3). The mean participation was 4.8 paracentesis sessions per person for the duration of the study. The range of paracentesis procedures performed varied based on PGY year: PGY1s performed 1 to > 10 procedures, PGY2s performed 2 to > 10 procedures, and PGY3s performed 5 to > 10 procedures. Thirty-six percent of residents completed > 10 procedures in the paracentesis clinic; 82% of PGY3s had completed > 10 procedures by December of their third year. Twenty-six residents (79%) were credentialed to perform paracentesis procedures independently after performing > 5 procedures, and 7 residents were not yet cleared for procedural independence.

In the survey, residents rated their comfort with performing paracentesis procedures independently at a mean of 7.9. The mean comfort reported by PGY1s was 7.2, PGY2s was 7.3, and PGY3s was 9.3. Residents also rated their opinion on whether or not the paracentesis clinic adequately prepared them for paracentesis procedural independence; the mean was 8.9 across all residents.

The total number of procedures performed by residents at CTVAH also increased. Starting in 2015, 3 years before the clinic was started, 38 procedures were performed by internal medicine residents, followed by 72 procedures in 2016; 76 in 2017; 58 in 2018; 94 in 2019; 88 in 2020; 136 in 2021; and 188 in 2022.

Paracentesis is a simple but invasive procedure to relieve ascites, often relieving patients’ symptoms, preventing hospital admission, and increasing patient satisfaction.⁴ The CTVAH does not have the capacity to perform outpatient paracentesis effectively in its emergency or radiology departments. Furthermore, the use of the emergency or radiology departments for routine paracentesis may not be feasible due to the acuity of care being provided, as these procedures can be time consuming and can draw away critical resources and time from patients that need emergent care. The paracentesis clinic was then formed to provide veterans access to the procedural care they need, while also preparing residents to ably and confidently perform the procedure independently.

Based on our study, most residents were cleared to independently perform paracentesis procedures across all 3 years, with 79% of residents having completed the required 5 supervised procedures to independently practice. A study assessing unsupervised practice standards showed that paracentesis skill declines as soon as 3 months after training. However, retraining was shown to potentially interrupt this skill decline.⁵ Studies have shown that procedure-driven electives or services significantly improved paracentesis certification rates and total logged procedures, with minimal funding or scheduling changes required.⁶ Our clinic showed a significant increase in the number of procedures logged starting with the minimum of 38 procedures in 2015 and ending with 188 procedures logged at the end of 2022.

By allowing residents to routinely return to the paracentesis clinic across all 3 years, residents were more likely to feel comfortable independently performing the procedure, with residents reporting a mean comfort score of 7.9. The spaced repetition and ability to work with the clinic during elective time allows regular opportunities to undergo supervised training in a controlled environment and created scheduled retraining opportunities. Future studies should evaluate residents prior to each paracentesis clinic to ascertain if skill decline is occurring at a slower rate.

The inpatient effect of the clinic is also multifocal. Pham and colleagues showed that integrating paracentesis into timely training can reduce paracentesis delay and delays in care.⁷ By increasing the volume of procedures each resident performs and creating a sense of confidence amongst residents, the clinic increases the number of residents able and willing to perform inpatient procedures, thus reducing the number of unnecessary consultations and hospital resources. One of the reasons the paracentesis clinic was started was to allow patients to have scheduled times to remove fluid from their abdomen, thus cutting down on emergency department procedures and unnecessary admissions. Additionally, the benefits of early paracentesis procedural performance by residents and internal medicine physicians have been demonstrated in the literature. A study by Gaetano and colleagues noted that patients undergoing early paracentesis had reduced mortality of 5.5% vs 7.5% in those undergoing late paracentesis.⁸ This study also showed the in-hospital mortality rate was decreased with paracentesis (6.3%) vs without paracentesis (8.9%).⁸ By offering residents a chance to participate in the clinic, we have shown that regular opportunities to perform paracentesis may increase the number of physicians capable of independently practicing, improve procedural competency, and improve patient access to this procedure.

Limitations

Our study was not free of bias and has potential weaknesses. The survey was sent to all current residents who have participated in the paracentesis clinic, but not every resident filled out the survey (55% of all residents across 3 years completed the survey, 68.7% who had done clinic that year completed the survey). There is a possibility that those not signed off avoided doing the survey, but we are unable to confirm this. The survey also depended on resident recall of the number of paracenteses completed or looking at their procedure log. It is possible that some procedures were not documented, changing the true number. Additionally, rating comfortability with procedures is subjective, which may also create a source of potential weakness. Future projects should include a baseline survey for residents, followed by a repeat survey a year later to show changes from baseline competency.

Conclusions

A dedicated paracentesis clinic with internal medicine resident involvement may increase resident paracentesis procedural independence, the number of procedures available and performed, and procedural comfort level.

Competency in paracentesis is an important procedural skill for medical practitioners caring for patients with decompensated liver cirrhosis. Paracentesis is performed to drain ascitic fluid for both diagnosis and/or therapeutic purposes.¹ While this procedure can be performed without the use of ultrasound, it is preferable to use ultrasound to identify an area of fluid that is away from dangerous anatomy including bowel loops, the liver, and spleen. After prepping the area, lidocaine is administered locally. A catheter is then inserted until fluid begins flowing freely. The catheter is connected to a suction canister or collection kit, and the patient is monitored until the flow ceases. Samples can be sent for analysis to determine the etiology of ascites, identify concerns for infection, and more.

Paracentesis is a very common procedure. Barsuk and colleagues noted that between 2010 and 2012, 97,577 procedures were performed across 120 academic medical centers and 290 affiliated hospitals.² Patients undergo paracentesis in a variety of settings including the emergency department, inpatient hospitalizations, and clinics. Some patients may require only 1 paracentesis procedure while others may require it regularly.

Due to the rising need for paracentesis in the Central Texas Veterans Affairs Hospital (CTVAH) in Temple, a paracentesis clinic was started in February 2018. The goal of the paracentesis clinic was multifocal—to reduce hospital admissions, improve access to regularly scheduled procedures, decrease wait times, and increase patient satisfaction.³ Through the CTVAH affiliation with the Texas A&M internal medicine residency program, the paracentesis clinic started involving and training residents on this procedure. Up to 3 residents are on weekly rotation and can perform up to 6 paracentesis procedures in a week. The purpose of this article was to evaluate resident competency in paracentesis after completion of the paracentesis clinic.

Methods

The paracentesis clinic schedules up to 3 patients on Tuesdays and Thursdays between 8 am and noon. All the necessary equipment is readily available and includes the paracentesis kit, lidocaine, sterile gloves, ultrasound, and albumin if needed. Because this procedure is performed at the hospital, direct access to the emergency department is available. Residents are scheduled weekly. Up to 2 residents are scheduled for the paracentesis clinic during their dedicated clinic week. They are expected to practice obtaining consent, performing the procedure, and documenting the encounter under staff supervision. Additionally, 1 or 2 residents participate in the paracentesis clinic as part of an ultrasound elective twice per year. In this elective, they practice ultrasound skills using a simulation and translate that information in the paracentesis clinic while identifying anatomy and performing the paracentesis procedure under staff supervision.

A survey was sent via email to all categorical internal medicine residents across all 3 program years at the time of data collection. Competency for paracentesis sign-off was defined as completing and logging 5 procedures supervised by a competent physician who confirmed that all portions of the procedure were performed correctly. Residents were also asked to answer questions on a scale from 1 to 10, with 1 representing no confidence and 10 representing strong confidence to practice independently (Table).

We also evaluated the number of procedures performed by internal medicine residents 3 years before the clinic was started in 2015 up to the completion of 2022. The numbers were obtained by examining procedural log data for each year for all internal medicine residents.

Results

Thirty-three residents completed the survey: 10 first-year internal medicine residents (PGY1), 12 second-year residents (PGY2), and 11 third-year residents (PGY3). The mean participation was 4.8 paracentesis sessions per person for the duration of the study. The range of paracentesis procedures performed varied based on PGY year: PGY1s performed 1 to > 10 procedures, PGY2s performed 2 to > 10 procedures, and PGY3s performed 5 to > 10 procedures. Thirty-six percent of residents completed > 10 procedures in the paracentesis clinic; 82% of PGY3s had completed > 10 procedures by December of their third year. Twenty-six residents (79%) were credentialed to perform paracentesis procedures independently after performing > 5 procedures, and 7 residents were not yet cleared for procedural independence.

In the survey, residents rated their comfort with performing paracentesis procedures independently at a mean of 7.9. The mean comfort reported by PGY1s was 7.2, PGY2s was 7.3, and PGY3s was 9.3. Residents also rated their opinion on whether or not the paracentesis clinic adequately prepared them for paracentesis procedural independence; the mean was 8.9 across all residents.

The total number of procedures performed by residents at CTVAH also increased. Starting in 2015, 3 years before the clinic was started, 38 procedures were performed by internal medicine residents, followed by 72 procedures in 2016; 76 in 2017; 58 in 2018; 94 in 2019; 88 in 2020; 136 in 2021; and 188 in 2022.

Paracentesis is a simple but invasive procedure to relieve ascites, often relieving patients’ symptoms, preventing hospital admission, and increasing patient satisfaction.⁴ The CTVAH does not have the capacity to perform outpatient paracentesis effectively in its emergency or radiology departments. Furthermore, the use of the emergency or radiology departments for routine paracentesis may not be feasible due to the acuity of care being provided, as these procedures can be time consuming and can draw away critical resources and time from patients that need emergent care. The paracentesis clinic was then formed to provide veterans access to the procedural care they need, while also preparing residents to ably and confidently perform the procedure independently.

Based on our study, most residents were cleared to independently perform paracentesis procedures across all 3 years, with 79% of residents having completed the required 5 supervised procedures to independently practice. A study assessing unsupervised practice standards showed that paracentesis skill declines as soon as 3 months after training. However, retraining was shown to potentially interrupt this skill decline.⁵ Studies have shown that procedure-driven electives or services significantly improved paracentesis certification rates and total logged procedures, with minimal funding or scheduling changes required.⁶ Our clinic showed a significant increase in the number of procedures logged starting with the minimum of 38 procedures in 2015 and ending with 188 procedures logged at the end of 2022.

By allowing residents to routinely return to the paracentesis clinic across all 3 years, residents were more likely to feel comfortable independently performing the procedure, with residents reporting a mean comfort score of 7.9. The spaced repetition and ability to work with the clinic during elective time allows regular opportunities to undergo supervised training in a controlled environment and created scheduled retraining opportunities. Future studies should evaluate residents prior to each paracentesis clinic to ascertain if skill decline is occurring at a slower rate.

The inpatient effect of the clinic is also multifocal. Pham and colleagues showed that integrating paracentesis into timely training can reduce paracentesis delay and delays in care.⁷ By increasing the volume of procedures each resident performs and creating a sense of confidence amongst residents, the clinic increases the number of residents able and willing to perform inpatient procedures, thus reducing the number of unnecessary consultations and hospital resources. One of the reasons the paracentesis clinic was started was to allow patients to have scheduled times to remove fluid from their abdomen, thus cutting down on emergency department procedures and unnecessary admissions. Additionally, the benefits of early paracentesis procedural performance by residents and internal medicine physicians have been demonstrated in the literature. A study by Gaetano and colleagues noted that patients undergoing early paracentesis had reduced mortality of 5.5% vs 7.5% in those undergoing late paracentesis.⁸ This study also showed the in-hospital mortality rate was decreased with paracentesis (6.3%) vs without paracentesis (8.9%).⁸ By offering residents a chance to participate in the clinic, we have shown that regular opportunities to perform paracentesis may increase the number of physicians capable of independently practicing, improve procedural competency, and improve patient access to this procedure.

Limitations

Our study was not free of bias and has potential weaknesses. The survey was sent to all current residents who have participated in the paracentesis clinic, but not every resident filled out the survey (55% of all residents across 3 years completed the survey, 68.7% who had done clinic that year completed the survey). There is a possibility that those not signed off avoided doing the survey, but we are unable to confirm this. The survey also depended on resident recall of the number of paracenteses completed or looking at their procedure log. It is possible that some procedures were not documented, changing the true number. Additionally, rating comfortability with procedures is subjective, which may also create a source of potential weakness. Future projects should include a baseline survey for residents, followed by a repeat survey a year later to show changes from baseline competency.

Conclusions

A dedicated paracentesis clinic with internal medicine resident involvement may increase resident paracentesis procedural independence, the number of procedures available and performed, and procedural comfort level.

Piperacillin/tazobactam (PTZ) is a combination IV antibiotic comprised of the semisynthetic antipseudomonal β-lactam, piperacillin sodium, and the β-lactamase inhibitor, tazobactam sodium.¹ PTZ is extensively prescribed in the hospital setting for a multitude of infections including but not limited to the US Food and Drug Administration–approved indications: intra-abdominal infection, skin and skin structure infection (SSTI), urinary tract infection (UTI), and pneumonia. Given its broad spectrum of activity and relative safety profile, PTZ is a mainstay of many empiric IV antibiotic regimens. The primary elimination pathway for PTZ is renal excretion, and dosage adjustments are recommended with reduced creatinine clearance. Additionally, PTZ use has been associated with acute renal injury and delayed renal recovery.^1-3

There are various mechanisms through which medications can contribute to acute decomopensated heart failure (ADHF).⁴ These mechanisms include direct cardiotoxicity; negative inotropic, lusitropic, or chronotropic effects; exacerbating hypertension; sodium loading; and drug-drug interactions that limit the benefits of heart failure (HF) medications. One potentially overlooked constituent of PTZ is the sodium content, with the standard formulation containing 65 mg of sodium per gram of piperacillin.^1-3 Furthermore, PTZ must be diluted in 50 to 150 mL of diluent, commonly 0.9% sodium chloride, which can contribute an additional 177 to 531 mg of sodium per dose. PTZ prescribing information advises caution for use in patients with decreased renal, hepatic, and/or cardiac function and notes that geriatric patients, particularly with HF, may be at risk of impaired natriuresis in the setting of large sodium doses.

It is estimated that roughly 6.2 million adults in the United States have HF and prevalence continues to rise.^5,6 Mortality rates after hospitalization due to HF are 20% to 25% at 1 year. Health care expenditures for the management of HF surpass $30 billion per year in the US, with most of this cost attributed to hospitalizations. Consequently, it is important to continue to identify and practice preventative strategies when managing patients with HF.

Methods

This single-center, retrospective, cohort study was conducted at James H. Quillen Veterans Affairs Medical Center (JHQVAMC) in Mountain Home, Tennessee, a 174-bed tertiary medical center. The purpose of this study was to compare the incidence of ADHF in patients who received PTZ vs cefepime (CFP). This project was reviewed by the JHQVAMC Institutional Review Board and deemed exempt as a clinical process improvement operations activity.

The antimicrobial stewardship team at JHQVAMC reviewed the use of PTZ in veterans between January 1, 2018, to December 31, 2019, and compared baseline demographics, history of HF, and outcomes in patients receiving analogous broad-spectrum empiric antibiotic therapy with CFP. Patients were included if they received at least 24 hours of PTZ or CFP. Patients were excluded if they were diagnosed with ADHF before initiation of antibiotic therapy. Patients with ADHF were identified by clinical diagnosis of ADHF documented by the treating clinician and reaffirmed by the study clinician during retrospective chart review. Clinical information used to determine ADHF included clinical presentation, imaging (ie, chest X-ray, echocardiograms), and laboratory parameters, such as B-type natriuretic peptide. The primary endpoint of this study was the incidence of ADHF during the current hospitalization. Secondary endpoints included the length of hospital stay, hospital readmission, and overall mortality. Patient chart reviews were performed using the JHQVAMC Computerized Patient Record System (CPRS).

Statistical Analysis

Analysis was conducted with R Software. Pearson χ² and t tests were used to compare baseline demographics, length of stay, readmission, and mortality. Significance used was α = .05.

A retrospective chart review was performed on 389 veterans. Of the 389, 204 patients received at least 24 hours of PTZ, and 185 patients received CFP. The mean age in both groups was 75 years. Patients in the PTZ group were more likely to have been admitted with the diagnosis of pneumonia (105 vs 49, P < .001). However, 29 patients (15.7%) in the CFP group were admitted with a UTI diagnosis compared with 6 patients (2.9%) in the PTZ group (P < .001) and 62 patients (33.5%) in the CFP group were admitted with a SSTI diagnosis compared with 48 patients (23.5%) in the PTZ group (P = .03). Otherwise, there were no differences between other admitting diagnoses. Additionally, there was no difference in prior history of HF between groups (Table 1).

Twenty-five patients (12.3%) in the PTZ group and 4 patients (2.2%) in the CFP group were subsequently diagnosed with ADHF (P < .001). Hospital readmissions due to HF were higher in the PTZ group compared with the CFP group (11 vs 2, P = .02). Hospital readmission due to other causes was not significantly different between groups. Hospital readmission due to infection occurred in 18 patients who received PTZ and 25 who received CFP (8.8% vs 13.5%, P = .14). Hospital readmission due to any other indication occurred in 24 patients who received PTZ and 24 who received CFP (11.8% vs 13.0%, P = .72). There was no statistically significant difference in all-cause mortality during the associated admission or within 6 months of discharge between groups, with 59 total deaths in the PTZ group and 50 in the CFP group (28.9% vs 27.0%, P = .63).

There was no difference in length of stay outcomes between patients receiving PTZ compared with CFP. Twenty-eight patients in the PTZ group and 20 in the CFP group had a length of stay duration of < 3 days (13.7% vs 10.8%, P = .46). Seventy-three patients in the PTZ group and 76 in the CFP group had a length of stay duration of 4 to 6 days (36.3% vs 41.1%, P = .28). One hundred three patients in the PTZ group and 89 in the CFP group had a length of stay duration ≥ 7 days (50.5% vs 48.1%, P = .78). Table 2 includes a complete overview of primary and secondary endpoint results.

Discussion

The American Heart Association (AHA) lists PTZ as a medication that may cause or exacerbate HF, though no studies have identified a clear association between PTZ use and ADHF.⁴ Sodium restriction is consistently recommended as an important strategy for the prevention of ADHF. Accordingly, PTZ prescribing information and the AHA advise careful consideration with PTZ use in this patient population.^1,4

The specific mechanism responsible for the association of PTZ with cardiac-related adverse outcomes is unclear. It is easy to presume that the sodium content of PTZ is solely responsible; however, other antibiotic regimens not included as agents of concern by the AHA, such as meropenem, can approach similar overall daily sodium amounts.^4,7 Additionally, total sodium and volume can also be contributed by various IV medications and fluids. This study did not evaluate total sodium intake from all sources, but it is notable that this study identified a possible trend toward the risk of ADHF with PTZ use in a routine practice environment. It is reasonable to postulate additional intrinsic properties of PTZ may be contributing to the development of ADHF, such as its association with renal injury possibly resulting in increased fluid retainment and subsequent fluid volume overload.^1,2,4 Other hypothesized mechanisms may include those previously described, such as direct myocardial toxicity; negative inotropic, lusitropic, or chronotropic effects; exacerbating hypertension; and drug-drug interactions that limit the benefits of HF medications, although these have not been overtly associated with PTZ in the literature to date.^4,8

ADHF can present similarly to other acute pulmonary conditions, including pneumonia.^9,10 It is important to acknowledge the challenge this creates for diagnosticians to differentiate between these conditions rapidly and precisely. As a result, this patient population is likely at increased risk of IV antibiotic exposure. Other studies have identified worse outcomes in patients who receive potentially unwarranted IV antibiotics in patients with ADHF.^9,10 The results of this study further emphasize the importance of careful considerate antibiotic selection and overall avoidance of unnecessary antibiotic exposure to limit potential adverse outcomes.

Limitations

There are various limitations to this study. Firstly, no women were included due to the predominantly male population within the Veterans Health Administration system. Secondly, this study was retrospective in design and was therefore limited to the completeness and accuracy of the available data collected. Additionally, this study evaluated any ADHF episode during the associated hospitalization as the primary endpoint. The time to diagnosis of ADHF in relation to PTZ initiation was not evaluated, which may have helped better elucidate this possible association. Furthermore, while a significant statistical difference was identified, the smaller sample size may have limited the ability to accurately identify differences in lower event rate outcomes.

Conclusions

This study identifies an association between PTZ use and significant cardiac-related adverse outcomes, including increased incidence of ADHF and readmission due to HF exacerbation. While more research is needed to define the exact mechanisms by which PTZ may precipitate acute decompensation in patients with HF, it is judicious to consider close monitoring or the avoidance of PTZ when appropriate antibiotic alternatives are available in patients with a known history of HF.

Piperacillin/tazobactam (PTZ) is a combination IV antibiotic comprised of the semisynthetic antipseudomonal β-lactam, piperacillin sodium, and the β-lactamase inhibitor, tazobactam sodium.¹ PTZ is extensively prescribed in the hospital setting for a multitude of infections including but not limited to the US Food and Drug Administration–approved indications: intra-abdominal infection, skin and skin structure infection (SSTI), urinary tract infection (UTI), and pneumonia. Given its broad spectrum of activity and relative safety profile, PTZ is a mainstay of many empiric IV antibiotic regimens. The primary elimination pathway for PTZ is renal excretion, and dosage adjustments are recommended with reduced creatinine clearance. Additionally, PTZ use has been associated with acute renal injury and delayed renal recovery.^1-3

There are various mechanisms through which medications can contribute to acute decomopensated heart failure (ADHF).⁴ These mechanisms include direct cardiotoxicity; negative inotropic, lusitropic, or chronotropic effects; exacerbating hypertension; sodium loading; and drug-drug interactions that limit the benefits of heart failure (HF) medications. One potentially overlooked constituent of PTZ is the sodium content, with the standard formulation containing 65 mg of sodium per gram of piperacillin.^1-3 Furthermore, PTZ must be diluted in 50 to 150 mL of diluent, commonly 0.9% sodium chloride, which can contribute an additional 177 to 531 mg of sodium per dose. PTZ prescribing information advises caution for use in patients with decreased renal, hepatic, and/or cardiac function and notes that geriatric patients, particularly with HF, may be at risk of impaired natriuresis in the setting of large sodium doses.

It is estimated that roughly 6.2 million adults in the United States have HF and prevalence continues to rise.^5,6 Mortality rates after hospitalization due to HF are 20% to 25% at 1 year. Health care expenditures for the management of HF surpass $30 billion per year in the US, with most of this cost attributed to hospitalizations. Consequently, it is important to continue to identify and practice preventative strategies when managing patients with HF.

Methods

This single-center, retrospective, cohort study was conducted at James H. Quillen Veterans Affairs Medical Center (JHQVAMC) in Mountain Home, Tennessee, a 174-bed tertiary medical center. The purpose of this study was to compare the incidence of ADHF in patients who received PTZ vs cefepime (CFP). This project was reviewed by the JHQVAMC Institutional Review Board and deemed exempt as a clinical process improvement operations activity.

The antimicrobial stewardship team at JHQVAMC reviewed the use of PTZ in veterans between January 1, 2018, to December 31, 2019, and compared baseline demographics, history of HF, and outcomes in patients receiving analogous broad-spectrum empiric antibiotic therapy with CFP. Patients were included if they received at least 24 hours of PTZ or CFP. Patients were excluded if they were diagnosed with ADHF before initiation of antibiotic therapy. Patients with ADHF were identified by clinical diagnosis of ADHF documented by the treating clinician and reaffirmed by the study clinician during retrospective chart review. Clinical information used to determine ADHF included clinical presentation, imaging (ie, chest X-ray, echocardiograms), and laboratory parameters, such as B-type natriuretic peptide. The primary endpoint of this study was the incidence of ADHF during the current hospitalization. Secondary endpoints included the length of hospital stay, hospital readmission, and overall mortality. Patient chart reviews were performed using the JHQVAMC Computerized Patient Record System (CPRS).

Statistical Analysis

Analysis was conducted with R Software. Pearson χ² and t tests were used to compare baseline demographics, length of stay, readmission, and mortality. Significance used was α = .05.

A retrospective chart review was performed on 389 veterans. Of the 389, 204 patients received at least 24 hours of PTZ, and 185 patients received CFP. The mean age in both groups was 75 years. Patients in the PTZ group were more likely to have been admitted with the diagnosis of pneumonia (105 vs 49, P < .001). However, 29 patients (15.7%) in the CFP group were admitted with a UTI diagnosis compared with 6 patients (2.9%) in the PTZ group (P < .001) and 62 patients (33.5%) in the CFP group were admitted with a SSTI diagnosis compared with 48 patients (23.5%) in the PTZ group (P = .03). Otherwise, there were no differences between other admitting diagnoses. Additionally, there was no difference in prior history of HF between groups (Table 1).

Twenty-five patients (12.3%) in the PTZ group and 4 patients (2.2%) in the CFP group were subsequently diagnosed with ADHF (P < .001). Hospital readmissions due to HF were higher in the PTZ group compared with the CFP group (11 vs 2, P = .02). Hospital readmission due to other causes was not significantly different between groups. Hospital readmission due to infection occurred in 18 patients who received PTZ and 25 who received CFP (8.8% vs 13.5%, P = .14). Hospital readmission due to any other indication occurred in 24 patients who received PTZ and 24 who received CFP (11.8% vs 13.0%, P = .72). There was no statistically significant difference in all-cause mortality during the associated admission or within 6 months of discharge between groups, with 59 total deaths in the PTZ group and 50 in the CFP group (28.9% vs 27.0%, P = .63).

There was no difference in length of stay outcomes between patients receiving PTZ compared with CFP. Twenty-eight patients in the PTZ group and 20 in the CFP group had a length of stay duration of < 3 days (13.7% vs 10.8%, P = .46). Seventy-three patients in the PTZ group and 76 in the CFP group had a length of stay duration of 4 to 6 days (36.3% vs 41.1%, P = .28). One hundred three patients in the PTZ group and 89 in the CFP group had a length of stay duration ≥ 7 days (50.5% vs 48.1%, P = .78). Table 2 includes a complete overview of primary and secondary endpoint results.

Discussion

The American Heart Association (AHA) lists PTZ as a medication that may cause or exacerbate HF, though no studies have identified a clear association between PTZ use and ADHF.⁴ Sodium restriction is consistently recommended as an important strategy for the prevention of ADHF. Accordingly, PTZ prescribing information and the AHA advise careful consideration with PTZ use in this patient population.^1,4

The specific mechanism responsible for the association of PTZ with cardiac-related adverse outcomes is unclear. It is easy to presume that the sodium content of PTZ is solely responsible; however, other antibiotic regimens not included as agents of concern by the AHA, such as meropenem, can approach similar overall daily sodium amounts.^4,7 Additionally, total sodium and volume can also be contributed by various IV medications and fluids. This study did not evaluate total sodium intake from all sources, but it is notable that this study identified a possible trend toward the risk of ADHF with PTZ use in a routine practice environment. It is reasonable to postulate additional intrinsic properties of PTZ may be contributing to the development of ADHF, such as its association with renal injury possibly resulting in increased fluid retainment and subsequent fluid volume overload.^1,2,4 Other hypothesized mechanisms may include those previously described, such as direct myocardial toxicity; negative inotropic, lusitropic, or chronotropic effects; exacerbating hypertension; and drug-drug interactions that limit the benefits of HF medications, although these have not been overtly associated with PTZ in the literature to date.^4,8

ADHF can present similarly to other acute pulmonary conditions, including pneumonia.^9,10 It is important to acknowledge the challenge this creates for diagnosticians to differentiate between these conditions rapidly and precisely. As a result, this patient population is likely at increased risk of IV antibiotic exposure. Other studies have identified worse outcomes in patients who receive potentially unwarranted IV antibiotics in patients with ADHF.^9,10 The results of this study further emphasize the importance of careful considerate antibiotic selection and overall avoidance of unnecessary antibiotic exposure to limit potential adverse outcomes.

Limitations

There are various limitations to this study. Firstly, no women were included due to the predominantly male population within the Veterans Health Administration system. Secondly, this study was retrospective in design and was therefore limited to the completeness and accuracy of the available data collected. Additionally, this study evaluated any ADHF episode during the associated hospitalization as the primary endpoint. The time to diagnosis of ADHF in relation to PTZ initiation was not evaluated, which may have helped better elucidate this possible association. Furthermore, while a significant statistical difference was identified, the smaller sample size may have limited the ability to accurately identify differences in lower event rate outcomes.

Conclusions

This study identifies an association between PTZ use and significant cardiac-related adverse outcomes, including increased incidence of ADHF and readmission due to HF exacerbation. While more research is needed to define the exact mechanisms by which PTZ may precipitate acute decompensation in patients with HF, it is judicious to consider close monitoring or the avoidance of PTZ when appropriate antibiotic alternatives are available in patients with a known history of HF.

Piperacillin/tazobactam (PTZ) is a combination IV antibiotic comprised of the semisynthetic antipseudomonal β-lactam, piperacillin sodium, and the β-lactamase inhibitor, tazobactam sodium.¹ PTZ is extensively prescribed in the hospital setting for a multitude of infections including but not limited to the US Food and Drug Administration–approved indications: intra-abdominal infection, skin and skin structure infection (SSTI), urinary tract infection (UTI), and pneumonia. Given its broad spectrum of activity and relative safety profile, PTZ is a mainstay of many empiric IV antibiotic regimens. The primary elimination pathway for PTZ is renal excretion, and dosage adjustments are recommended with reduced creatinine clearance. Additionally, PTZ use has been associated with acute renal injury and delayed renal recovery.^1-3

There are various mechanisms through which medications can contribute to acute decomopensated heart failure (ADHF).⁴ These mechanisms include direct cardiotoxicity; negative inotropic, lusitropic, or chronotropic effects; exacerbating hypertension; sodium loading; and drug-drug interactions that limit the benefits of heart failure (HF) medications. One potentially overlooked constituent of PTZ is the sodium content, with the standard formulation containing 65 mg of sodium per gram of piperacillin.^1-3 Furthermore, PTZ must be diluted in 50 to 150 mL of diluent, commonly 0.9% sodium chloride, which can contribute an additional 177 to 531 mg of sodium per dose. PTZ prescribing information advises caution for use in patients with decreased renal, hepatic, and/or cardiac function and notes that geriatric patients, particularly with HF, may be at risk of impaired natriuresis in the setting of large sodium doses.

It is estimated that roughly 6.2 million adults in the United States have HF and prevalence continues to rise.^5,6 Mortality rates after hospitalization due to HF are 20% to 25% at 1 year. Health care expenditures for the management of HF surpass $30 billion per year in the US, with most of this cost attributed to hospitalizations. Consequently, it is important to continue to identify and practice preventative strategies when managing patients with HF.

Methods

This single-center, retrospective, cohort study was conducted at James H. Quillen Veterans Affairs Medical Center (JHQVAMC) in Mountain Home, Tennessee, a 174-bed tertiary medical center. The purpose of this study was to compare the incidence of ADHF in patients who received PTZ vs cefepime (CFP). This project was reviewed by the JHQVAMC Institutional Review Board and deemed exempt as a clinical process improvement operations activity.

The antimicrobial stewardship team at JHQVAMC reviewed the use of PTZ in veterans between January 1, 2018, to December 31, 2019, and compared baseline demographics, history of HF, and outcomes in patients receiving analogous broad-spectrum empiric antibiotic therapy with CFP. Patients were included if they received at least 24 hours of PTZ or CFP. Patients were excluded if they were diagnosed with ADHF before initiation of antibiotic therapy. Patients with ADHF were identified by clinical diagnosis of ADHF documented by the treating clinician and reaffirmed by the study clinician during retrospective chart review. Clinical information used to determine ADHF included clinical presentation, imaging (ie, chest X-ray, echocardiograms), and laboratory parameters, such as B-type natriuretic peptide. The primary endpoint of this study was the incidence of ADHF during the current hospitalization. Secondary endpoints included the length of hospital stay, hospital readmission, and overall mortality. Patient chart reviews were performed using the JHQVAMC Computerized Patient Record System (CPRS).

Statistical Analysis

Analysis was conducted with R Software. Pearson χ² and t tests were used to compare baseline demographics, length of stay, readmission, and mortality. Significance used was α = .05.

A retrospective chart review was performed on 389 veterans. Of the 389, 204 patients received at least 24 hours of PTZ, and 185 patients received CFP. The mean age in both groups was 75 years. Patients in the PTZ group were more likely to have been admitted with the diagnosis of pneumonia (105 vs 49, P < .001). However, 29 patients (15.7%) in the CFP group were admitted with a UTI diagnosis compared with 6 patients (2.9%) in the PTZ group (P < .001) and 62 patients (33.5%) in the CFP group were admitted with a SSTI diagnosis compared with 48 patients (23.5%) in the PTZ group (P = .03). Otherwise, there were no differences between other admitting diagnoses. Additionally, there was no difference in prior history of HF between groups (Table 1).

Twenty-five patients (12.3%) in the PTZ group and 4 patients (2.2%) in the CFP group were subsequently diagnosed with ADHF (P < .001). Hospital readmissions due to HF were higher in the PTZ group compared with the CFP group (11 vs 2, P = .02). Hospital readmission due to other causes was not significantly different between groups. Hospital readmission due to infection occurred in 18 patients who received PTZ and 25 who received CFP (8.8% vs 13.5%, P = .14). Hospital readmission due to any other indication occurred in 24 patients who received PTZ and 24 who received CFP (11.8% vs 13.0%, P = .72). There was no statistically significant difference in all-cause mortality during the associated admission or within 6 months of discharge between groups, with 59 total deaths in the PTZ group and 50 in the CFP group (28.9% vs 27.0%, P = .63).

There was no difference in length of stay outcomes between patients receiving PTZ compared with CFP. Twenty-eight patients in the PTZ group and 20 in the CFP group had a length of stay duration of < 3 days (13.7% vs 10.8%, P = .46). Seventy-three patients in the PTZ group and 76 in the CFP group had a length of stay duration of 4 to 6 days (36.3% vs 41.1%, P = .28). One hundred three patients in the PTZ group and 89 in the CFP group had a length of stay duration ≥ 7 days (50.5% vs 48.1%, P = .78). Table 2 includes a complete overview of primary and secondary endpoint results.

Discussion

The American Heart Association (AHA) lists PTZ as a medication that may cause or exacerbate HF, though no studies have identified a clear association between PTZ use and ADHF.⁴ Sodium restriction is consistently recommended as an important strategy for the prevention of ADHF. Accordingly, PTZ prescribing information and the AHA advise careful consideration with PTZ use in this patient population.^1,4

The specific mechanism responsible for the association of PTZ with cardiac-related adverse outcomes is unclear. It is easy to presume that the sodium content of PTZ is solely responsible; however, other antibiotic regimens not included as agents of concern by the AHA, such as meropenem, can approach similar overall daily sodium amounts.^4,7 Additionally, total sodium and volume can also be contributed by various IV medications and fluids. This study did not evaluate total sodium intake from all sources, but it is notable that this study identified a possible trend toward the risk of ADHF with PTZ use in a routine practice environment. It is reasonable to postulate additional intrinsic properties of PTZ may be contributing to the development of ADHF, such as its association with renal injury possibly resulting in increased fluid retainment and subsequent fluid volume overload.^1,2,4 Other hypothesized mechanisms may include those previously described, such as direct myocardial toxicity; negative inotropic, lusitropic, or chronotropic effects; exacerbating hypertension; and drug-drug interactions that limit the benefits of HF medications, although these have not been overtly associated with PTZ in the literature to date.^4,8

ADHF can present similarly to other acute pulmonary conditions, including pneumonia.^9,10 It is important to acknowledge the challenge this creates for diagnosticians to differentiate between these conditions rapidly and precisely. As a result, this patient population is likely at increased risk of IV antibiotic exposure. Other studies have identified worse outcomes in patients who receive potentially unwarranted IV antibiotics in patients with ADHF.^9,10 The results of this study further emphasize the importance of careful considerate antibiotic selection and overall avoidance of unnecessary antibiotic exposure to limit potential adverse outcomes.

Limitations

There are various limitations to this study. Firstly, no women were included due to the predominantly male population within the Veterans Health Administration system. Secondly, this study was retrospective in design and was therefore limited to the completeness and accuracy of the available data collected. Additionally, this study evaluated any ADHF episode during the associated hospitalization as the primary endpoint. The time to diagnosis of ADHF in relation to PTZ initiation was not evaluated, which may have helped better elucidate this possible association. Furthermore, while a significant statistical difference was identified, the smaller sample size may have limited the ability to accurately identify differences in lower event rate outcomes.

Conclusions

This study identifies an association between PTZ use and significant cardiac-related adverse outcomes, including increased incidence of ADHF and readmission due to HF exacerbation. While more research is needed to define the exact mechanisms by which PTZ may precipitate acute decompensation in patients with HF, it is judicious to consider close monitoring or the avoidance of PTZ when appropriate antibiotic alternatives are available in patients with a known history of HF.

Artificial intelligence (AI) has lagged in health care but has considerable potential to improve quality, safety, clinician experience, and access to care. It is being tested in areas like billing, hospital operations, and preventing adverse events (eg, sepsis mortality) with some early success. However, there are still many barriers preventing the widespread use of AI, such as data problems, mismatched rewards, and workplace obstacles. Innovative projects, partnerships, better rewards, and more investment could remove barriers. Implemented reliably and safely, AI can add to what clinicians know, help them work faster, cut costs, and, most importantly, improve patient care.¹

AI can potentially bring several clinical benefits, such as reducing the administrative strain on clinicians and granting them more time for direct patient care. It can also improve diagnostic accuracy by analyzing patient data and diagnostic images, providing differential diagnoses, and increasing access to care by providing medical information and essential online services to patients.²

High Reliability Organizations

High reliability health care organizations have considerable experience safely launching new programs. For example, the Patient Safety Adoption Framework gives practical tips for smoothly rolling out safety initiatives (Table 1). Developed with experts and diverse views, this framework has 5 key areas: leadership, culture and context, process, measurement, and person-centeredness. These address adoption problems, guide leaders step-by-step, and focus on leadership buy-in, safety culture, cooperation, and local customization. Checklists and tools make it systematic to go from ideas to action on patient safety.³

Leadership involves establishing organizational commitment behind new safety programs. This visible commitment signals importance and priorities to others. Leaders model desired behaviors and language around safety, allocate resources, remove obstacles, and keep initiatives energized over time through consistent messaging.⁴ Culture and context recognizes that safety culture differs across units and facilities. Local input tailors programs to fit and examines strengths to build on, like psychological safety. Surveys gauge the existing culture and its need for change. Process details how to plan, design, test, implement, and improve new safety practices and provides a phased roadmap from idea to results. Measurement collects data to drive improvement and show impact. Metrics track progress and allow benchmarking. Person-centeredness puts patients first in safety efforts through participation, education, and transparency.

The Veterans Health Administration piloted a comprehensive high reliability hospital (HRH) model. Over 3 years, the Veterans Health Administration focused on leadership, culture, and process improvement at a hospital. After initiating the model, the pilot hospital improved its safety culture, reported more minor safety issues, and reduced deaths and complications better than other hospitals. The high-reliability approach successfully instilled principles and improved culture and outcomes. The HRH model is set to be expanded to 18 more US Department of Veterans Affairs (VA) sites for further evaluation across diverse settings.⁵

Trustworthy AI Framework

AI systems are growing more powerful and widespread, including in health care. Unfortunately, irresponsible AI can introduce new harm. ChatGPT and other large language models, for example, sometimes are known to provide erroneous information in a compelling way. Clinicians and patients who use such programs can act on such information, which would lead to unforeseen negative consequences. Several frameworks on ethical AI have come from governmental groups.^6-9 In 2023, the VA National AI Institute suggested a Trustworthy AI Framework based on core principles tailored for federal health care. The framework has 6 key principles: purposeful, effective and safe, secure and private, fair and equitable, transparent and explainable, and accountable and monitored (Table 2).¹⁰

First, AI must clearly help veterans while minimizing risks. To ensure purpose, the VA will assess patient and clinician needs and design AI that targets meaningful problems to avoid scope creep or feature bloat. For example, adding new features to the AI software after release can clutter and complicate the interface, making it difficult to use. Rigorous testing will confirm that AI meets intent prior to deployment. Second, AI is designed and checked for effectiveness, safety, and reliability. The VA pledges to monitor AI’s impact to ensure it performs as expected without unintended consequences. Algorithms will be stress tested across representative datasets and approval processes will screen for safety issues. Third, AI models are secured from vulnerabilities and misuse. Technical controls will prevent unauthorized access or changes to AI systems. Audits will check for appropriate internal usage per policies. Continual patches and upgrades will maintain security. Fourth, the VA manages AI for fairness, avoiding bias. They will proactively assess datasets and algorithms for potential biases based on protected attributes like race, gender, or age. Biased outputs will be addressed through techniques such as data augmentation, reweighting, and algorithm tweaks. Fifth, transparency explains AI’s role in care. Documentation will detail an AI system’s data sources, methodology, testing, limitations, and integration with clinical workflows. Clinicians and patients will receive education on interpreting AI outputs. Finally, the VA pledges to closely monitor AI systems to sustain trust. The VA will establish oversight processes to quickly identify any declines in reliability or unfair impacts on subgroups. AI models will be retrained as needed based on incoming data patterns.

Each Trustworthy AI Framework principle connects to others in existing frameworks. The purpose principle aligns with human-centric AI focused on benefits. Effectiveness and safety link to technical robustness and risk management principles. Security maps to privacy protection principles. Fairness connects to principles of avoiding bias and discrimination. Transparency corresponds with accountable and explainable AI. Monitoring and accountability tie back to governance principles. Overall, the VA framework aims to guide ethical AI based on context. It offers a model for managing risks and building trust in health care AI.

Combining VA principles with high-reliability safety principles can ensure that AI benefits veterans. The leadership and culture aspects will drive commitment to trustworthy AI practices. Leaders will communicate the importance of responsible AI through words and actions. Culture surveys can assess baseline awareness of AI ethics issues to target education. AI security and fairness will be emphasized as safety critical. The process aspect will institute policies and procedures to uphold AI principles through the project lifecycle. For example, structured testing processes will validate safety. Measurement will collect data on principles like transparency and fairness. Dashboards can track metrics like explainability and biases. A patient-centered approach will incorporate veteran perspectives on AI through participatory design and advisory councils. They can give input on AI explainability and potential biases based on their diverse backgrounds.

Conclusions

Joint principles will lead to successful AI that improves care while proactively managing risks. Involve leaders to stress the necessity of eliminating biases. Build security into the AI development process. Co-design AI transparency features with end users. Closely monitor the impact of AI across safety, fairness, and other principles. Adhering to both Trustworthy AI and high reliability organizations principles will earn veterans’ confidence. Health care organizations like the VA can integrate ethical AI safely via established frameworks. With responsible design and implementation, AI’s potential to enhance care quality, safety, and access can be realized.

Acknowledgments

We would like to acknowledge Joshua Mueller, Theo Tiffney, John Zachary, and Gil Alterovitz for their excellent work creating the VA Trustworthy Principles. This material is the result of work supported by resources and the use of facilities at the James A. Haley Veterans’ Hospital.

Artificial intelligence (AI) has lagged in health care but has considerable potential to improve quality, safety, clinician experience, and access to care. It is being tested in areas like billing, hospital operations, and preventing adverse events (eg, sepsis mortality) with some early success. However, there are still many barriers preventing the widespread use of AI, such as data problems, mismatched rewards, and workplace obstacles. Innovative projects, partnerships, better rewards, and more investment could remove barriers. Implemented reliably and safely, AI can add to what clinicians know, help them work faster, cut costs, and, most importantly, improve patient care.¹

AI can potentially bring several clinical benefits, such as reducing the administrative strain on clinicians and granting them more time for direct patient care. It can also improve diagnostic accuracy by analyzing patient data and diagnostic images, providing differential diagnoses, and increasing access to care by providing medical information and essential online services to patients.²

High Reliability Organizations

High reliability health care organizations have considerable experience safely launching new programs. For example, the Patient Safety Adoption Framework gives practical tips for smoothly rolling out safety initiatives (Table 1). Developed with experts and diverse views, this framework has 5 key areas: leadership, culture and context, process, measurement, and person-centeredness. These address adoption problems, guide leaders step-by-step, and focus on leadership buy-in, safety culture, cooperation, and local customization. Checklists and tools make it systematic to go from ideas to action on patient safety.³

Leadership involves establishing organizational commitment behind new safety programs. This visible commitment signals importance and priorities to others. Leaders model desired behaviors and language around safety, allocate resources, remove obstacles, and keep initiatives energized over time through consistent messaging.⁴ Culture and context recognizes that safety culture differs across units and facilities. Local input tailors programs to fit and examines strengths to build on, like psychological safety. Surveys gauge the existing culture and its need for change. Process details how to plan, design, test, implement, and improve new safety practices and provides a phased roadmap from idea to results. Measurement collects data to drive improvement and show impact. Metrics track progress and allow benchmarking. Person-centeredness puts patients first in safety efforts through participation, education, and transparency.

The Veterans Health Administration piloted a comprehensive high reliability hospital (HRH) model. Over 3 years, the Veterans Health Administration focused on leadership, culture, and process improvement at a hospital. After initiating the model, the pilot hospital improved its safety culture, reported more minor safety issues, and reduced deaths and complications better than other hospitals. The high-reliability approach successfully instilled principles and improved culture and outcomes. The HRH model is set to be expanded to 18 more US Department of Veterans Affairs (VA) sites for further evaluation across diverse settings.⁵

Trustworthy AI Framework

AI systems are growing more powerful and widespread, including in health care. Unfortunately, irresponsible AI can introduce new harm. ChatGPT and other large language models, for example, sometimes are known to provide erroneous information in a compelling way. Clinicians and patients who use such programs can act on such information, which would lead to unforeseen negative consequences. Several frameworks on ethical AI have come from governmental groups.^6-9 In 2023, the VA National AI Institute suggested a Trustworthy AI Framework based on core principles tailored for federal health care. The framework has 6 key principles: purposeful, effective and safe, secure and private, fair and equitable, transparent and explainable, and accountable and monitored (Table 2).¹⁰

First, AI must clearly help veterans while minimizing risks. To ensure purpose, the VA will assess patient and clinician needs and design AI that targets meaningful problems to avoid scope creep or feature bloat. For example, adding new features to the AI software after release can clutter and complicate the interface, making it difficult to use. Rigorous testing will confirm that AI meets intent prior to deployment. Second, AI is designed and checked for effectiveness, safety, and reliability. The VA pledges to monitor AI’s impact to ensure it performs as expected without unintended consequences. Algorithms will be stress tested across representative datasets and approval processes will screen for safety issues. Third, AI models are secured from vulnerabilities and misuse. Technical controls will prevent unauthorized access or changes to AI systems. Audits will check for appropriate internal usage per policies. Continual patches and upgrades will maintain security. Fourth, the VA manages AI for fairness, avoiding bias. They will proactively assess datasets and algorithms for potential biases based on protected attributes like race, gender, or age. Biased outputs will be addressed through techniques such as data augmentation, reweighting, and algorithm tweaks. Fifth, transparency explains AI’s role in care. Documentation will detail an AI system’s data sources, methodology, testing, limitations, and integration with clinical workflows. Clinicians and patients will receive education on interpreting AI outputs. Finally, the VA pledges to closely monitor AI systems to sustain trust. The VA will establish oversight processes to quickly identify any declines in reliability or unfair impacts on subgroups. AI models will be retrained as needed based on incoming data patterns.

Each Trustworthy AI Framework principle connects to others in existing frameworks. The purpose principle aligns with human-centric AI focused on benefits. Effectiveness and safety link to technical robustness and risk management principles. Security maps to privacy protection principles. Fairness connects to principles of avoiding bias and discrimination. Transparency corresponds with accountable and explainable AI. Monitoring and accountability tie back to governance principles. Overall, the VA framework aims to guide ethical AI based on context. It offers a model for managing risks and building trust in health care AI.

Combining VA principles with high-reliability safety principles can ensure that AI benefits veterans. The leadership and culture aspects will drive commitment to trustworthy AI practices. Leaders will communicate the importance of responsible AI through words and actions. Culture surveys can assess baseline awareness of AI ethics issues to target education. AI security and fairness will be emphasized as safety critical. The process aspect will institute policies and procedures to uphold AI principles through the project lifecycle. For example, structured testing processes will validate safety. Measurement will collect data on principles like transparency and fairness. Dashboards can track metrics like explainability and biases. A patient-centered approach will incorporate veteran perspectives on AI through participatory design and advisory councils. They can give input on AI explainability and potential biases based on their diverse backgrounds.

Conclusions

Joint principles will lead to successful AI that improves care while proactively managing risks. Involve leaders to stress the necessity of eliminating biases. Build security into the AI development process. Co-design AI transparency features with end users. Closely monitor the impact of AI across safety, fairness, and other principles. Adhering to both Trustworthy AI and high reliability organizations principles will earn veterans’ confidence. Health care organizations like the VA can integrate ethical AI safely via established frameworks. With responsible design and implementation, AI’s potential to enhance care quality, safety, and access can be realized.

Acknowledgments

We would like to acknowledge Joshua Mueller, Theo Tiffney, John Zachary, and Gil Alterovitz for their excellent work creating the VA Trustworthy Principles. This material is the result of work supported by resources and the use of facilities at the James A. Haley Veterans’ Hospital.

Artificial intelligence (AI) has lagged in health care but has considerable potential to improve quality, safety, clinician experience, and access to care. It is being tested in areas like billing, hospital operations, and preventing adverse events (eg, sepsis mortality) with some early success. However, there are still many barriers preventing the widespread use of AI, such as data problems, mismatched rewards, and workplace obstacles. Innovative projects, partnerships, better rewards, and more investment could remove barriers. Implemented reliably and safely, AI can add to what clinicians know, help them work faster, cut costs, and, most importantly, improve patient care.¹

AI can potentially bring several clinical benefits, such as reducing the administrative strain on clinicians and granting them more time for direct patient care. It can also improve diagnostic accuracy by analyzing patient data and diagnostic images, providing differential diagnoses, and increasing access to care by providing medical information and essential online services to patients.²

High Reliability Organizations

High reliability health care organizations have considerable experience safely launching new programs. For example, the Patient Safety Adoption Framework gives practical tips for smoothly rolling out safety initiatives (Table 1). Developed with experts and diverse views, this framework has 5 key areas: leadership, culture and context, process, measurement, and person-centeredness. These address adoption problems, guide leaders step-by-step, and focus on leadership buy-in, safety culture, cooperation, and local customization. Checklists and tools make it systematic to go from ideas to action on patient safety.³

Leadership involves establishing organizational commitment behind new safety programs. This visible commitment signals importance and priorities to others. Leaders model desired behaviors and language around safety, allocate resources, remove obstacles, and keep initiatives energized over time through consistent messaging.⁴ Culture and context recognizes that safety culture differs across units and facilities. Local input tailors programs to fit and examines strengths to build on, like psychological safety. Surveys gauge the existing culture and its need for change. Process details how to plan, design, test, implement, and improve new safety practices and provides a phased roadmap from idea to results. Measurement collects data to drive improvement and show impact. Metrics track progress and allow benchmarking. Person-centeredness puts patients first in safety efforts through participation, education, and transparency.

The Veterans Health Administration piloted a comprehensive high reliability hospital (HRH) model. Over 3 years, the Veterans Health Administration focused on leadership, culture, and process improvement at a hospital. After initiating the model, the pilot hospital improved its safety culture, reported more minor safety issues, and reduced deaths and complications better than other hospitals. The high-reliability approach successfully instilled principles and improved culture and outcomes. The HRH model is set to be expanded to 18 more US Department of Veterans Affairs (VA) sites for further evaluation across diverse settings.⁵

Trustworthy AI Framework

AI systems are growing more powerful and widespread, including in health care. Unfortunately, irresponsible AI can introduce new harm. ChatGPT and other large language models, for example, sometimes are known to provide erroneous information in a compelling way. Clinicians and patients who use such programs can act on such information, which would lead to unforeseen negative consequences. Several frameworks on ethical AI have come from governmental groups.^6-9 In 2023, the VA National AI Institute suggested a Trustworthy AI Framework based on core principles tailored for federal health care. The framework has 6 key principles: purposeful, effective and safe, secure and private, fair and equitable, transparent and explainable, and accountable and monitored (Table 2).¹⁰

First, AI must clearly help veterans while minimizing risks. To ensure purpose, the VA will assess patient and clinician needs and design AI that targets meaningful problems to avoid scope creep or feature bloat. For example, adding new features to the AI software after release can clutter and complicate the interface, making it difficult to use. Rigorous testing will confirm that AI meets intent prior to deployment. Second, AI is designed and checked for effectiveness, safety, and reliability. The VA pledges to monitor AI’s impact to ensure it performs as expected without unintended consequences. Algorithms will be stress tested across representative datasets and approval processes will screen for safety issues. Third, AI models are secured from vulnerabilities and misuse. Technical controls will prevent unauthorized access or changes to AI systems. Audits will check for appropriate internal usage per policies. Continual patches and upgrades will maintain security. Fourth, the VA manages AI for fairness, avoiding bias. They will proactively assess datasets and algorithms for potential biases based on protected attributes like race, gender, or age. Biased outputs will be addressed through techniques such as data augmentation, reweighting, and algorithm tweaks. Fifth, transparency explains AI’s role in care. Documentation will detail an AI system’s data sources, methodology, testing, limitations, and integration with clinical workflows. Clinicians and patients will receive education on interpreting AI outputs. Finally, the VA pledges to closely monitor AI systems to sustain trust. The VA will establish oversight processes to quickly identify any declines in reliability or unfair impacts on subgroups. AI models will be retrained as needed based on incoming data patterns.

Each Trustworthy AI Framework principle connects to others in existing frameworks. The purpose principle aligns with human-centric AI focused on benefits. Effectiveness and safety link to technical robustness and risk management principles. Security maps to privacy protection principles. Fairness connects to principles of avoiding bias and discrimination. Transparency corresponds with accountable and explainable AI. Monitoring and accountability tie back to governance principles. Overall, the VA framework aims to guide ethical AI based on context. It offers a model for managing risks and building trust in health care AI.

Combining VA principles with high-reliability safety principles can ensure that AI benefits veterans. The leadership and culture aspects will drive commitment to trustworthy AI practices. Leaders will communicate the importance of responsible AI through words and actions. Culture surveys can assess baseline awareness of AI ethics issues to target education. AI security and fairness will be emphasized as safety critical. The process aspect will institute policies and procedures to uphold AI principles through the project lifecycle. For example, structured testing processes will validate safety. Measurement will collect data on principles like transparency and fairness. Dashboards can track metrics like explainability and biases. A patient-centered approach will incorporate veteran perspectives on AI through participatory design and advisory councils. They can give input on AI explainability and potential biases based on their diverse backgrounds.

Conclusions

Joint principles will lead to successful AI that improves care while proactively managing risks. Involve leaders to stress the necessity of eliminating biases. Build security into the AI development process. Co-design AI transparency features with end users. Closely monitor the impact of AI across safety, fairness, and other principles. Adhering to both Trustworthy AI and high reliability organizations principles will earn veterans’ confidence. Health care organizations like the VA can integrate ethical AI safely via established frameworks. With responsible design and implementation, AI’s potential to enhance care quality, safety, and access can be realized.

Acknowledgments

We would like to acknowledge Joshua Mueller, Theo Tiffney, John Zachary, and Gil Alterovitz for their excellent work creating the VA Trustworthy Principles. This material is the result of work supported by resources and the use of facilities at the James A. Haley Veterans’ Hospital.

To the Editor:

A 14-year-old Black adolescent girl presented with episodic, painful, edematous plaques that occurred symmetrically on the arms and legs of 5 years’ duration. The plaques evolved into hyperpigmented patches within 24 to 48 hours before eventually resolving. Fatigue, headache, arthralgias of the arms and legs, chest pain, abdominal pain, nausea, and vomiting variably accompanied these episodes.

Prior to visiting our clinic, the patient had been seen by numerous specialists. A review of her medical records revealed an initial diagnosis of Henoch-Schönlein purpura (HSP), then urticarial vasculitis. She had been treated with antihistamines, topical and systemic steroids, hydroxychloroquine, mycophenolate mofetil, dapsone, azathioprine, and gabapentin. All treatments were ineffectual. She underwent extensive diagnostic testing and imaging, which were normal or noncontributory, including type I allergy testing; multiple exhaustive batteries of hematologic testing; and computed tomography/magnetic resonance imaging/magnetic resonance angiography of the brain, chest, abdomen, and pelvic region. Biopsies from symptomatic segments of the gastrointestinal tract were normal.

Chronic treatment with systemic steroids over 9 months resulted in gastritis and an episode of hematemesis requiring emergent hospitalization. A lengthy multidisciplinary evaluation was conducted at the patient’s local community hospital; the team concluded that she had an urticarial-type rash with accompanying symptoms that did not have an autoimmune, rheumatologic, or inflammatory basis.

The patient’s medical history was remarkable for recent-onset panic attacks. Her family medical history was noncontributory. Physical examination revealed multiple violaceous hyperpigmented patches diffusely located on the proximal upper arms (Figure 1). There were no additional findings on physical examination.

Punch biopsies were performed on lesional areas of the arm. Histopathology indicated a mild superficial perivascular dermal mixed infiltrate and extravasated erythrocytes (Figure 2). Direct immunofluorescence (DIF) testing was negative for vasculitis. Immunohistochemical stains for CD117 and tryptase demonstrated a slight increase in the number of dermal mast cells; however, the increase was not sufficient to diagnose cutaneous mastocytosis, which was in the differential. We proposed a diagnosis of psychogenic purpura (PP)(also known as Gardner-Diamond syndrome). She was treated with gabapentin, a selective serotonin reuptake inhibitor, and cognitive therapy. Unfortunately, after starting therapy the patient was lost to follow-up.

Psychogenic purpura is a rare vasculopathy of unknown etiology that may be a special form of factitious disorder.^1,2 In one study, PP occurred predominantly in females aged 15 to 66 years, with a median onset age of 33 years.³ A prodrome of localized itching, burning, and/or pain precedes the development of edematous plaques. The plaques evolve into painful ecchymoses within 1 to 2 days and resolve in 10 days or fewer without treatment. Lesions most commonly occur on the extremities but may occur anywhere on the body. The most common associated finding is an underlying depressive disorder. Episodes may be accompanied by headache, dizziness, fatigue, fever, arthralgia, nausea, vomiting, abdominal pain, menstrual irregularities, myalgia, and urologic conditions.

In 1955, Gardner and Diamond⁴ described the first cases of PP in 4 female patients at Peter Bent Brigham Hospital in Boston, Massachusetts. The investigators were able to replicate the painful ecchymoses with intradermal injection of the patient’s own erythrocytes into the skin. They proposed that the underlying pathogenesis involved autosensitization to erythrocyte stroma.⁴ Since then, others have suggested that the pathogenesis may include autosensitization to erythrocyte phosphatidylserine, tonus dysregulation of venous capillaries, abnormal endothelial fibrin synthesis, and capillary wall instability.^5-7 

Histopathology typically reveals superficial and deep perivascular inflammation with extravasated erythrocytes. Direct immunofluorescence is negative for vasculitis.⁸ Diagnostics and laboratory findings for underlying systemic illness are negative or noncontributory. Cutaneous injection of 1 mL of the patient’s own washed erythrocytes may result in the formation of the characteristic painful plaques within 24 hours; however, this test is limited by lack of standardization and low sensitivity.³

Psychogenic purpura may share clinical features with cutaneous small vessel vasculitis, such as HSP or urticarial vasculitis. Some of the findings that our patient was experiencing, including purpura, arthralgia, and abdominal pain, are associated with HSP. However, HSP typically is self-limiting and classically features palpable purpura distributed across the lower extremities and buttocks. Histopathology demonstrates the classic findings of leukocytoclastic vasculitis; DIF typically is positive for perivascular IgA and C3 deposition. Increased serum IgA may be present.⁹ Urticarial vasculitis appears as erythematous indurated wheals that favor a proximal extremity and truncal distribution. They characteristically last longer than 24 hours, are frequently associated with nonprodromal pain or burning, and resolve with hyperpigmentation. Arthralgia and gastrointestinal, renal, pulmonary, cardiac, and neurologic symptoms may be present, especially in patients with low complement levels.¹⁰ Skin biopsy demonstrates leukocytoclasia that must be accompanied by vessel wall necrosis. Fibrinoid deposition, erythrocyte extravasation, or perivascular inflammation may be present. In 70% of cases revealing perivascular immunoglobulin, C3, and fibrinogen deposition, DIF is positive. Serum C1q autoantibody may be associated with the hypocomplementemic form.¹⁰

The classic histopathologic findings in leukocytoclastic vasculitis include transmural neutrophilic infiltration of the walls of small vessels, fibrinoid necrosis of vessel walls, leukocytoclasia, extravasated erythrocytes, and signs of endothelial cell damage.⁹ A prior punch biopsy in this patient demonstrated rare neutrophilic nuclear debris within the vessel walls without fibrin deposition. Although the presence of nuclear debris and extravasated erythrocytes could be compatible with a manifestation of urticarial vasculitis, the lack of direct evidence of vessel wall necrosis combined with subsequent biopsies unequivocally ruled out cutaneous small vessel vasculitis in our patient.

Psychogenic purpura has been reported to occur frequently in the background of psycho-emotional distress. In 1989, Ratnoff¹¹ noted that many of the patients he was treating at the University Hospitals of Cleveland, Ohio, had a depressive syndrome. A review of patients treated at the Mayo Clinic in Rochester, Minnesota, illustrated concomitant psychiatric illnesses in 41 of 76 (54%) patients treated for PP, most commonly depressive, personality, and anxiety disorders.³

There is no consensus on therapy for PP. Treatment is based on providing symptomatic relief and relieving underlying psychiatric distress. Block et al¹² found the use of selective serotonin reuptake inhibitors, tricyclic antidepressants, and psychotherapy to be successful in improving symptoms and reducing lesions at follow-up visits.

To the Editor:

A 14-year-old Black adolescent girl presented with episodic, painful, edematous plaques that occurred symmetrically on the arms and legs of 5 years’ duration. The plaques evolved into hyperpigmented patches within 24 to 48 hours before eventually resolving. Fatigue, headache, arthralgias of the arms and legs, chest pain, abdominal pain, nausea, and vomiting variably accompanied these episodes.

Prior to visiting our clinic, the patient had been seen by numerous specialists. A review of her medical records revealed an initial diagnosis of Henoch-Schönlein purpura (HSP), then urticarial vasculitis. She had been treated with antihistamines, topical and systemic steroids, hydroxychloroquine, mycophenolate mofetil, dapsone, azathioprine, and gabapentin. All treatments were ineffectual. She underwent extensive diagnostic testing and imaging, which were normal or noncontributory, including type I allergy testing; multiple exhaustive batteries of hematologic testing; and computed tomography/magnetic resonance imaging/magnetic resonance angiography of the brain, chest, abdomen, and pelvic region. Biopsies from symptomatic segments of the gastrointestinal tract were normal.

Chronic treatment with systemic steroids over 9 months resulted in gastritis and an episode of hematemesis requiring emergent hospitalization. A lengthy multidisciplinary evaluation was conducted at the patient’s local community hospital; the team concluded that she had an urticarial-type rash with accompanying symptoms that did not have an autoimmune, rheumatologic, or inflammatory basis.

The patient’s medical history was remarkable for recent-onset panic attacks. Her family medical history was noncontributory. Physical examination revealed multiple violaceous hyperpigmented patches diffusely located on the proximal upper arms (Figure 1). There were no additional findings on physical examination.

Punch biopsies were performed on lesional areas of the arm. Histopathology indicated a mild superficial perivascular dermal mixed infiltrate and extravasated erythrocytes (Figure 2). Direct immunofluorescence (DIF) testing was negative for vasculitis. Immunohistochemical stains for CD117 and tryptase demonstrated a slight increase in the number of dermal mast cells; however, the increase was not sufficient to diagnose cutaneous mastocytosis, which was in the differential. We proposed a diagnosis of psychogenic purpura (PP)(also known as Gardner-Diamond syndrome). She was treated with gabapentin, a selective serotonin reuptake inhibitor, and cognitive therapy. Unfortunately, after starting therapy the patient was lost to follow-up.

Psychogenic purpura is a rare vasculopathy of unknown etiology that may be a special form of factitious disorder.^1,2 In one study, PP occurred predominantly in females aged 15 to 66 years, with a median onset age of 33 years.³ A prodrome of localized itching, burning, and/or pain precedes the development of edematous plaques. The plaques evolve into painful ecchymoses within 1 to 2 days and resolve in 10 days or fewer without treatment. Lesions most commonly occur on the extremities but may occur anywhere on the body. The most common associated finding is an underlying depressive disorder. Episodes may be accompanied by headache, dizziness, fatigue, fever, arthralgia, nausea, vomiting, abdominal pain, menstrual irregularities, myalgia, and urologic conditions.

In 1955, Gardner and Diamond⁴ described the first cases of PP in 4 female patients at Peter Bent Brigham Hospital in Boston, Massachusetts. The investigators were able to replicate the painful ecchymoses with intradermal injection of the patient’s own erythrocytes into the skin. They proposed that the underlying pathogenesis involved autosensitization to erythrocyte stroma.⁴ Since then, others have suggested that the pathogenesis may include autosensitization to erythrocyte phosphatidylserine, tonus dysregulation of venous capillaries, abnormal endothelial fibrin synthesis, and capillary wall instability.^5-7 

Histopathology typically reveals superficial and deep perivascular inflammation with extravasated erythrocytes. Direct immunofluorescence is negative for vasculitis.⁸ Diagnostics and laboratory findings for underlying systemic illness are negative or noncontributory. Cutaneous injection of 1 mL of the patient’s own washed erythrocytes may result in the formation of the characteristic painful plaques within 24 hours; however, this test is limited by lack of standardization and low sensitivity.³

Psychogenic purpura may share clinical features with cutaneous small vessel vasculitis, such as HSP or urticarial vasculitis. Some of the findings that our patient was experiencing, including purpura, arthralgia, and abdominal pain, are associated with HSP. However, HSP typically is self-limiting and classically features palpable purpura distributed across the lower extremities and buttocks. Histopathology demonstrates the classic findings of leukocytoclastic vasculitis; DIF typically is positive for perivascular IgA and C3 deposition. Increased serum IgA may be present.⁹ Urticarial vasculitis appears as erythematous indurated wheals that favor a proximal extremity and truncal distribution. They characteristically last longer than 24 hours, are frequently associated with nonprodromal pain or burning, and resolve with hyperpigmentation. Arthralgia and gastrointestinal, renal, pulmonary, cardiac, and neurologic symptoms may be present, especially in patients with low complement levels.¹⁰ Skin biopsy demonstrates leukocytoclasia that must be accompanied by vessel wall necrosis. Fibrinoid deposition, erythrocyte extravasation, or perivascular inflammation may be present. In 70% of cases revealing perivascular immunoglobulin, C3, and fibrinogen deposition, DIF is positive. Serum C1q autoantibody may be associated with the hypocomplementemic form.¹⁰

The classic histopathologic findings in leukocytoclastic vasculitis include transmural neutrophilic infiltration of the walls of small vessels, fibrinoid necrosis of vessel walls, leukocytoclasia, extravasated erythrocytes, and signs of endothelial cell damage.⁹ A prior punch biopsy in this patient demonstrated rare neutrophilic nuclear debris within the vessel walls without fibrin deposition. Although the presence of nuclear debris and extravasated erythrocytes could be compatible with a manifestation of urticarial vasculitis, the lack of direct evidence of vessel wall necrosis combined with subsequent biopsies unequivocally ruled out cutaneous small vessel vasculitis in our patient.

Psychogenic purpura has been reported to occur frequently in the background of psycho-emotional distress. In 1989, Ratnoff¹¹ noted that many of the patients he was treating at the University Hospitals of Cleveland, Ohio, had a depressive syndrome. A review of patients treated at the Mayo Clinic in Rochester, Minnesota, illustrated concomitant psychiatric illnesses in 41 of 76 (54%) patients treated for PP, most commonly depressive, personality, and anxiety disorders.³

There is no consensus on therapy for PP. Treatment is based on providing symptomatic relief and relieving underlying psychiatric distress. Block et al¹² found the use of selective serotonin reuptake inhibitors, tricyclic antidepressants, and psychotherapy to be successful in improving symptoms and reducing lesions at follow-up visits.

To the Editor:

A 14-year-old Black adolescent girl presented with episodic, painful, edematous plaques that occurred symmetrically on the arms and legs of 5 years’ duration. The plaques evolved into hyperpigmented patches within 24 to 48 hours before eventually resolving. Fatigue, headache, arthralgias of the arms and legs, chest pain, abdominal pain, nausea, and vomiting variably accompanied these episodes.

Prior to visiting our clinic, the patient had been seen by numerous specialists. A review of her medical records revealed an initial diagnosis of Henoch-Schönlein purpura (HSP), then urticarial vasculitis. She had been treated with antihistamines, topical and systemic steroids, hydroxychloroquine, mycophenolate mofetil, dapsone, azathioprine, and gabapentin. All treatments were ineffectual. She underwent extensive diagnostic testing and imaging, which were normal or noncontributory, including type I allergy testing; multiple exhaustive batteries of hematologic testing; and computed tomography/magnetic resonance imaging/magnetic resonance angiography of the brain, chest, abdomen, and pelvic region. Biopsies from symptomatic segments of the gastrointestinal tract were normal.

Chronic treatment with systemic steroids over 9 months resulted in gastritis and an episode of hematemesis requiring emergent hospitalization. A lengthy multidisciplinary evaluation was conducted at the patient’s local community hospital; the team concluded that she had an urticarial-type rash with accompanying symptoms that did not have an autoimmune, rheumatologic, or inflammatory basis.

The patient’s medical history was remarkable for recent-onset panic attacks. Her family medical history was noncontributory. Physical examination revealed multiple violaceous hyperpigmented patches diffusely located on the proximal upper arms (Figure 1). There were no additional findings on physical examination.

Punch biopsies were performed on lesional areas of the arm. Histopathology indicated a mild superficial perivascular dermal mixed infiltrate and extravasated erythrocytes (Figure 2). Direct immunofluorescence (DIF) testing was negative for vasculitis. Immunohistochemical stains for CD117 and tryptase demonstrated a slight increase in the number of dermal mast cells; however, the increase was not sufficient to diagnose cutaneous mastocytosis, which was in the differential. We proposed a diagnosis of psychogenic purpura (PP)(also known as Gardner-Diamond syndrome). She was treated with gabapentin, a selective serotonin reuptake inhibitor, and cognitive therapy. Unfortunately, after starting therapy the patient was lost to follow-up.

Psychogenic purpura is a rare vasculopathy of unknown etiology that may be a special form of factitious disorder.^1,2 In one study, PP occurred predominantly in females aged 15 to 66 years, with a median onset age of 33 years.³ A prodrome of localized itching, burning, and/or pain precedes the development of edematous plaques. The plaques evolve into painful ecchymoses within 1 to 2 days and resolve in 10 days or fewer without treatment. Lesions most commonly occur on the extremities but may occur anywhere on the body. The most common associated finding is an underlying depressive disorder. Episodes may be accompanied by headache, dizziness, fatigue, fever, arthralgia, nausea, vomiting, abdominal pain, menstrual irregularities, myalgia, and urologic conditions.

In 1955, Gardner and Diamond⁴ described the first cases of PP in 4 female patients at Peter Bent Brigham Hospital in Boston, Massachusetts. The investigators were able to replicate the painful ecchymoses with intradermal injection of the patient’s own erythrocytes into the skin. They proposed that the underlying pathogenesis involved autosensitization to erythrocyte stroma.⁴ Since then, others have suggested that the pathogenesis may include autosensitization to erythrocyte phosphatidylserine, tonus dysregulation of venous capillaries, abnormal endothelial fibrin synthesis, and capillary wall instability.^5-7 

Histopathology typically reveals superficial and deep perivascular inflammation with extravasated erythrocytes. Direct immunofluorescence is negative for vasculitis.⁸ Diagnostics and laboratory findings for underlying systemic illness are negative or noncontributory. Cutaneous injection of 1 mL of the patient’s own washed erythrocytes may result in the formation of the characteristic painful plaques within 24 hours; however, this test is limited by lack of standardization and low sensitivity.³

Psychogenic purpura may share clinical features with cutaneous small vessel vasculitis, such as HSP or urticarial vasculitis. Some of the findings that our patient was experiencing, including purpura, arthralgia, and abdominal pain, are associated with HSP. However, HSP typically is self-limiting and classically features palpable purpura distributed across the lower extremities and buttocks. Histopathology demonstrates the classic findings of leukocytoclastic vasculitis; DIF typically is positive for perivascular IgA and C3 deposition. Increased serum IgA may be present.⁹ Urticarial vasculitis appears as erythematous indurated wheals that favor a proximal extremity and truncal distribution. They characteristically last longer than 24 hours, are frequently associated with nonprodromal pain or burning, and resolve with hyperpigmentation. Arthralgia and gastrointestinal, renal, pulmonary, cardiac, and neurologic symptoms may be present, especially in patients with low complement levels.¹⁰ Skin biopsy demonstrates leukocytoclasia that must be accompanied by vessel wall necrosis. Fibrinoid deposition, erythrocyte extravasation, or perivascular inflammation may be present. In 70% of cases revealing perivascular immunoglobulin, C3, and fibrinogen deposition, DIF is positive. Serum C1q autoantibody may be associated with the hypocomplementemic form.¹⁰

The classic histopathologic findings in leukocytoclastic vasculitis include transmural neutrophilic infiltration of the walls of small vessels, fibrinoid necrosis of vessel walls, leukocytoclasia, extravasated erythrocytes, and signs of endothelial cell damage.⁹ A prior punch biopsy in this patient demonstrated rare neutrophilic nuclear debris within the vessel walls without fibrin deposition. Although the presence of nuclear debris and extravasated erythrocytes could be compatible with a manifestation of urticarial vasculitis, the lack of direct evidence of vessel wall necrosis combined with subsequent biopsies unequivocally ruled out cutaneous small vessel vasculitis in our patient.

Psychogenic purpura has been reported to occur frequently in the background of psycho-emotional distress. In 1989, Ratnoff¹¹ noted that many of the patients he was treating at the University Hospitals of Cleveland, Ohio, had a depressive syndrome. A review of patients treated at the Mayo Clinic in Rochester, Minnesota, illustrated concomitant psychiatric illnesses in 41 of 76 (54%) patients treated for PP, most commonly depressive, personality, and anxiety disorders.³

There is no consensus on therapy for PP. Treatment is based on providing symptomatic relief and relieving underlying psychiatric distress. Block et al¹² found the use of selective serotonin reuptake inhibitors, tricyclic antidepressants, and psychotherapy to be successful in improving symptoms and reducing lesions at follow-up visits.

Characteristics

Rhipicephalus ticks belong to the Ixodidae family of hard-bodied ticks. They are large and teardrop shaped with an inornate scutum (hard dorsal plate) and relatively short mouthparts attached at a hexagonal basis capitulum (base of the head to which mouthparts are attached)(Figure).¹ Widely spaced eyes and festoons also are present. The first pair of coxae—attachment base for the first pair of legs—are characteristically bifid; males have a pair of sclerotized adanal plates on the ventral surface adjacent to the anus as well as accessory adanal shields.²Rhipicephalus (formerly Boophilus) microplus (the so-called cattle tick) is a newly added species; it lacks posterior festoons, and the anal groove is absent.³

Almost all Rhipicephalus ticks, except for R microplus, are 3-host ticks in which a single blood meal is consumed from a vertebrate host at each active life stage—larva, nymph, and adult—to complete development.^4,5 In contrast to most ixodid ticks, which are exophilic (living outside of human habitation), the Rhipicephalus sanguineus sensu lato species (the brown dog tick) is highly endophilic (adapted to indoor living) and often can be found hidden in cracks and crevices of walls in homes and peridomestic structures.⁶ It is predominately monotropic (all developmental stages feed on the same host species) and has a strong host preference for dogs, though it occasionally feeds on other hosts (eg, humans).⁷ Although most common in tropical and subtropical climates, they can be found anywhere there are dogs due to their ability to colonize indoor dwellings.⁸ In contrast, R microplus ticks have a predilection for cattle and livestock rather than humans, posing a notable concern to livestock worldwide. Infestation results in transmission of disease-causing pathogens, such as Babesia and Anaplasma species, which costs the cattle industry billions of dollars annually.⁹

Clinical Manifestations and Treatment

Tick bites usually manifest as intensely pruritic, erythematous papules at the site of tick attachment due to a local type IV hypersensitivity reaction to antigens in the tick’s saliva. This reaction can be long-lasting. In addition to pruritic papules following a bite, an attached tick can be mistaken for a skin neoplasm or nevus. Given that ticks are small, especially during the larval stage, dermoscopy may be helpful in making a diagnosis.¹⁰ Symptomatic relief usually can be achieved with topical antipruritics or oral antihistamines.

Of public health concern, brown dog ticks are important vectors of Rickettsia rickettsii (the causative organism of Rocky Mountain spotted fever [RMSF]) in the Western hemisphere, and Rickettsia conorii (the causative organism of Mediterranean spotted fever [MSF][also known as Boutonneuse fever]) in the Eastern hemisphere.¹¹ Bites by ticks carrying rickettsial disease classically manifest with early symptoms of fever, headache, and myalgia, followed by a rash or by a localized eschar or tache noire (a black, necrotic, scabbed lesion) that represents direct endothelial invasion and vascular damage by Rickettsia.¹² Rocky Mountain spotted fever and MSF are more prevalent during summer, likely due, in part, to the combination of increased outdoor activity and a higher rate of tick-questing (host-seeking) behavior in warmer climates.^4,7

Rocky Mountain Spotted Fever—Dermacentor variabilis is the primary vector of RMSF in the southeastern United States; Dermacentor andersoni is the major vector of RMSF in Rocky Mountain states. Rhipicephalus sanguineus sensu lato is an important vector of RMSF in the southwestern United States, Mexico, and Central America.^11,13

Early symptoms of RMSF are nonspecific and can include fever, headache, arthralgia, myalgia, and malaise. Gastrointestinal tract symptoms (eg, nausea, vomiting, anorexia) may occur; notable abdominal pain occurs in some patients, particularly children. A characteristic petechial rash occurs in as many as 90% of patients, typically at the third to fifth day of illness, and classically begins on the wrists and ankles, with progression to the palms and soles before spreading centripetally to the arms, legs, and trunk.¹⁴ An eschar at the inoculation site is uncommon in RMSF; when present, it is more suggestive of MSF.¹⁵

The classic triad of fever, headache, and rash is present in 3% of patients during the first 3 days after a tick bite and in 60% to 70% within 2 weeks.¹⁶ A rash often is absent when patients first seek medical attention and may not develop (absent in 9% to 12% of cases; so-called spotless RMSF). Therefore, absence of rash should not be a reason to withhold treatment.¹⁶ Empiric treatment with doxycycline should be started promptly for all suspected cases of RMSF because of the rapid progression of disease and an increased risk for morbidity and mortality with delayed diagnosis.

Patients do not become antibody positive until 7 to 10 days after symptoms begin; therefore, treatment should not be delayed while awaiting serologic test results. The case fatality rate in the United States is estimated to be 5% to 10% overall and as high as 40% to 50% among patients who are not treated until day 8 or 9 of illness.¹⁷

Cutaneous complications include skin necrosis and gangrene due to continuous tissue damage in severe cases.¹⁶ Severe infection also may manifest with signs of multiorgan system damage, including altered mental status, cerebral edema, meningismus, transient deafness, myocarditis, pulmonary hemorrhage and edema, conjunctivitis, retinal abnormalities, and acute renal failure.^14,16 Risk factors for more severe illness include delayed treatment, age 40 years or older or younger than 10 years, and underlying medical conditions such as alcoholic liver disease and glucose-6-phosphate dehydrogenase deficiency. However, even some healthy young patients die of this disease.¹⁷

Mediterranean Spotted Fever—Rhipicephalus sanguineus sensu lato is the primary vector of MSF, which is prevalent in areas adjacent to the Mediterranean Sea, including southern Europe, Africa, and Central Asia; Sicily is the most highly affected region.¹⁸ Findings with MSF are nearly identical to those of RMSF, except that tache noire is more common, present in as many as 70% of cases at the site of the inoculating tick bite, and MSF typically follows a less severe clinical course.¹² Similar to other rickettsial diseases, the pathogenesis of MSF involves direct injury to vascular endothelial cells, causing a vasculitis that is responsible for the clinical abnormalities observed.

Patients with severe MSF experience complications similar to severe RMSF, including neurologic manifestations and multiorgan damage.¹⁸ Risk factors include advanced age, immunocompromised state, cardiac disease, chronic alcoholism, diabetes mellitus, glucose-6-phosphate dehydrogenase deficiency, respiratory insufficiency, and delayed treatment.¹⁸

Treatment—For all spotted fever group rickettsial infections, doxycycline is the treatment of choice for all patients, including children and pregnant women. Treatment should be started without delay; recommended dosages are 100 mg twice daily for children weighing more than 45 kg and adults, and 2.2 mg/kg twice daily for children weighing 45 kg or less.¹²

Rhipicephalus tick bites rarely can result in paralysis; however, Dermacentor ticks are responsible for most cases of tick-related paralysis in North America. Other pathogens proven or reputed to be transmitted by Rhipicephalus sanguineus sensu lato with zoonotic potential include but are not limited to Rickettsia massiliae, Coxiella burnetti, Anaplasma platys, Leishmania infantum, and Crimean-Congo hemorrhagic fever virus (Nairovirus).¹⁹

Environmental Treatment and Prevention

The most effective way to prevent tick-borne illness is avoidance of tick bites. Primary prevention methods include vector control, use of repellents (eg, N,N-diethyl-meta-toluamide [DEET]), picaridin, permethrin), avoidance of areas with a high tick burden, use of protective clothing, and detection and removal of ticks as soon as possible.

Environmental and veterinary controls also are important methods of tick-bite prevention. A veterinarian can recommend a variety of agents for dogs and cats that prevent attachment of ticks. Environmental controls include synthetic or natural product-based chemical acaricides and nonchemical methods, such as landscape management (eg, sealing cracks and crevices in homes and controlling tall grasses, weeds, and leaf debris) to minimize potential tick habitat.²⁰ Secondary prevention includes antibiotics for prophylaxis or for treatment of tick-borne disease, when indicated.

Numerous tick repellents are available commercially; others are being studied. DEET, the most widely used topical repellent, has a broad spectrum of activity against many tick species.²¹ In addition, DEET has a well-known safety and toxicity profile, with rare adverse effects, and is safe for use in pregnant women and children older than 2 years. Alternative repellents, such as those containing picaridin, ethyl butylacetylaminopropionate (IR3535 [Merck]), oil of lemon eucalyptus, and 2-undecanone can be effective; some show efficacy comparable to that of DEET.²² Permethrin, a synthetic pyrethroid, is a highly efficacious tick repellent and insecticide, especially when used in conjunction with a topical repellent such as DEET. Unlike topically applied repellents, permethrin spray is applied to fabric (eg, clothing, shoes, bed nets, camping gear), not to skin.

Indiscriminate use of acaricides worldwide has led to increasing selection of acaricide resistance in Rhipicephalus tick species, which is especially true with the use of acaricides in controlling R microplus livestock infestations; several tick populations now show resistance to all major classes of these compounds.^23-25 For that reason, there has been an increasing effort to develop new chemical and nonchemical approaches to tick control that are more environmentally sustainable and strategies to minimize development and progression of resistance such as rotation of acaricides; reducing the frequency of their application; use of pesticide mixtures, synergists, or both; and increasing use of nonacaricidal methods of control.²⁶

Prompt removal of ticks is important for preventing the transmission of tick-borne disease. Proper removal involves rubbing the tick in a circular motion with a moist gauze pad or using fine-tipped tweezers to grasp the tick as close to the skin surface as possible and pulling upward with a steady pressure.^17,27 It is important not to jerk, twist, squeeze, smash, or burn the tick, as this can result in insufficient removal of mouthparts or spread contaminated tick fluids to mucous membranes, increasing the risk for infection. Application of petroleum jelly or nail polish to aid in tick removal have not been shown to be effective and are not recommended.^16,28

Characteristics

Rhipicephalus ticks belong to the Ixodidae family of hard-bodied ticks. They are large and teardrop shaped with an inornate scutum (hard dorsal plate) and relatively short mouthparts attached at a hexagonal basis capitulum (base of the head to which mouthparts are attached)(Figure).¹ Widely spaced eyes and festoons also are present. The first pair of coxae—attachment base for the first pair of legs—are characteristically bifid; males have a pair of sclerotized adanal plates on the ventral surface adjacent to the anus as well as accessory adanal shields.²Rhipicephalus (formerly Boophilus) microplus (the so-called cattle tick) is a newly added species; it lacks posterior festoons, and the anal groove is absent.³

Almost all Rhipicephalus ticks, except for R microplus, are 3-host ticks in which a single blood meal is consumed from a vertebrate host at each active life stage—larva, nymph, and adult—to complete development.^4,5 In contrast to most ixodid ticks, which are exophilic (living outside of human habitation), the Rhipicephalus sanguineus sensu lato species (the brown dog tick) is highly endophilic (adapted to indoor living) and often can be found hidden in cracks and crevices of walls in homes and peridomestic structures.⁶ It is predominately monotropic (all developmental stages feed on the same host species) and has a strong host preference for dogs, though it occasionally feeds on other hosts (eg, humans).⁷ Although most common in tropical and subtropical climates, they can be found anywhere there are dogs due to their ability to colonize indoor dwellings.⁸ In contrast, R microplus ticks have a predilection for cattle and livestock rather than humans, posing a notable concern to livestock worldwide. Infestation results in transmission of disease-causing pathogens, such as Babesia and Anaplasma species, which costs the cattle industry billions of dollars annually.⁹

Clinical Manifestations and Treatment

Tick bites usually manifest as intensely pruritic, erythematous papules at the site of tick attachment due to a local type IV hypersensitivity reaction to antigens in the tick’s saliva. This reaction can be long-lasting. In addition to pruritic papules following a bite, an attached tick can be mistaken for a skin neoplasm or nevus. Given that ticks are small, especially during the larval stage, dermoscopy may be helpful in making a diagnosis.¹⁰ Symptomatic relief usually can be achieved with topical antipruritics or oral antihistamines.

Of public health concern, brown dog ticks are important vectors of Rickettsia rickettsii (the causative organism of Rocky Mountain spotted fever [RMSF]) in the Western hemisphere, and Rickettsia conorii (the causative organism of Mediterranean spotted fever [MSF][also known as Boutonneuse fever]) in the Eastern hemisphere.¹¹ Bites by ticks carrying rickettsial disease classically manifest with early symptoms of fever, headache, and myalgia, followed by a rash or by a localized eschar or tache noire (a black, necrotic, scabbed lesion) that represents direct endothelial invasion and vascular damage by Rickettsia.¹² Rocky Mountain spotted fever and MSF are more prevalent during summer, likely due, in part, to the combination of increased outdoor activity and a higher rate of tick-questing (host-seeking) behavior in warmer climates.^4,7

Rocky Mountain Spotted Fever—Dermacentor variabilis is the primary vector of RMSF in the southeastern United States; Dermacentor andersoni is the major vector of RMSF in Rocky Mountain states. Rhipicephalus sanguineus sensu lato is an important vector of RMSF in the southwestern United States, Mexico, and Central America.^11,13

Early symptoms of RMSF are nonspecific and can include fever, headache, arthralgia, myalgia, and malaise. Gastrointestinal tract symptoms (eg, nausea, vomiting, anorexia) may occur; notable abdominal pain occurs in some patients, particularly children. A characteristic petechial rash occurs in as many as 90% of patients, typically at the third to fifth day of illness, and classically begins on the wrists and ankles, with progression to the palms and soles before spreading centripetally to the arms, legs, and trunk.¹⁴ An eschar at the inoculation site is uncommon in RMSF; when present, it is more suggestive of MSF.¹⁵

The classic triad of fever, headache, and rash is present in 3% of patients during the first 3 days after a tick bite and in 60% to 70% within 2 weeks.¹⁶ A rash often is absent when patients first seek medical attention and may not develop (absent in 9% to 12% of cases; so-called spotless RMSF). Therefore, absence of rash should not be a reason to withhold treatment.¹⁶ Empiric treatment with doxycycline should be started promptly for all suspected cases of RMSF because of the rapid progression of disease and an increased risk for morbidity and mortality with delayed diagnosis.

Patients do not become antibody positive until 7 to 10 days after symptoms begin; therefore, treatment should not be delayed while awaiting serologic test results. The case fatality rate in the United States is estimated to be 5% to 10% overall and as high as 40% to 50% among patients who are not treated until day 8 or 9 of illness.¹⁷

Cutaneous complications include skin necrosis and gangrene due to continuous tissue damage in severe cases.¹⁶ Severe infection also may manifest with signs of multiorgan system damage, including altered mental status, cerebral edema, meningismus, transient deafness, myocarditis, pulmonary hemorrhage and edema, conjunctivitis, retinal abnormalities, and acute renal failure.^14,16 Risk factors for more severe illness include delayed treatment, age 40 years or older or younger than 10 years, and underlying medical conditions such as alcoholic liver disease and glucose-6-phosphate dehydrogenase deficiency. However, even some healthy young patients die of this disease.¹⁷

Mediterranean Spotted Fever—Rhipicephalus sanguineus sensu lato is the primary vector of MSF, which is prevalent in areas adjacent to the Mediterranean Sea, including southern Europe, Africa, and Central Asia; Sicily is the most highly affected region.¹⁸ Findings with MSF are nearly identical to those of RMSF, except that tache noire is more common, present in as many as 70% of cases at the site of the inoculating tick bite, and MSF typically follows a less severe clinical course.¹² Similar to other rickettsial diseases, the pathogenesis of MSF involves direct injury to vascular endothelial cells, causing a vasculitis that is responsible for the clinical abnormalities observed.

Patients with severe MSF experience complications similar to severe RMSF, including neurologic manifestations and multiorgan damage.¹⁸ Risk factors include advanced age, immunocompromised state, cardiac disease, chronic alcoholism, diabetes mellitus, glucose-6-phosphate dehydrogenase deficiency, respiratory insufficiency, and delayed treatment.¹⁸

Treatment—For all spotted fever group rickettsial infections, doxycycline is the treatment of choice for all patients, including children and pregnant women. Treatment should be started without delay; recommended dosages are 100 mg twice daily for children weighing more than 45 kg and adults, and 2.2 mg/kg twice daily for children weighing 45 kg or less.¹²

Rhipicephalus tick bites rarely can result in paralysis; however, Dermacentor ticks are responsible for most cases of tick-related paralysis in North America. Other pathogens proven or reputed to be transmitted by Rhipicephalus sanguineus sensu lato with zoonotic potential include but are not limited to Rickettsia massiliae, Coxiella burnetti, Anaplasma platys, Leishmania infantum, and Crimean-Congo hemorrhagic fever virus (Nairovirus).¹⁹

Environmental Treatment and Prevention

The most effective way to prevent tick-borne illness is avoidance of tick bites. Primary prevention methods include vector control, use of repellents (eg, N,N-diethyl-meta-toluamide [DEET]), picaridin, permethrin), avoidance of areas with a high tick burden, use of protective clothing, and detection and removal of ticks as soon as possible.

Environmental and veterinary controls also are important methods of tick-bite prevention. A veterinarian can recommend a variety of agents for dogs and cats that prevent attachment of ticks. Environmental controls include synthetic or natural product-based chemical acaricides and nonchemical methods, such as landscape management (eg, sealing cracks and crevices in homes and controlling tall grasses, weeds, and leaf debris) to minimize potential tick habitat.²⁰ Secondary prevention includes antibiotics for prophylaxis or for treatment of tick-borne disease, when indicated.

Numerous tick repellents are available commercially; others are being studied. DEET, the most widely used topical repellent, has a broad spectrum of activity against many tick species.²¹ In addition, DEET has a well-known safety and toxicity profile, with rare adverse effects, and is safe for use in pregnant women and children older than 2 years. Alternative repellents, such as those containing picaridin, ethyl butylacetylaminopropionate (IR3535 [Merck]), oil of lemon eucalyptus, and 2-undecanone can be effective; some show efficacy comparable to that of DEET.²² Permethrin, a synthetic pyrethroid, is a highly efficacious tick repellent and insecticide, especially when used in conjunction with a topical repellent such as DEET. Unlike topically applied repellents, permethrin spray is applied to fabric (eg, clothing, shoes, bed nets, camping gear), not to skin.

Indiscriminate use of acaricides worldwide has led to increasing selection of acaricide resistance in Rhipicephalus tick species, which is especially true with the use of acaricides in controlling R microplus livestock infestations; several tick populations now show resistance to all major classes of these compounds.^23-25 For that reason, there has been an increasing effort to develop new chemical and nonchemical approaches to tick control that are more environmentally sustainable and strategies to minimize development and progression of resistance such as rotation of acaricides; reducing the frequency of their application; use of pesticide mixtures, synergists, or both; and increasing use of nonacaricidal methods of control.²⁶

Prompt removal of ticks is important for preventing the transmission of tick-borne disease. Proper removal involves rubbing the tick in a circular motion with a moist gauze pad or using fine-tipped tweezers to grasp the tick as close to the skin surface as possible and pulling upward with a steady pressure.^17,27 It is important not to jerk, twist, squeeze, smash, or burn the tick, as this can result in insufficient removal of mouthparts or spread contaminated tick fluids to mucous membranes, increasing the risk for infection. Application of petroleum jelly or nail polish to aid in tick removal have not been shown to be effective and are not recommended.^16,28

Characteristics

Rhipicephalus ticks belong to the Ixodidae family of hard-bodied ticks. They are large and teardrop shaped with an inornate scutum (hard dorsal plate) and relatively short mouthparts attached at a hexagonal basis capitulum (base of the head to which mouthparts are attached)(Figure).¹ Widely spaced eyes and festoons also are present. The first pair of coxae—attachment base for the first pair of legs—are characteristically bifid; males have a pair of sclerotized adanal plates on the ventral surface adjacent to the anus as well as accessory adanal shields.²Rhipicephalus (formerly Boophilus) microplus (the so-called cattle tick) is a newly added species; it lacks posterior festoons, and the anal groove is absent.³

Almost all Rhipicephalus ticks, except for R microplus, are 3-host ticks in which a single blood meal is consumed from a vertebrate host at each active life stage—larva, nymph, and adult—to complete development.^4,5 In contrast to most ixodid ticks, which are exophilic (living outside of human habitation), the Rhipicephalus sanguineus sensu lato species (the brown dog tick) is highly endophilic (adapted to indoor living) and often can be found hidden in cracks and crevices of walls in homes and peridomestic structures.⁶ It is predominately monotropic (all developmental stages feed on the same host species) and has a strong host preference for dogs, though it occasionally feeds on other hosts (eg, humans).⁷ Although most common in tropical and subtropical climates, they can be found anywhere there are dogs due to their ability to colonize indoor dwellings.⁸ In contrast, R microplus ticks have a predilection for cattle and livestock rather than humans, posing a notable concern to livestock worldwide. Infestation results in transmission of disease-causing pathogens, such as Babesia and Anaplasma species, which costs the cattle industry billions of dollars annually.⁹

Clinical Manifestations and Treatment

Tick bites usually manifest as intensely pruritic, erythematous papules at the site of tick attachment due to a local type IV hypersensitivity reaction to antigens in the tick’s saliva. This reaction can be long-lasting. In addition to pruritic papules following a bite, an attached tick can be mistaken for a skin neoplasm or nevus. Given that ticks are small, especially during the larval stage, dermoscopy may be helpful in making a diagnosis.¹⁰ Symptomatic relief usually can be achieved with topical antipruritics or oral antihistamines.

Of public health concern, brown dog ticks are important vectors of Rickettsia rickettsii (the causative organism of Rocky Mountain spotted fever [RMSF]) in the Western hemisphere, and Rickettsia conorii (the causative organism of Mediterranean spotted fever [MSF][also known as Boutonneuse fever]) in the Eastern hemisphere.¹¹ Bites by ticks carrying rickettsial disease classically manifest with early symptoms of fever, headache, and myalgia, followed by a rash or by a localized eschar or tache noire (a black, necrotic, scabbed lesion) that represents direct endothelial invasion and vascular damage by Rickettsia.¹² Rocky Mountain spotted fever and MSF are more prevalent during summer, likely due, in part, to the combination of increased outdoor activity and a higher rate of tick-questing (host-seeking) behavior in warmer climates.^4,7

Rocky Mountain Spotted Fever—Dermacentor variabilis is the primary vector of RMSF in the southeastern United States; Dermacentor andersoni is the major vector of RMSF in Rocky Mountain states. Rhipicephalus sanguineus sensu lato is an important vector of RMSF in the southwestern United States, Mexico, and Central America.^11,13

Early symptoms of RMSF are nonspecific and can include fever, headache, arthralgia, myalgia, and malaise. Gastrointestinal tract symptoms (eg, nausea, vomiting, anorexia) may occur; notable abdominal pain occurs in some patients, particularly children. A characteristic petechial rash occurs in as many as 90% of patients, typically at the third to fifth day of illness, and classically begins on the wrists and ankles, with progression to the palms and soles before spreading centripetally to the arms, legs, and trunk.¹⁴ An eschar at the inoculation site is uncommon in RMSF; when present, it is more suggestive of MSF.¹⁵

The classic triad of fever, headache, and rash is present in 3% of patients during the first 3 days after a tick bite and in 60% to 70% within 2 weeks.¹⁶ A rash often is absent when patients first seek medical attention and may not develop (absent in 9% to 12% of cases; so-called spotless RMSF). Therefore, absence of rash should not be a reason to withhold treatment.¹⁶ Empiric treatment with doxycycline should be started promptly for all suspected cases of RMSF because of the rapid progression of disease and an increased risk for morbidity and mortality with delayed diagnosis.

Patients do not become antibody positive until 7 to 10 days after symptoms begin; therefore, treatment should not be delayed while awaiting serologic test results. The case fatality rate in the United States is estimated to be 5% to 10% overall and as high as 40% to 50% among patients who are not treated until day 8 or 9 of illness.¹⁷

Cutaneous complications include skin necrosis and gangrene due to continuous tissue damage in severe cases.¹⁶ Severe infection also may manifest with signs of multiorgan system damage, including altered mental status, cerebral edema, meningismus, transient deafness, myocarditis, pulmonary hemorrhage and edema, conjunctivitis, retinal abnormalities, and acute renal failure.^14,16 Risk factors for more severe illness include delayed treatment, age 40 years or older or younger than 10 years, and underlying medical conditions such as alcoholic liver disease and glucose-6-phosphate dehydrogenase deficiency. However, even some healthy young patients die of this disease.¹⁷

Mediterranean Spotted Fever—Rhipicephalus sanguineus sensu lato is the primary vector of MSF, which is prevalent in areas adjacent to the Mediterranean Sea, including southern Europe, Africa, and Central Asia; Sicily is the most highly affected region.¹⁸ Findings with MSF are nearly identical to those of RMSF, except that tache noire is more common, present in as many as 70% of cases at the site of the inoculating tick bite, and MSF typically follows a less severe clinical course.¹² Similar to other rickettsial diseases, the pathogenesis of MSF involves direct injury to vascular endothelial cells, causing a vasculitis that is responsible for the clinical abnormalities observed.

Patients with severe MSF experience complications similar to severe RMSF, including neurologic manifestations and multiorgan damage.¹⁸ Risk factors include advanced age, immunocompromised state, cardiac disease, chronic alcoholism, diabetes mellitus, glucose-6-phosphate dehydrogenase deficiency, respiratory insufficiency, and delayed treatment.¹⁸

Treatment—For all spotted fever group rickettsial infections, doxycycline is the treatment of choice for all patients, including children and pregnant women. Treatment should be started without delay; recommended dosages are 100 mg twice daily for children weighing more than 45 kg and adults, and 2.2 mg/kg twice daily for children weighing 45 kg or less.¹²

Rhipicephalus tick bites rarely can result in paralysis; however, Dermacentor ticks are responsible for most cases of tick-related paralysis in North America. Other pathogens proven or reputed to be transmitted by Rhipicephalus sanguineus sensu lato with zoonotic potential include but are not limited to Rickettsia massiliae, Coxiella burnetti, Anaplasma platys, Leishmania infantum, and Crimean-Congo hemorrhagic fever virus (Nairovirus).¹⁹

Environmental Treatment and Prevention

The most effective way to prevent tick-borne illness is avoidance of tick bites. Primary prevention methods include vector control, use of repellents (eg, N,N-diethyl-meta-toluamide [DEET]), picaridin, permethrin), avoidance of areas with a high tick burden, use of protective clothing, and detection and removal of ticks as soon as possible.

Environmental and veterinary controls also are important methods of tick-bite prevention. A veterinarian can recommend a variety of agents for dogs and cats that prevent attachment of ticks. Environmental controls include synthetic or natural product-based chemical acaricides and nonchemical methods, such as landscape management (eg, sealing cracks and crevices in homes and controlling tall grasses, weeds, and leaf debris) to minimize potential tick habitat.²⁰ Secondary prevention includes antibiotics for prophylaxis or for treatment of tick-borne disease, when indicated.

Numerous tick repellents are available commercially; others are being studied. DEET, the most widely used topical repellent, has a broad spectrum of activity against many tick species.²¹ In addition, DEET has a well-known safety and toxicity profile, with rare adverse effects, and is safe for use in pregnant women and children older than 2 years. Alternative repellents, such as those containing picaridin, ethyl butylacetylaminopropionate (IR3535 [Merck]), oil of lemon eucalyptus, and 2-undecanone can be effective; some show efficacy comparable to that of DEET.²² Permethrin, a synthetic pyrethroid, is a highly efficacious tick repellent and insecticide, especially when used in conjunction with a topical repellent such as DEET. Unlike topically applied repellents, permethrin spray is applied to fabric (eg, clothing, shoes, bed nets, camping gear), not to skin.

Indiscriminate use of acaricides worldwide has led to increasing selection of acaricide resistance in Rhipicephalus tick species, which is especially true with the use of acaricides in controlling R microplus livestock infestations; several tick populations now show resistance to all major classes of these compounds.^23-25 For that reason, there has been an increasing effort to develop new chemical and nonchemical approaches to tick control that are more environmentally sustainable and strategies to minimize development and progression of resistance such as rotation of acaricides; reducing the frequency of their application; use of pesticide mixtures, synergists, or both; and increasing use of nonacaricidal methods of control.²⁶

Prompt removal of ticks is important for preventing the transmission of tick-borne disease. Proper removal involves rubbing the tick in a circular motion with a moist gauze pad or using fine-tipped tweezers to grasp the tick as close to the skin surface as possible and pulling upward with a steady pressure.^17,27 It is important not to jerk, twist, squeeze, smash, or burn the tick, as this can result in insufficient removal of mouthparts or spread contaminated tick fluids to mucous membranes, increasing the risk for infection. Application of petroleum jelly or nail polish to aid in tick removal have not been shown to be effective and are not recommended.^16,28

Another study investigated the persistence of targeted therapies for PsA in women compared with men. In a nationwide cohort study using administrative information from French health insurance, the study looked at 14,778 patients (57% women) with PsA who were new users of targeted therapies. The study showed that women had 20%-40% lower treatment persistence rates than men for tumour necrosis factor (TNF) inhibitors (adjusted hazard ratio [aHR] 1.4; 99% CI 1.3-1.5) and interleukin (IL)-17 inhibitors (aHR 1.2; 99% CI 1.1-1.3). However, the treatment persistence between both sexes was comparable for IL-12/23 inhibitor (aHR 1.1; 99% CI 0.9-1.3), IL-23 inhibitor (aHR 1.1; 99% CI 0.7-1.5), and Janus kinase (JAK) inhibitor (aHR 1.2; 99% CI 0.9-1.6) therapies. The paradigm that women have lower treatment persistence is based on studies done primarily in patients treated with TNF inhibitors. This study and a few other recent studies challenge this paradigm by indicating that other targeted therapies, especially JAK inhibitors, may not have lower persistence in women. Sex should be taken into consideration while choosing and counseling women about PsA therapies.

There are few studies on exercise and its impact on PsA. Functional training (FT) and resistance training (RT) may improve functional capacity and quality of life of patients with PsA. The safety of exercise is also not known, given that (micro)trauma is a risk factor for PsA. To evaluate this, Silva and colleagues conducted a 12-week, single-blind trial including 41 patients with PsA who were randomly assigned to undergo FT with elastic bands or RT with weight machines. They demonstrated that FT and RT led to similar improvements in functional capacity measured by the Bath Ankylosing Spondylitis Functional Index (P = .919), functional status measured by the Health Assessment Questionnaire for Spondyloarthritis (P = .932), disease activity measured by the Bath Ankylosing Spondylitis Disease Activity Index (P = .700), and muscle strength. No adverse events occurred in either group. Thus, FT and RT improved functional capacity, functional status, disease activity, and muscle strength to a comparable extent in patients with PsA, with no adverse events. Both modalities may be recommended for PsA patients.

Finally, a cross-sectional study that included 503 patients with PsA, of whom 160 patients underwent treatment escalation, evaluated whether the patient-reported outcome (PsA Impact of Disease questionnaire [PsAID-12]) affected treatment decisions by the treating rheumatologist. Coyle and colleagues demonstrated that although PsAID-12 scores were higher in patients who did vs did not have a treatment escalation, physicians relied more on their assessment of disease activity rather than the PsAID-12 scores when making treatment-related decisions. Of note, physicians also reported that PsAID-12 scores influenced treatment reduction decisions.

Another study investigated the persistence of targeted therapies for PsA in women compared with men. In a nationwide cohort study using administrative information from French health insurance, the study looked at 14,778 patients (57% women) with PsA who were new users of targeted therapies. The study showed that women had 20%-40% lower treatment persistence rates than men for tumour necrosis factor (TNF) inhibitors (adjusted hazard ratio [aHR] 1.4; 99% CI 1.3-1.5) and interleukin (IL)-17 inhibitors (aHR 1.2; 99% CI 1.1-1.3). However, the treatment persistence between both sexes was comparable for IL-12/23 inhibitor (aHR 1.1; 99% CI 0.9-1.3), IL-23 inhibitor (aHR 1.1; 99% CI 0.7-1.5), and Janus kinase (JAK) inhibitor (aHR 1.2; 99% CI 0.9-1.6) therapies. The paradigm that women have lower treatment persistence is based on studies done primarily in patients treated with TNF inhibitors. This study and a few other recent studies challenge this paradigm by indicating that other targeted therapies, especially JAK inhibitors, may not have lower persistence in women. Sex should be taken into consideration while choosing and counseling women about PsA therapies.

There are few studies on exercise and its impact on PsA. Functional training (FT) and resistance training (RT) may improve functional capacity and quality of life of patients with PsA. The safety of exercise is also not known, given that (micro)trauma is a risk factor for PsA. To evaluate this, Silva and colleagues conducted a 12-week, single-blind trial including 41 patients with PsA who were randomly assigned to undergo FT with elastic bands or RT with weight machines. They demonstrated that FT and RT led to similar improvements in functional capacity measured by the Bath Ankylosing Spondylitis Functional Index (P = .919), functional status measured by the Health Assessment Questionnaire for Spondyloarthritis (P = .932), disease activity measured by the Bath Ankylosing Spondylitis Disease Activity Index (P = .700), and muscle strength. No adverse events occurred in either group. Thus, FT and RT improved functional capacity, functional status, disease activity, and muscle strength to a comparable extent in patients with PsA, with no adverse events. Both modalities may be recommended for PsA patients.

Finally, a cross-sectional study that included 503 patients with PsA, of whom 160 patients underwent treatment escalation, evaluated whether the patient-reported outcome (PsA Impact of Disease questionnaire [PsAID-12]) affected treatment decisions by the treating rheumatologist. Coyle and colleagues demonstrated that although PsAID-12 scores were higher in patients who did vs did not have a treatment escalation, physicians relied more on their assessment of disease activity rather than the PsAID-12 scores when making treatment-related decisions. Of note, physicians also reported that PsAID-12 scores influenced treatment reduction decisions.

Another study investigated the persistence of targeted therapies for PsA in women compared with men. In a nationwide cohort study using administrative information from French health insurance, the study looked at 14,778 patients (57% women) with PsA who were new users of targeted therapies. The study showed that women had 20%-40% lower treatment persistence rates than men for tumour necrosis factor (TNF) inhibitors (adjusted hazard ratio [aHR] 1.4; 99% CI 1.3-1.5) and interleukin (IL)-17 inhibitors (aHR 1.2; 99% CI 1.1-1.3). However, the treatment persistence between both sexes was comparable for IL-12/23 inhibitor (aHR 1.1; 99% CI 0.9-1.3), IL-23 inhibitor (aHR 1.1; 99% CI 0.7-1.5), and Janus kinase (JAK) inhibitor (aHR 1.2; 99% CI 0.9-1.6) therapies. The paradigm that women have lower treatment persistence is based on studies done primarily in patients treated with TNF inhibitors. This study and a few other recent studies challenge this paradigm by indicating that other targeted therapies, especially JAK inhibitors, may not have lower persistence in women. Sex should be taken into consideration while choosing and counseling women about PsA therapies.

There are few studies on exercise and its impact on PsA. Functional training (FT) and resistance training (RT) may improve functional capacity and quality of life of patients with PsA. The safety of exercise is also not known, given that (micro)trauma is a risk factor for PsA. To evaluate this, Silva and colleagues conducted a 12-week, single-blind trial including 41 patients with PsA who were randomly assigned to undergo FT with elastic bands or RT with weight machines. They demonstrated that FT and RT led to similar improvements in functional capacity measured by the Bath Ankylosing Spondylitis Functional Index (P = .919), functional status measured by the Health Assessment Questionnaire for Spondyloarthritis (P = .932), disease activity measured by the Bath Ankylosing Spondylitis Disease Activity Index (P = .700), and muscle strength. No adverse events occurred in either group. Thus, FT and RT improved functional capacity, functional status, disease activity, and muscle strength to a comparable extent in patients with PsA, with no adverse events. Both modalities may be recommended for PsA patients.

Finally, a cross-sectional study that included 503 patients with PsA, of whom 160 patients underwent treatment escalation, evaluated whether the patient-reported outcome (PsA Impact of Disease questionnaire [PsAID-12]) affected treatment decisions by the treating rheumatologist. Coyle and colleagues demonstrated that although PsAID-12 scores were higher in patients who did vs did not have a treatment escalation, physicians relied more on their assessment of disease activity rather than the PsAID-12 scores when making treatment-related decisions. Of note, physicians also reported that PsAID-12 scores influenced treatment reduction decisions.

The benefit of immunotherapy in combination with chemotherapy for programmed death–ligand 1–positive (PD-L1+) metastatic triple-negative breast cancer (mTNBC) has been shown in both the IMpassion130 and KEYNOTE-355 trials.^[2,3] However, the IMpassion131 trial, which evaluated atezolizumab plus paclitaxel, did not show a progression-free survival (PFS) or overall survival (OS) benefit vs paclitaxel alone in PD-L1+ mTNBC.^[4] Various explanations for these divergent results have been proposed, including the inherent properties of the chemotherapy backbone, patient populations, and the heterogenous nature of TNBC, which can affect response to immunotherapy. Of present, the various KEYNOTE-355 regimens (pembrolizumab plus investigator's choice chemotherapy [nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin]) are US Food and Drug Administration approved for PD-L1+ mTNBC in the first-line setting. The phase 2 randomized TBCRC 043 trial investigated the effect of atezolizumab with carboplatin in patients with mTNBC and further looked at clinical and molecular correlates of response (Lehmann et al). A total of 106 patients were randomly assigned to carboplatin or carboplatin plus atezolizumab; the combination improved PFS (median PFS, 4.1 vs 2.2 mo; hazard ratio [HR] 0.66; P = .05) and OS (12.6 vs 8.6 mo; HR 0.60; P = .03). Grade 3/4 serious adverse events were more common with carboplatin-atezolizumab vs carboplatin alone (41% vs 8%). In addition, an association of better responses with PD-L1 immunotherapy was seen in patients with obesity, uncontrolled blood glucose levels, high tumor mutation burden, and increased tumor infiltrating lymphocytes. These data support the role of immunotherapy in mTNBC, highlight tumor heterogeneity within this subtype and encourage correlative studies to better define which patients benefit from immunotherapy.

Various studies have demonstrated the favorable impact of physical activity on breast cancer risk in postmenopausal women.^[5] However, data in premenopausal women is less clear. Various mechanisms connecting physical activity to premenopausal breast cancer risk have been proposed including the effect of exercise on sex steroid hormones, fasting insulin levels, and inflammation.^[6] A pooled analysis from 19 cohort studies including 547,601 premenopausal women, with 10,231 incident cases of breast cancer, aimed to examine the relationship between leisure-time physical activity (sports, exercise, recreational walking) and breast cancer risk in young women (Timmins et al). Higher (90th percentile) vs lower (10th percentile) levels of leisure-time physical activity were associated with a 10% reduction in breast cancer risk after adjustment for body mass index (BMI; adjusted HR 0.90; 95% CI 0.85-0.95; P < .001). They also found a significant reduction in risk: 32% (HR 0.68; P = .01) and 9% (HR 0.91; P = .005) for women with underweight (BMI < 18.5) and with average weight (BMI 18.5-24.9), respectively. Further, the effect of physical activity was most pronounced in the human epidermal growth factor receptor 2 (HER2)–enriched breast cancer subtype, wherein higher vs lower levels of activity were associated with an estimated 45% reduction in breast cancer risk (adjusted HR 0.55; 95% CI 0.37-0.82). These findings support the beneficial role of aerobic exercise and healthy body weight on breast cancer risk among premenopausal women and highlight the value of incorporating this information into counseling for our patients.

Additional References

1. Figueroa JD, Gierach GL, Duggan MA, et al. Risk factors for breast cancer development by tumor characteristics among women with benign breast disease. Breast Cancer Res. 2021;23:34. doi: 10.1186/s13058-021-01410-1 Source
2. Schmid P, Adams S, Rugo HS, et al, for the IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108-2121. doi: 10.1056/nejmoa1809615 Source
3. Cortes J, Rugo HS, Cescon DW, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387:217-226. doi: 10.1056/NEJMoa2202809 Source
4. Miles D, Gligorov J, André F, et al, on behalf of the IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32:994-1004. doi: 10.1016/j.annonc.2021.05.801 Source
5. Eliassen AH, Hankinson SE, Rosner B, et al. Physical activity and risk of breast cancer among postmenopausal women. Arch Intern Med. 2010;170:1758-1764. doi: 10.1001/archinternmed.2010.363 Source
6. Swain CTV, Drummond AE, Boing L, et al. Linking physical activity to breast cancer via sex hormones, part 1: The effect of physical activity on sex steroid hormones. Cancer Epidemiol Biomarkers Prev. 2022;31:16-27. doi: 10.1158/1055-9965.EPI-21-0437 Source

The benefit of immunotherapy in combination with chemotherapy for programmed death–ligand 1–positive (PD-L1+) metastatic triple-negative breast cancer (mTNBC) has been shown in both the IMpassion130 and KEYNOTE-355 trials.^[2,3] However, the IMpassion131 trial, which evaluated atezolizumab plus paclitaxel, did not show a progression-free survival (PFS) or overall survival (OS) benefit vs paclitaxel alone in PD-L1+ mTNBC.^[4] Various explanations for these divergent results have been proposed, including the inherent properties of the chemotherapy backbone, patient populations, and the heterogenous nature of TNBC, which can affect response to immunotherapy. Of present, the various KEYNOTE-355 regimens (pembrolizumab plus investigator's choice chemotherapy [nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin]) are US Food and Drug Administration approved for PD-L1+ mTNBC in the first-line setting. The phase 2 randomized TBCRC 043 trial investigated the effect of atezolizumab with carboplatin in patients with mTNBC and further looked at clinical and molecular correlates of response (Lehmann et al). A total of 106 patients were randomly assigned to carboplatin or carboplatin plus atezolizumab; the combination improved PFS (median PFS, 4.1 vs 2.2 mo; hazard ratio [HR] 0.66; P = .05) and OS (12.6 vs 8.6 mo; HR 0.60; P = .03). Grade 3/4 serious adverse events were more common with carboplatin-atezolizumab vs carboplatin alone (41% vs 8%). In addition, an association of better responses with PD-L1 immunotherapy was seen in patients with obesity, uncontrolled blood glucose levels, high tumor mutation burden, and increased tumor infiltrating lymphocytes. These data support the role of immunotherapy in mTNBC, highlight tumor heterogeneity within this subtype and encourage correlative studies to better define which patients benefit from immunotherapy.

Various studies have demonstrated the favorable impact of physical activity on breast cancer risk in postmenopausal women.^[5] However, data in premenopausal women is less clear. Various mechanisms connecting physical activity to premenopausal breast cancer risk have been proposed including the effect of exercise on sex steroid hormones, fasting insulin levels, and inflammation.^[6] A pooled analysis from 19 cohort studies including 547,601 premenopausal women, with 10,231 incident cases of breast cancer, aimed to examine the relationship between leisure-time physical activity (sports, exercise, recreational walking) and breast cancer risk in young women (Timmins et al). Higher (90th percentile) vs lower (10th percentile) levels of leisure-time physical activity were associated with a 10% reduction in breast cancer risk after adjustment for body mass index (BMI; adjusted HR 0.90; 95% CI 0.85-0.95; P < .001). They also found a significant reduction in risk: 32% (HR 0.68; P = .01) and 9% (HR 0.91; P = .005) for women with underweight (BMI < 18.5) and with average weight (BMI 18.5-24.9), respectively. Further, the effect of physical activity was most pronounced in the human epidermal growth factor receptor 2 (HER2)–enriched breast cancer subtype, wherein higher vs lower levels of activity were associated with an estimated 45% reduction in breast cancer risk (adjusted HR 0.55; 95% CI 0.37-0.82). These findings support the beneficial role of aerobic exercise and healthy body weight on breast cancer risk among premenopausal women and highlight the value of incorporating this information into counseling for our patients.

Additional References

1. Figueroa JD, Gierach GL, Duggan MA, et al. Risk factors for breast cancer development by tumor characteristics among women with benign breast disease. Breast Cancer Res. 2021;23:34. doi: 10.1186/s13058-021-01410-1 Source
2. Schmid P, Adams S, Rugo HS, et al, for the IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108-2121. doi: 10.1056/nejmoa1809615 Source
3. Cortes J, Rugo HS, Cescon DW, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387:217-226. doi: 10.1056/NEJMoa2202809 Source
4. Miles D, Gligorov J, André F, et al, on behalf of the IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32:994-1004. doi: 10.1016/j.annonc.2021.05.801 Source
5. Eliassen AH, Hankinson SE, Rosner B, et al. Physical activity and risk of breast cancer among postmenopausal women. Arch Intern Med. 2010;170:1758-1764. doi: 10.1001/archinternmed.2010.363 Source
6. Swain CTV, Drummond AE, Boing L, et al. Linking physical activity to breast cancer via sex hormones, part 1: The effect of physical activity on sex steroid hormones. Cancer Epidemiol Biomarkers Prev. 2022;31:16-27. doi: 10.1158/1055-9965.EPI-21-0437 Source

The benefit of immunotherapy in combination with chemotherapy for programmed death–ligand 1–positive (PD-L1+) metastatic triple-negative breast cancer (mTNBC) has been shown in both the IMpassion130 and KEYNOTE-355 trials.^[2,3] However, the IMpassion131 trial, which evaluated atezolizumab plus paclitaxel, did not show a progression-free survival (PFS) or overall survival (OS) benefit vs paclitaxel alone in PD-L1+ mTNBC.^[4] Various explanations for these divergent results have been proposed, including the inherent properties of the chemotherapy backbone, patient populations, and the heterogenous nature of TNBC, which can affect response to immunotherapy. Of present, the various KEYNOTE-355 regimens (pembrolizumab plus investigator's choice chemotherapy [nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin]) are US Food and Drug Administration approved for PD-L1+ mTNBC in the first-line setting. The phase 2 randomized TBCRC 043 trial investigated the effect of atezolizumab with carboplatin in patients with mTNBC and further looked at clinical and molecular correlates of response (Lehmann et al). A total of 106 patients were randomly assigned to carboplatin or carboplatin plus atezolizumab; the combination improved PFS (median PFS, 4.1 vs 2.2 mo; hazard ratio [HR] 0.66; P = .05) and OS (12.6 vs 8.6 mo; HR 0.60; P = .03). Grade 3/4 serious adverse events were more common with carboplatin-atezolizumab vs carboplatin alone (41% vs 8%). In addition, an association of better responses with PD-L1 immunotherapy was seen in patients with obesity, uncontrolled blood glucose levels, high tumor mutation burden, and increased tumor infiltrating lymphocytes. These data support the role of immunotherapy in mTNBC, highlight tumor heterogeneity within this subtype and encourage correlative studies to better define which patients benefit from immunotherapy.

Various studies have demonstrated the favorable impact of physical activity on breast cancer risk in postmenopausal women.^[5] However, data in premenopausal women is less clear. Various mechanisms connecting physical activity to premenopausal breast cancer risk have been proposed including the effect of exercise on sex steroid hormones, fasting insulin levels, and inflammation.^[6] A pooled analysis from 19 cohort studies including 547,601 premenopausal women, with 10,231 incident cases of breast cancer, aimed to examine the relationship between leisure-time physical activity (sports, exercise, recreational walking) and breast cancer risk in young women (Timmins et al). Higher (90th percentile) vs lower (10th percentile) levels of leisure-time physical activity were associated with a 10% reduction in breast cancer risk after adjustment for body mass index (BMI; adjusted HR 0.90; 95% CI 0.85-0.95; P < .001). They also found a significant reduction in risk: 32% (HR 0.68; P = .01) and 9% (HR 0.91; P = .005) for women with underweight (BMI < 18.5) and with average weight (BMI 18.5-24.9), respectively. Further, the effect of physical activity was most pronounced in the human epidermal growth factor receptor 2 (HER2)–enriched breast cancer subtype, wherein higher vs lower levels of activity were associated with an estimated 45% reduction in breast cancer risk (adjusted HR 0.55; 95% CI 0.37-0.82). These findings support the beneficial role of aerobic exercise and healthy body weight on breast cancer risk among premenopausal women and highlight the value of incorporating this information into counseling for our patients.

Additional References

1. Figueroa JD, Gierach GL, Duggan MA, et al. Risk factors for breast cancer development by tumor characteristics among women with benign breast disease. Breast Cancer Res. 2021;23:34. doi: 10.1186/s13058-021-01410-1 Source
2. Schmid P, Adams S, Rugo HS, et al, for the IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108-2121. doi: 10.1056/nejmoa1809615 Source
3. Cortes J, Rugo HS, Cescon DW, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387:217-226. doi: 10.1056/NEJMoa2202809 Source
4. Miles D, Gligorov J, André F, et al, on behalf of the IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32:994-1004. doi: 10.1016/j.annonc.2021.05.801 Source
5. Eliassen AH, Hankinson SE, Rosner B, et al. Physical activity and risk of breast cancer among postmenopausal women. Arch Intern Med. 2010;170:1758-1764. doi: 10.1001/archinternmed.2010.363 Source
6. Swain CTV, Drummond AE, Boing L, et al. Linking physical activity to breast cancer via sex hormones, part 1: The effect of physical activity on sex steroid hormones. Cancer Epidemiol Biomarkers Prev. 2022;31:16-27. doi: 10.1158/1055-9965.EPI-21-0437 Source

The Diagnosis: Giant Apocrine Hidrocystoma

Histopathology of the noduloplaque revealed an unremarkable epidermis with multilocular cystic spaces centered in the dermis. The cysts had a double-lined epithelium with inner columnar to cuboidal cells and outer myoepithelial cells (bottom quiz image). Columnar cells showing decapitation secretion could be appreciated at places indicating apocrine secretion (Figure). A final diagnosis of apocrine hidrocystoma was made.

Hidrocystomas are rare, benign, cystic lesions derived either from apocrine or eccrine glands.¹ Apocrine hidrocystoma usually manifests as asymptomatic, solitary, dome-shaped papules or nodules with a predilection for the head and neck region. Hidrocystomas can vary from flesh colored to blue, brown, or black. Pigmentation in hidrocystoma is seen in 5% to 80% of cases and is attributed to the Tyndall effect.¹ The tumor usually is less than 20 mm in diameter; larger lesions are termed giant apocrine hidrocystoma.² Apocrine hidrocystoma manifesting with multiple lesions and a size greater than 10 mm, as seen in our case, is uncommon.

Zaballos et al³ described dermoscopy of apocrine hidrocystoma in 22 patients. Hallmark dermoscopic findings were the presence of a homogeneous flesh-colored, yellowish, blue to pinkish-blue area involving the entire lesion with arborizing vessels and whitish structures.³ Similar dermoscopic findings were present in our patient. The homogeneous area histologically correlates to the multiloculated cysts located in the dermis. The exact reason for white structures is unknown; however, their visualization in apocrine hidrocystoma could be attributed to the alternation in collagen orientation secondary to the presence of large or multiple cysts in the dermis.

The presence of shiny white dots arranged in a square resembling a four-leaf clover (also known as white rosettes) was a unique dermoscopic finding in our patient. These rosettes can be appreciated only with polarized dermoscopy, and they have been described in actinic keratosis, seborrheic keratosis, squamous cell carcinoma, and basal cell carcinoma.⁴ The exact morphologic correlate of white rosettes is unknown but is postulated to be secondary to material inside adnexal openings in small rosettes and concentric perifollicular fibrosis in larger rosettes.⁴ In our patient, we believe the white rosettes can be attributed to the accumulated secretions in the dermal glands, which also were seen via histopathology. Dermoscopy also revealed increased peripheral, brown, networklike pigmentation, which was unique and could be secondary to the patient’s darker skin phenotype.

Differential diagnoses of apocrine hidrocystoma include both melanocytic and nonmelanocytic conditions such as epidermal cyst, nodular melanoma, nodular hidradenoma, syringoma, blue nevus, pilomatricoma, eccrine poroma, nodular Kaposi sarcoma, and venous lake.1 Histopathology showing large unilocular or multilocular dermal cysts with double lining comprising outer myoepithelial cells and inner columnar or cuboidal cell with decapitation secretion is paramount in confirming the diagnosis of apocrine hidrocystoma.

Dermoscopy can act as a valuable noninvasive modality in differentiating apocrine hidrocystoma from its melanocytic and nonmelanocytic differential diagnoses (Table).^5-8 In our patient, the presence of a homogeneous pink to bluish area involving the entire lesion, linear branched vessels, and whitish structures on dermoscopy pointed to the diagnosis of apocrine hidrocystoma, which was further confirmed by characteristic histopathologic findings.

The treatment of apocrine hidrocystoma includes surgical excision for solitary lesions, with electrodesiccation and curettage, chemical cautery, and CO₂ laser ablation employed for multiple lesions.¹ Our patient was scheduled for CO₂ laser ablation, considering the multiple lesions and size of the apocrine hidrocystoma but was subsequently lost to follow-up.

The Diagnosis: Giant Apocrine Hidrocystoma

Histopathology of the noduloplaque revealed an unremarkable epidermis with multilocular cystic spaces centered in the dermis. The cysts had a double-lined epithelium with inner columnar to cuboidal cells and outer myoepithelial cells (bottom quiz image). Columnar cells showing decapitation secretion could be appreciated at places indicating apocrine secretion (Figure). A final diagnosis of apocrine hidrocystoma was made.

Hidrocystomas are rare, benign, cystic lesions derived either from apocrine or eccrine glands.¹ Apocrine hidrocystoma usually manifests as asymptomatic, solitary, dome-shaped papules or nodules with a predilection for the head and neck region. Hidrocystomas can vary from flesh colored to blue, brown, or black. Pigmentation in hidrocystoma is seen in 5% to 80% of cases and is attributed to the Tyndall effect.¹ The tumor usually is less than 20 mm in diameter; larger lesions are termed giant apocrine hidrocystoma.² Apocrine hidrocystoma manifesting with multiple lesions and a size greater than 10 mm, as seen in our case, is uncommon.

Zaballos et al³ described dermoscopy of apocrine hidrocystoma in 22 patients. Hallmark dermoscopic findings were the presence of a homogeneous flesh-colored, yellowish, blue to pinkish-blue area involving the entire lesion with arborizing vessels and whitish structures.³ Similar dermoscopic findings were present in our patient. The homogeneous area histologically correlates to the multiloculated cysts located in the dermis. The exact reason for white structures is unknown; however, their visualization in apocrine hidrocystoma could be attributed to the alternation in collagen orientation secondary to the presence of large or multiple cysts in the dermis.

The presence of shiny white dots arranged in a square resembling a four-leaf clover (also known as white rosettes) was a unique dermoscopic finding in our patient. These rosettes can be appreciated only with polarized dermoscopy, and they have been described in actinic keratosis, seborrheic keratosis, squamous cell carcinoma, and basal cell carcinoma.⁴ The exact morphologic correlate of white rosettes is unknown but is postulated to be secondary to material inside adnexal openings in small rosettes and concentric perifollicular fibrosis in larger rosettes.⁴ In our patient, we believe the white rosettes can be attributed to the accumulated secretions in the dermal glands, which also were seen via histopathology. Dermoscopy also revealed increased peripheral, brown, networklike pigmentation, which was unique and could be secondary to the patient’s darker skin phenotype.

Differential diagnoses of apocrine hidrocystoma include both melanocytic and nonmelanocytic conditions such as epidermal cyst, nodular melanoma, nodular hidradenoma, syringoma, blue nevus, pilomatricoma, eccrine poroma, nodular Kaposi sarcoma, and venous lake.1 Histopathology showing large unilocular or multilocular dermal cysts with double lining comprising outer myoepithelial cells and inner columnar or cuboidal cell with decapitation secretion is paramount in confirming the diagnosis of apocrine hidrocystoma.

Dermoscopy can act as a valuable noninvasive modality in differentiating apocrine hidrocystoma from its melanocytic and nonmelanocytic differential diagnoses (Table).^5-8 In our patient, the presence of a homogeneous pink to bluish area involving the entire lesion, linear branched vessels, and whitish structures on dermoscopy pointed to the diagnosis of apocrine hidrocystoma, which was further confirmed by characteristic histopathologic findings.

The treatment of apocrine hidrocystoma includes surgical excision for solitary lesions, with electrodesiccation and curettage, chemical cautery, and CO₂ laser ablation employed for multiple lesions.¹ Our patient was scheduled for CO₂ laser ablation, considering the multiple lesions and size of the apocrine hidrocystoma but was subsequently lost to follow-up.

The Diagnosis: Giant Apocrine Hidrocystoma

Histopathology of the noduloplaque revealed an unremarkable epidermis with multilocular cystic spaces centered in the dermis. The cysts had a double-lined epithelium with inner columnar to cuboidal cells and outer myoepithelial cells (bottom quiz image). Columnar cells showing decapitation secretion could be appreciated at places indicating apocrine secretion (Figure). A final diagnosis of apocrine hidrocystoma was made.

Hidrocystomas are rare, benign, cystic lesions derived either from apocrine or eccrine glands.¹ Apocrine hidrocystoma usually manifests as asymptomatic, solitary, dome-shaped papules or nodules with a predilection for the head and neck region. Hidrocystomas can vary from flesh colored to blue, brown, or black. Pigmentation in hidrocystoma is seen in 5% to 80% of cases and is attributed to the Tyndall effect.¹ The tumor usually is less than 20 mm in diameter; larger lesions are termed giant apocrine hidrocystoma.² Apocrine hidrocystoma manifesting with multiple lesions and a size greater than 10 mm, as seen in our case, is uncommon.

Zaballos et al³ described dermoscopy of apocrine hidrocystoma in 22 patients. Hallmark dermoscopic findings were the presence of a homogeneous flesh-colored, yellowish, blue to pinkish-blue area involving the entire lesion with arborizing vessels and whitish structures.³ Similar dermoscopic findings were present in our patient. The homogeneous area histologically correlates to the multiloculated cysts located in the dermis. The exact reason for white structures is unknown; however, their visualization in apocrine hidrocystoma could be attributed to the alternation in collagen orientation secondary to the presence of large or multiple cysts in the dermis.

The presence of shiny white dots arranged in a square resembling a four-leaf clover (also known as white rosettes) was a unique dermoscopic finding in our patient. These rosettes can be appreciated only with polarized dermoscopy, and they have been described in actinic keratosis, seborrheic keratosis, squamous cell carcinoma, and basal cell carcinoma.⁴ The exact morphologic correlate of white rosettes is unknown but is postulated to be secondary to material inside adnexal openings in small rosettes and concentric perifollicular fibrosis in larger rosettes.⁴ In our patient, we believe the white rosettes can be attributed to the accumulated secretions in the dermal glands, which also were seen via histopathology. Dermoscopy also revealed increased peripheral, brown, networklike pigmentation, which was unique and could be secondary to the patient’s darker skin phenotype.

Differential diagnoses of apocrine hidrocystoma include both melanocytic and nonmelanocytic conditions such as epidermal cyst, nodular melanoma, nodular hidradenoma, syringoma, blue nevus, pilomatricoma, eccrine poroma, nodular Kaposi sarcoma, and venous lake.1 Histopathology showing large unilocular or multilocular dermal cysts with double lining comprising outer myoepithelial cells and inner columnar or cuboidal cell with decapitation secretion is paramount in confirming the diagnosis of apocrine hidrocystoma.

Dermoscopy can act as a valuable noninvasive modality in differentiating apocrine hidrocystoma from its melanocytic and nonmelanocytic differential diagnoses (Table).^5-8 In our patient, the presence of a homogeneous pink to bluish area involving the entire lesion, linear branched vessels, and whitish structures on dermoscopy pointed to the diagnosis of apocrine hidrocystoma, which was further confirmed by characteristic histopathologic findings.

The treatment of apocrine hidrocystoma includes surgical excision for solitary lesions, with electrodesiccation and curettage, chemical cautery, and CO₂ laser ablation employed for multiple lesions.¹ Our patient was scheduled for CO₂ laser ablation, considering the multiple lesions and size of the apocrine hidrocystoma but was subsequently lost to follow-up.

The Diagnosis: Coral Dermatitis

At 3-week follow-up, the patient demonstrated remarkable improvement in the intensity and size of the erythematous cerebriform plaques following daily application of triamcinolone acetonide cream 0.1% (Figure). The lesion disappeared after several months and did not recur. The delayed presentation of symptoms with a history of incidental coral contact during snorkeling most likely represents the type IV hypersensitivity reaction seen in the diagnosis of coral dermatitis, an extraordinarily rare form of contact dermatitis.¹ Not all coral trigger skin reactions. Species of coral that contain nematocysts in their tentacles (aptly named stinging capsules) are responsible for the sting preceding coral dermatitis, as the nematocysts eject a coiled filament in response to human tactile stimulation that injects toxins into the epidermis.²

Acute, delayed, or chronic cutaneous changes follow envenomation. Acute responses arise immediately to a few hours after initial contact and are considered an irritant contact dermatitis.³ Local tissue histamine release and cascades of cytotoxic reactions often result in the characteristic urticarial or vesiculobullous plaques in addition to necrosis, piloerection, and localized lymphadenopathy.^2-4 Although relatively uncommon, there may be rapid onset of systemic symptoms such as fever, malaise, hives, nausea, or emesis. Cardiopulmonary events, hepatotoxicity, renal failure, or anaphylaxis are rare.² Histopathology of biopsy specimens reveals epidermal spongiosis with microvesicles and papillary dermal edema.^1,5 In comparison, delayed reactions occur within days to weeks and exhibit epidermal parakeratosis, spongiosis, basal layer vacuolization, focal necrosis, lymphocyte exocytosis, and papillary dermal edema with extravasated erythrocytes.1,6 Clinically, it may present as linear rows of erythematous papules with burning and pruritus.⁶ Chronic reactions manifest after months as difficult-to-treat, persistent lichenoid dermatitis occasionally accompanied by granulomatous changes.^1,2,4 Primary prevention measures after initial contact include an acetic acid rinse and cold compression to wash away residual nematocysts in the affected area.^4,7,8 If a rash develops, topical steroids are the mainstay of treatment.^3,8

In tandem with toxic nematocysts, the rigid calcified bodies of coral provide an additional self-defense mechanism against human contact.^2,4 The irregular haphazard nature of coral may catch novice divers off guard and lead to laceration of a mispositioned limb, thereby increasing the risk for secondary infections due to the introduction of calcium carbonate and toxic mucinous deposits at the wound site, warranting antibiotic treatment.^2,4,7 Because tropical locales are home to other natural dangers that inflict disease and mimic early signs of coral dermatitis, reaching an accurate diagnosis can be difficult, particularly for lower limb lesions. In summary, the diagnosis of coral dermatitis can be rendered based on morphology of the lesion and clinical context (exposure to corals and delayed symptoms) as well as response to topical steroids.

The differential diagnosis includes accidental trauma. Variations in impact force and patient skin integrity lead to a number of possible cutaneous manifestations seen in accidental trauma,⁹ which includes contusions resulting from burst capillaries underneath intact skin, abrasions due to the superficial epidermis scuffing away, and lacerations caused by enough force to rip and split the skin, leaving subcutaneous tissue between the intact tissue.^9,10 Typically, the pattern of injury can provide hints to match what object or organism caused the wound.⁹ However, delayed response and worsening symptoms, as seen in coral dermatitis, would be unusual in accidental trauma unless it is complicated by secondary infection (infectious dermatitis), which does not respond to topical steroids and requires antibiotic treatment.

Another differential diagnosis includes cutaneous larva migrans, which infests domesticated and stray animals. For example, hookworm larvae propagate their eggs inside the intestines of their host before fecal-soil transmission in sandy locales.¹¹ Unexpecting beachgoers travel barefoot on this contaminated soil, offering ample opportunity for the parasite to burrow into the upper dermis.^11,12 The clinical presentation includes signs and symptoms of creeping eruption such as pruritic, linear, serpiginous tracks. Topical treatment with thiabendazole requires application 3 times daily for 15 days, which increases the risk for nonadherence, yet this therapy proves advantageous if a patient does not tolerate oral agents due to systemic adverse effects.^11,12 Oral agents (eg, ivermectin, albendazole) offer improved adherence with a single dose^11,13; the cure rate was higher with a single dose of ivermectin 12 mg vs a single dose of albendazole 400 mg.13 The current suggested treatment is ivermectin 200 μg/kg by mouth daily for 1 or 2 days.¹⁴

The incidence of seabather’s eruption (also known as chinkui dermatitis) is highest during the summer season and fluctuates between epidemic and nonepidemic years.^15,16 It occurs sporadically worldwide mostly in tropical climates due to trapping of larvae spawn of sea animals such as crustaceans in swimwear. Initially, it presents as a pruritic and burning sensation after exiting the water, manifesting as a macular, papular, or maculopapular rash on areas covered by the swimsuit.^15,16 The sensation is worse in areas that are tightly banded on the swimsuit, including the waistband and elastic straps.¹⁵ Commonly, the affected individual will seek relief via a shower, which intensifies the burning, especially if the swimsuit has not been removed. The contaminated swimwear should be immediately discarded, as the trapped sea larvae’s nematocysts activate with the pressure and friction of movement.¹⁵ Seabather’s eruption typically resolves spontaneously within a week, but symptom management can be achieved with topical steroids (triamcinolone 0.1% or clobetasol 0.05%).^15,16 Unlike coral dermatitis, in seabather’s eruption the symptoms are immediate and the location of the eruption coincides with areas covered by the swimsuit.

The Diagnosis: Coral Dermatitis

At 3-week follow-up, the patient demonstrated remarkable improvement in the intensity and size of the erythematous cerebriform plaques following daily application of triamcinolone acetonide cream 0.1% (Figure). The lesion disappeared after several months and did not recur. The delayed presentation of symptoms with a history of incidental coral contact during snorkeling most likely represents the type IV hypersensitivity reaction seen in the diagnosis of coral dermatitis, an extraordinarily rare form of contact dermatitis.¹ Not all coral trigger skin reactions. Species of coral that contain nematocysts in their tentacles (aptly named stinging capsules) are responsible for the sting preceding coral dermatitis, as the nematocysts eject a coiled filament in response to human tactile stimulation that injects toxins into the epidermis.²

Acute, delayed, or chronic cutaneous changes follow envenomation. Acute responses arise immediately to a few hours after initial contact and are considered an irritant contact dermatitis.³ Local tissue histamine release and cascades of cytotoxic reactions often result in the characteristic urticarial or vesiculobullous plaques in addition to necrosis, piloerection, and localized lymphadenopathy.^2-4 Although relatively uncommon, there may be rapid onset of systemic symptoms such as fever, malaise, hives, nausea, or emesis. Cardiopulmonary events, hepatotoxicity, renal failure, or anaphylaxis are rare.² Histopathology of biopsy specimens reveals epidermal spongiosis with microvesicles and papillary dermal edema.^1,5 In comparison, delayed reactions occur within days to weeks and exhibit epidermal parakeratosis, spongiosis, basal layer vacuolization, focal necrosis, lymphocyte exocytosis, and papillary dermal edema with extravasated erythrocytes.1,6 Clinically, it may present as linear rows of erythematous papules with burning and pruritus.⁶ Chronic reactions manifest after months as difficult-to-treat, persistent lichenoid dermatitis occasionally accompanied by granulomatous changes.^1,2,4 Primary prevention measures after initial contact include an acetic acid rinse and cold compression to wash away residual nematocysts in the affected area.^4,7,8 If a rash develops, topical steroids are the mainstay of treatment.^3,8

In tandem with toxic nematocysts, the rigid calcified bodies of coral provide an additional self-defense mechanism against human contact.^2,4 The irregular haphazard nature of coral may catch novice divers off guard and lead to laceration of a mispositioned limb, thereby increasing the risk for secondary infections due to the introduction of calcium carbonate and toxic mucinous deposits at the wound site, warranting antibiotic treatment.^2,4,7 Because tropical locales are home to other natural dangers that inflict disease and mimic early signs of coral dermatitis, reaching an accurate diagnosis can be difficult, particularly for lower limb lesions. In summary, the diagnosis of coral dermatitis can be rendered based on morphology of the lesion and clinical context (exposure to corals and delayed symptoms) as well as response to topical steroids.

The differential diagnosis includes accidental trauma. Variations in impact force and patient skin integrity lead to a number of possible cutaneous manifestations seen in accidental trauma,⁹ which includes contusions resulting from burst capillaries underneath intact skin, abrasions due to the superficial epidermis scuffing away, and lacerations caused by enough force to rip and split the skin, leaving subcutaneous tissue between the intact tissue.^9,10 Typically, the pattern of injury can provide hints to match what object or organism caused the wound.⁹ However, delayed response and worsening symptoms, as seen in coral dermatitis, would be unusual in accidental trauma unless it is complicated by secondary infection (infectious dermatitis), which does not respond to topical steroids and requires antibiotic treatment.

Another differential diagnosis includes cutaneous larva migrans, which infests domesticated and stray animals. For example, hookworm larvae propagate their eggs inside the intestines of their host before fecal-soil transmission in sandy locales.¹¹ Unexpecting beachgoers travel barefoot on this contaminated soil, offering ample opportunity for the parasite to burrow into the upper dermis.^11,12 The clinical presentation includes signs and symptoms of creeping eruption such as pruritic, linear, serpiginous tracks. Topical treatment with thiabendazole requires application 3 times daily for 15 days, which increases the risk for nonadherence, yet this therapy proves advantageous if a patient does not tolerate oral agents due to systemic adverse effects.^11,12 Oral agents (eg, ivermectin, albendazole) offer improved adherence with a single dose^11,13; the cure rate was higher with a single dose of ivermectin 12 mg vs a single dose of albendazole 400 mg.13 The current suggested treatment is ivermectin 200 μg/kg by mouth daily for 1 or 2 days.¹⁴

The incidence of seabather’s eruption (also known as chinkui dermatitis) is highest during the summer season and fluctuates between epidemic and nonepidemic years.^15,16 It occurs sporadically worldwide mostly in tropical climates due to trapping of larvae spawn of sea animals such as crustaceans in swimwear. Initially, it presents as a pruritic and burning sensation after exiting the water, manifesting as a macular, papular, or maculopapular rash on areas covered by the swimsuit.^15,16 The sensation is worse in areas that are tightly banded on the swimsuit, including the waistband and elastic straps.¹⁵ Commonly, the affected individual will seek relief via a shower, which intensifies the burning, especially if the swimsuit has not been removed. The contaminated swimwear should be immediately discarded, as the trapped sea larvae’s nematocysts activate with the pressure and friction of movement.¹⁵ Seabather’s eruption typically resolves spontaneously within a week, but symptom management can be achieved with topical steroids (triamcinolone 0.1% or clobetasol 0.05%).^15,16 Unlike coral dermatitis, in seabather’s eruption the symptoms are immediate and the location of the eruption coincides with areas covered by the swimsuit.

The Diagnosis: Coral Dermatitis

At 3-week follow-up, the patient demonstrated remarkable improvement in the intensity and size of the erythematous cerebriform plaques following daily application of triamcinolone acetonide cream 0.1% (Figure). The lesion disappeared after several months and did not recur. The delayed presentation of symptoms with a history of incidental coral contact during snorkeling most likely represents the type IV hypersensitivity reaction seen in the diagnosis of coral dermatitis, an extraordinarily rare form of contact dermatitis.¹ Not all coral trigger skin reactions. Species of coral that contain nematocysts in their tentacles (aptly named stinging capsules) are responsible for the sting preceding coral dermatitis, as the nematocysts eject a coiled filament in response to human tactile stimulation that injects toxins into the epidermis.²

Acute, delayed, or chronic cutaneous changes follow envenomation. Acute responses arise immediately to a few hours after initial contact and are considered an irritant contact dermatitis.³ Local tissue histamine release and cascades of cytotoxic reactions often result in the characteristic urticarial or vesiculobullous plaques in addition to necrosis, piloerection, and localized lymphadenopathy.^2-4 Although relatively uncommon, there may be rapid onset of systemic symptoms such as fever, malaise, hives, nausea, or emesis. Cardiopulmonary events, hepatotoxicity, renal failure, or anaphylaxis are rare.² Histopathology of biopsy specimens reveals epidermal spongiosis with microvesicles and papillary dermal edema.^1,5 In comparison, delayed reactions occur within days to weeks and exhibit epidermal parakeratosis, spongiosis, basal layer vacuolization, focal necrosis, lymphocyte exocytosis, and papillary dermal edema with extravasated erythrocytes.1,6 Clinically, it may present as linear rows of erythematous papules with burning and pruritus.⁶ Chronic reactions manifest after months as difficult-to-treat, persistent lichenoid dermatitis occasionally accompanied by granulomatous changes.^1,2,4 Primary prevention measures after initial contact include an acetic acid rinse and cold compression to wash away residual nematocysts in the affected area.^4,7,8 If a rash develops, topical steroids are the mainstay of treatment.^3,8

In tandem with toxic nematocysts, the rigid calcified bodies of coral provide an additional self-defense mechanism against human contact.^2,4 The irregular haphazard nature of coral may catch novice divers off guard and lead to laceration of a mispositioned limb, thereby increasing the risk for secondary infections due to the introduction of calcium carbonate and toxic mucinous deposits at the wound site, warranting antibiotic treatment.^2,4,7 Because tropical locales are home to other natural dangers that inflict disease and mimic early signs of coral dermatitis, reaching an accurate diagnosis can be difficult, particularly for lower limb lesions. In summary, the diagnosis of coral dermatitis can be rendered based on morphology of the lesion and clinical context (exposure to corals and delayed symptoms) as well as response to topical steroids.

The differential diagnosis includes accidental trauma. Variations in impact force and patient skin integrity lead to a number of possible cutaneous manifestations seen in accidental trauma,⁹ which includes contusions resulting from burst capillaries underneath intact skin, abrasions due to the superficial epidermis scuffing away, and lacerations caused by enough force to rip and split the skin, leaving subcutaneous tissue between the intact tissue.^9,10 Typically, the pattern of injury can provide hints to match what object or organism caused the wound.⁹ However, delayed response and worsening symptoms, as seen in coral dermatitis, would be unusual in accidental trauma unless it is complicated by secondary infection (infectious dermatitis), which does not respond to topical steroids and requires antibiotic treatment.

Another differential diagnosis includes cutaneous larva migrans, which infests domesticated and stray animals. For example, hookworm larvae propagate their eggs inside the intestines of their host before fecal-soil transmission in sandy locales.¹¹ Unexpecting beachgoers travel barefoot on this contaminated soil, offering ample opportunity for the parasite to burrow into the upper dermis.^11,12 The clinical presentation includes signs and symptoms of creeping eruption such as pruritic, linear, serpiginous tracks. Topical treatment with thiabendazole requires application 3 times daily for 15 days, which increases the risk for nonadherence, yet this therapy proves advantageous if a patient does not tolerate oral agents due to systemic adverse effects.^11,12 Oral agents (eg, ivermectin, albendazole) offer improved adherence with a single dose^11,13; the cure rate was higher with a single dose of ivermectin 12 mg vs a single dose of albendazole 400 mg.13 The current suggested treatment is ivermectin 200 μg/kg by mouth daily for 1 or 2 days.¹⁴

The incidence of seabather’s eruption (also known as chinkui dermatitis) is highest during the summer season and fluctuates between epidemic and nonepidemic years.^15,16 It occurs sporadically worldwide mostly in tropical climates due to trapping of larvae spawn of sea animals such as crustaceans in swimwear. Initially, it presents as a pruritic and burning sensation after exiting the water, manifesting as a macular, papular, or maculopapular rash on areas covered by the swimsuit.^15,16 The sensation is worse in areas that are tightly banded on the swimsuit, including the waistband and elastic straps.¹⁵ Commonly, the affected individual will seek relief via a shower, which intensifies the burning, especially if the swimsuit has not been removed. The contaminated swimwear should be immediately discarded, as the trapped sea larvae’s nematocysts activate with the pressure and friction of movement.¹⁵ Seabather’s eruption typically resolves spontaneously within a week, but symptom management can be achieved with topical steroids (triamcinolone 0.1% or clobetasol 0.05%).^15,16 Unlike coral dermatitis, in seabather’s eruption the symptoms are immediate and the location of the eruption coincides with areas covered by the swimsuit.