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Continuous Glucose Monitoring vs Fingerstick Monitoring for Hemoglobin A1c Control in Veterans
In the United States, 1 in 4 veterans lives with type 2 diabetes mellitus (T2DM), double the rate of the general population.1 Medications are important for the treatment of T2DM and preventing complications that may develop if not properly managed. Common classes of medications for diabetes include biguanides, sodiumglucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, sulfonylureas, and insulin. The selection of treatment depends on patient-specific factors including hemoglobin A1c (HbA1c) goal, potential effects on weight, risk of hypoglycemia, and comorbidities such as atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease.2
HbA1c level reflects the mean blood glucose over the previous 3 months and serves as an indication of diabetes control. In patients with diabetes, it is recommended that HbA1c is checked ≥ 2 times annually for those meeting treatment goals, or more often if the patient needs to adjust medications to reach their HbA1c goal. The goal HbA1c level for most adults with diabetes is < 7%.3 This target can be adjusted based on age, comorbidities, or other patient factors. It is generally recommended that frequent glucose monitoring is not needed for patients with T2DM who are only taking oral agents and/or noninsulin injectables. However, for those on insulin regimens, it is advised to monitor glucose closely, with even more frequent testing for those with an intensive insulin regimen.3
Most patients with diabetes use fingerstick testing to self-monitor their blood glucose. However, continuous glucose monitors (CGMs) are becoming widely available and offer a solution to those who do not have the ability to check their glucose multiple times a day and throughout the night. The American Diabetes Association recommends that the frequency and timing of blood glucose monitoring, or the consideration of CGM use, should be based on the specific needs and goals of each patient.3 Guidelines also encourage those on intensive insulin regimens to check glucose levels when fasting, before and after meals, prior to exercise, and when hypoglycemia or hyperglycemia is suspected. Frequent testing can become a burden for patients, whereas once a CGM sensor is placed, it can be worn for 10 to 14 days. CGMs are also capable of transmitting glucose readings every 1 to 15 minutes to a receiver or mobile phone, allowing for further adaptability to a patient’s lifestyle.3
CGMs work by measuring the interstitial glucose with a small filament sensor and have demonstrated accuracy when compared to blood glucose readings. The ability of a CGM to accurately reflect HbA1c levels is a potential benefit, reducing the need for frequent testing to determine whether patients have achieved glycemic control.4 Another benefit of a CGM is the ease of sharing data; patient accounts can be linked with a health care site, allowing clinicians to access glucose data even if the patient is not able to be seen in clinic. This allows health care practitioners (HCPs) to more efficiently tailor medications and optimize regimens based on patient-specific data that was not available by fingerstick testing alone.
Vigersky and colleagues provided one of the few studies on the long-term effects of CGM in patients managing T2DM through diet and exercise alone, oral medications, or basal insulin and found significant improvement in HbA1c after only 3 months of CGM use.5
An important aspect of CGM use is the ability to alert the patient to low blood glucose readings, which can be dangerous for those unaware of hypoglycemia. Many studies have investigated the association between CGM use and acute metabolic events, demonstrating the potential for CGMs to prevent these emergencies. Karter and colleagues found a reduction in emergency department visits and hospitalizations for hypoglycemia associated with the use of CGMs in patients with type 1 DM (T1DM) and T2DM.6
There have been few studies on the use of CGM in veterans. Langford and colleagues found a reduction of HbA1c among veterans with T2DM using CGMs. However, > 50% of the patients in the study were not receiving insulin therapy, which currently is a US Department of Veterans Affairs (VA) CGM criteria for use.7 While current studies provide evidence that supports improvement in HbA1c levels with the use of CGMs, data are lacking for veterans with T2DM taking insulin. There is also minimal research that indicates which patients should be offered a CGM. The objective of this study was to evaluate glycemic control in veterans with T2DM on insulin using a CGM who were previously monitoring blood glucose with fingerstick testing. Secondary endpoints were explored to identify subgroups that may benefit from a CGM and other potential advantages of CGMs.
Methods
This was a retrospective study of veterans who transitioned from fingerstick testing to CGM for glucose monitoring. Each veteran served as their own control to limit confounding variables when comparing HbA1c levels. Veterans with an active or suspended CGM order were identified by reviewing outpatient prescription data. All data collection and analysis were done within the Veterans Affairs Sioux Falls Health Care System.
The primary objective of this study was to assess glycemic control from the use of a CGM by evaluating the change in HbA1c after transitioning to a CGM compared to the change in HbA1c with standard fingerstick monitoring. Three HbA1c values were collected for each veteran: before starting CGM, at initiation, and following CGM initiation (Figure 1). CGM start date was the date the CGM prescription order was placed. The pre-CGM HbA1c level was ≥ 1 year prior to the CGM start date or the HbA1c closest to 1 year. The start CGM HbA1c level was within 3 months before or 1 month after the CGM start date. The post-CGM HbA1c level was the most recent time of data collection and at least 6 months after CGM initiation. The change in HbA1c from fingerstick glucose monitoring was the difference between the pre-CGM and start CGM values. The change in HbA1c from use of a CGM was the difference between start CGM and post-CGM values, which were compared to determine HbA1c reduction from CGM use.
This study also explored secondary outcomes including changes in HbA1c by prescriber type, differences in HbA1c reduction based on age, and changes in diabetes medications, including total daily insulin doses. For secondary outcomes, diabetes medication information and the total daily dose of insulin were gathered at the start of CGM use and at the time of data collection. The most recent CGM order prescribed was also collected.
Veterans were included if they were aged ≥ 18 years, had an active order for a CGM, T2DM diagnosis, an insulin prescription, and previously used test strips for glucose monitoring. Patients with T1DM, those who accessed CGMs or care in the community, and patients without HbA1c values pre-CGM, were excluded.
Statistical Analysis
The primary endpoint of change in HbA1c level before and after CGM use was compared using a paired t test. A 0.5% change in HbA1c was considered clinically significant, as suggested in other studies.8,9P < .05 was considered statistically significant. Analysis for continuous baseline characteristics, including age and total daily insulin, were reported as mean values. Nominal characteristics including sex, race, diabetes medications, and prescriber type are reported as percentages.
Results
A total of 402 veterans were identified with an active CGM at the time of initial data collection in January 2024 and 175 met inclusion criteria. Sixty patients were excluded due to diabetes managed through a community HCP, 38 had T1DM, and 129 lacked HbA1c within all specified time periods. The 175 veterans were randomized, and 150 were selected to perform a chart review for data collection. The mean age was 70 years, most were male and identified as White (Table 1). The majority of patients were managed by endocrinology (53.3%), followed by primary care (24.0%), and pharmacy (22.7%) (Table 2). The mean baseline HbA1c was 8.6%.
The difference in HbA1c before and after use of CGM was -0.97% (P = .0001). Prior to use of a CGM the change in HbA1c was minimal, with an increase of 0.003% with the use of selfmonitoring glucose. After use of a CGM, HbA1c decreased by 0.971%. This reduction in HbA1c would also be considered clinically significant as the change was > 0.5%. The mean pre-, at start, and post-CGM HbA1c levels were 8.6%, 8.6%, and 7.6%, respectively (Figure 2). Pharmacy prescribers had a 0.7% reduction in HbA1c post-CGM, the least of all prescribers. While most age groups saw a reduction in HbA1c, those aged ≥ 80 years had an increase of 0.18% (Table 3). There was an overall mean reduction in insulin of 22 units, which was similar between all prescribers.
Discussion
The primary endpoint of difference in change of HbA1c before and after CGM use was found to be statistically and clinically significant, with a nearly 1% reduction in HbA1c, which was similar to the reduction found by Vigersky and colleagues. 5 Across all prescribers, post-CGM HbA1c levels were similar; however, patients with CGM prescribed by pharmacists had the smallest change in HbA1c. VA pharmacists primarily assess veterans taking insulin who have HbA1c levels that are below the goal with the aim of decreasing insulin to reduce the risk of hypoglycemia, which could result in increased HbA1c levels. This may also explain the observed increase in post-CGM HbA1c levels in patients aged ≥ 80 years. Patients under the care of pharmacists also had baseline mean HbA1c levels that were lower than primary care and endocrinology prescribers and were closer to their HbA1c goal at baseline, which likely was reflected in the smaller reduction in post-CGM HbA1c level.
While there was a decrease in HbA1c levels with CGM use, there were also changes to medications during this timeframe that also may have impacted HbA1c levels. The most common diabetes medications started during CGM use were GLP-1 agonists and SGLT2-inhibitors. Additionally, there was a reduction in the total daily dose of insulin in the study population. These results demonstrate the potential benefits of CGMs for prescribers who take advantage of the CGM glucose data available to assist with medication adjustments. Another consideration for differences in changes of HbA1c among prescriber types is the opportunity for more frequent follow- up visits with pharmacy or endocrinology compared with primary care. If veterans are followed more closely, it may be associated with improved HbA1c control. Further research investigating changes in HbA1c levels based on followup frequency may be useful.
Strengths and Limitations
The crossover design was a strength of this study. This design reduced confounding variables by having veterans serve as their own controls. In addition, the collection of multiple secondary outcomes adds to the knowledge base for future studies. This study focused on a unique population of veterans with T2DM who were taking insulin, an area that previously had very little data available to determine the benefits of CGM use.
Although the use of a CGM showed statistical significance in lowering HbA1c, many veterans were started on new diabetes medication during the period of CGM use, which also likely contributed to the reduction in HbA1c and may have confounded the results. The study was limited by its small population size due to time constraints of chart reviews and the limited generalizability of results outside of the VA system. The majority of patients were from a single site, male and identified as White, which may not be reflective of other VA and community health care systems. It was also noted that the time from the initiation of CGM use to the most recent HbA1c level varied from 6 months to several years. Additionally, veterans managed by community-based HCPs with complex diabetes cases were excluded.
Conclusions
This study demonstrated a clinically and statistically significant reduction in HbA1c with the use of a CGM compared to fingerstick monitoring in veterans with T2DM who were being treated with insulin. The change in post-CGM HbA1c levels across prescribers was similar. In the subgroup analysis of change in HbA1c among age groups, there was a lower HbA1c reduction in individuals aged ≥ 80 years. The results from this study support the idea that CGM use may be beneficial for patients who require a reduction in HbA1c by allowing more precise adjustments to medications and optimization of therapy, as well as the potential to reduce insulin requirements, which is especially valuable in the older adult veteran population.
- US Department of Veterans Affairs. VA supports veterans who have type 2 diabetes. VA News. Accessed September 30, 2024. https://news.va.gov/107579/va-supports-veterans-who-have-type-2-diabetes/
- ElSayed NA, Aleppo G, Aroda VR, et al. 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S140- S157. doi:10.2337/dc23-S009
- ElSayed NA, Aleppo G, Aroda VR, et al. 6. Glycemic targets: standards of care in diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S97-S110. doi:10.2337/dc23-S006
- Miller E, Gavin JR, Kruger DF, Brunton SA. Continuous glucose monitoring: optimizing diabetes care: executive summary. Clin Diabetes. 2022;40(4):394-398. doi:10.2337/cd22-0043
- Vigersky RA, Fonda SJ, Chellappa M, Walker MS, Ehrhardt NM. Short- and long-term effects of real-time continuous glucose monitoring in patients with type 2 diabetes. Diabetes Care. 2012;35(1):32-38. doi:10.2337/dc11-1438
- Karter AJ, Parker MM, Moffet HH, Gilliam LK, Dlott R. Association of real-time continuous glucose monitoring with glycemic control and acute metabolic events among patients with insulin-treated diabetes. JAMA. 2021;325(22):2273-2284. doi:10.1001/JAMA.2021.6530
- Langford SN, Lane M, Karounos D. Continuous blood glucose monitoring outcomes in veterans with type 2 diabetes. Fed Pract. 2021;38(Suppl 4):S14-S17. doi:10.12788/fp.0189
- Radin MS. Pitfalls in hemoglobin A1c measurement: when results may be misleading. J Gen Intern Med. 2014;29(2):388-394. doi:10.1007/s11606-013-2595-x.
- Little RR, Rohlfing CL, Sacks DB; National Glycohemoglobin Standardization Program (NGSP) steering committee. Status of hemoglobin A1c measurement and goals for improvement: from chaos to order for improving diabetes care. Clin Chem. 2011;57(2):205-214. doi:10.1373/clinchem.2010.148841
In the United States, 1 in 4 veterans lives with type 2 diabetes mellitus (T2DM), double the rate of the general population.1 Medications are important for the treatment of T2DM and preventing complications that may develop if not properly managed. Common classes of medications for diabetes include biguanides, sodiumglucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, sulfonylureas, and insulin. The selection of treatment depends on patient-specific factors including hemoglobin A1c (HbA1c) goal, potential effects on weight, risk of hypoglycemia, and comorbidities such as atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease.2
HbA1c level reflects the mean blood glucose over the previous 3 months and serves as an indication of diabetes control. In patients with diabetes, it is recommended that HbA1c is checked ≥ 2 times annually for those meeting treatment goals, or more often if the patient needs to adjust medications to reach their HbA1c goal. The goal HbA1c level for most adults with diabetes is < 7%.3 This target can be adjusted based on age, comorbidities, or other patient factors. It is generally recommended that frequent glucose monitoring is not needed for patients with T2DM who are only taking oral agents and/or noninsulin injectables. However, for those on insulin regimens, it is advised to monitor glucose closely, with even more frequent testing for those with an intensive insulin regimen.3
Most patients with diabetes use fingerstick testing to self-monitor their blood glucose. However, continuous glucose monitors (CGMs) are becoming widely available and offer a solution to those who do not have the ability to check their glucose multiple times a day and throughout the night. The American Diabetes Association recommends that the frequency and timing of blood glucose monitoring, or the consideration of CGM use, should be based on the specific needs and goals of each patient.3 Guidelines also encourage those on intensive insulin regimens to check glucose levels when fasting, before and after meals, prior to exercise, and when hypoglycemia or hyperglycemia is suspected. Frequent testing can become a burden for patients, whereas once a CGM sensor is placed, it can be worn for 10 to 14 days. CGMs are also capable of transmitting glucose readings every 1 to 15 minutes to a receiver or mobile phone, allowing for further adaptability to a patient’s lifestyle.3
CGMs work by measuring the interstitial glucose with a small filament sensor and have demonstrated accuracy when compared to blood glucose readings. The ability of a CGM to accurately reflect HbA1c levels is a potential benefit, reducing the need for frequent testing to determine whether patients have achieved glycemic control.4 Another benefit of a CGM is the ease of sharing data; patient accounts can be linked with a health care site, allowing clinicians to access glucose data even if the patient is not able to be seen in clinic. This allows health care practitioners (HCPs) to more efficiently tailor medications and optimize regimens based on patient-specific data that was not available by fingerstick testing alone.
Vigersky and colleagues provided one of the few studies on the long-term effects of CGM in patients managing T2DM through diet and exercise alone, oral medications, or basal insulin and found significant improvement in HbA1c after only 3 months of CGM use.5
An important aspect of CGM use is the ability to alert the patient to low blood glucose readings, which can be dangerous for those unaware of hypoglycemia. Many studies have investigated the association between CGM use and acute metabolic events, demonstrating the potential for CGMs to prevent these emergencies. Karter and colleagues found a reduction in emergency department visits and hospitalizations for hypoglycemia associated with the use of CGMs in patients with type 1 DM (T1DM) and T2DM.6
There have been few studies on the use of CGM in veterans. Langford and colleagues found a reduction of HbA1c among veterans with T2DM using CGMs. However, > 50% of the patients in the study were not receiving insulin therapy, which currently is a US Department of Veterans Affairs (VA) CGM criteria for use.7 While current studies provide evidence that supports improvement in HbA1c levels with the use of CGMs, data are lacking for veterans with T2DM taking insulin. There is also minimal research that indicates which patients should be offered a CGM. The objective of this study was to evaluate glycemic control in veterans with T2DM on insulin using a CGM who were previously monitoring blood glucose with fingerstick testing. Secondary endpoints were explored to identify subgroups that may benefit from a CGM and other potential advantages of CGMs.
Methods
This was a retrospective study of veterans who transitioned from fingerstick testing to CGM for glucose monitoring. Each veteran served as their own control to limit confounding variables when comparing HbA1c levels. Veterans with an active or suspended CGM order were identified by reviewing outpatient prescription data. All data collection and analysis were done within the Veterans Affairs Sioux Falls Health Care System.
The primary objective of this study was to assess glycemic control from the use of a CGM by evaluating the change in HbA1c after transitioning to a CGM compared to the change in HbA1c with standard fingerstick monitoring. Three HbA1c values were collected for each veteran: before starting CGM, at initiation, and following CGM initiation (Figure 1). CGM start date was the date the CGM prescription order was placed. The pre-CGM HbA1c level was ≥ 1 year prior to the CGM start date or the HbA1c closest to 1 year. The start CGM HbA1c level was within 3 months before or 1 month after the CGM start date. The post-CGM HbA1c level was the most recent time of data collection and at least 6 months after CGM initiation. The change in HbA1c from fingerstick glucose monitoring was the difference between the pre-CGM and start CGM values. The change in HbA1c from use of a CGM was the difference between start CGM and post-CGM values, which were compared to determine HbA1c reduction from CGM use.
This study also explored secondary outcomes including changes in HbA1c by prescriber type, differences in HbA1c reduction based on age, and changes in diabetes medications, including total daily insulin doses. For secondary outcomes, diabetes medication information and the total daily dose of insulin were gathered at the start of CGM use and at the time of data collection. The most recent CGM order prescribed was also collected.
Veterans were included if they were aged ≥ 18 years, had an active order for a CGM, T2DM diagnosis, an insulin prescription, and previously used test strips for glucose monitoring. Patients with T1DM, those who accessed CGMs or care in the community, and patients without HbA1c values pre-CGM, were excluded.
Statistical Analysis
The primary endpoint of change in HbA1c level before and after CGM use was compared using a paired t test. A 0.5% change in HbA1c was considered clinically significant, as suggested in other studies.8,9P < .05 was considered statistically significant. Analysis for continuous baseline characteristics, including age and total daily insulin, were reported as mean values. Nominal characteristics including sex, race, diabetes medications, and prescriber type are reported as percentages.
Results
A total of 402 veterans were identified with an active CGM at the time of initial data collection in January 2024 and 175 met inclusion criteria. Sixty patients were excluded due to diabetes managed through a community HCP, 38 had T1DM, and 129 lacked HbA1c within all specified time periods. The 175 veterans were randomized, and 150 were selected to perform a chart review for data collection. The mean age was 70 years, most were male and identified as White (Table 1). The majority of patients were managed by endocrinology (53.3%), followed by primary care (24.0%), and pharmacy (22.7%) (Table 2). The mean baseline HbA1c was 8.6%.
The difference in HbA1c before and after use of CGM was -0.97% (P = .0001). Prior to use of a CGM the change in HbA1c was minimal, with an increase of 0.003% with the use of selfmonitoring glucose. After use of a CGM, HbA1c decreased by 0.971%. This reduction in HbA1c would also be considered clinically significant as the change was > 0.5%. The mean pre-, at start, and post-CGM HbA1c levels were 8.6%, 8.6%, and 7.6%, respectively (Figure 2). Pharmacy prescribers had a 0.7% reduction in HbA1c post-CGM, the least of all prescribers. While most age groups saw a reduction in HbA1c, those aged ≥ 80 years had an increase of 0.18% (Table 3). There was an overall mean reduction in insulin of 22 units, which was similar between all prescribers.
Discussion
The primary endpoint of difference in change of HbA1c before and after CGM use was found to be statistically and clinically significant, with a nearly 1% reduction in HbA1c, which was similar to the reduction found by Vigersky and colleagues. 5 Across all prescribers, post-CGM HbA1c levels were similar; however, patients with CGM prescribed by pharmacists had the smallest change in HbA1c. VA pharmacists primarily assess veterans taking insulin who have HbA1c levels that are below the goal with the aim of decreasing insulin to reduce the risk of hypoglycemia, which could result in increased HbA1c levels. This may also explain the observed increase in post-CGM HbA1c levels in patients aged ≥ 80 years. Patients under the care of pharmacists also had baseline mean HbA1c levels that were lower than primary care and endocrinology prescribers and were closer to their HbA1c goal at baseline, which likely was reflected in the smaller reduction in post-CGM HbA1c level.
While there was a decrease in HbA1c levels with CGM use, there were also changes to medications during this timeframe that also may have impacted HbA1c levels. The most common diabetes medications started during CGM use were GLP-1 agonists and SGLT2-inhibitors. Additionally, there was a reduction in the total daily dose of insulin in the study population. These results demonstrate the potential benefits of CGMs for prescribers who take advantage of the CGM glucose data available to assist with medication adjustments. Another consideration for differences in changes of HbA1c among prescriber types is the opportunity for more frequent follow- up visits with pharmacy or endocrinology compared with primary care. If veterans are followed more closely, it may be associated with improved HbA1c control. Further research investigating changes in HbA1c levels based on followup frequency may be useful.
Strengths and Limitations
The crossover design was a strength of this study. This design reduced confounding variables by having veterans serve as their own controls. In addition, the collection of multiple secondary outcomes adds to the knowledge base for future studies. This study focused on a unique population of veterans with T2DM who were taking insulin, an area that previously had very little data available to determine the benefits of CGM use.
Although the use of a CGM showed statistical significance in lowering HbA1c, many veterans were started on new diabetes medication during the period of CGM use, which also likely contributed to the reduction in HbA1c and may have confounded the results. The study was limited by its small population size due to time constraints of chart reviews and the limited generalizability of results outside of the VA system. The majority of patients were from a single site, male and identified as White, which may not be reflective of other VA and community health care systems. It was also noted that the time from the initiation of CGM use to the most recent HbA1c level varied from 6 months to several years. Additionally, veterans managed by community-based HCPs with complex diabetes cases were excluded.
Conclusions
This study demonstrated a clinically and statistically significant reduction in HbA1c with the use of a CGM compared to fingerstick monitoring in veterans with T2DM who were being treated with insulin. The change in post-CGM HbA1c levels across prescribers was similar. In the subgroup analysis of change in HbA1c among age groups, there was a lower HbA1c reduction in individuals aged ≥ 80 years. The results from this study support the idea that CGM use may be beneficial for patients who require a reduction in HbA1c by allowing more precise adjustments to medications and optimization of therapy, as well as the potential to reduce insulin requirements, which is especially valuable in the older adult veteran population.
In the United States, 1 in 4 veterans lives with type 2 diabetes mellitus (T2DM), double the rate of the general population.1 Medications are important for the treatment of T2DM and preventing complications that may develop if not properly managed. Common classes of medications for diabetes include biguanides, sodiumglucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, sulfonylureas, and insulin. The selection of treatment depends on patient-specific factors including hemoglobin A1c (HbA1c) goal, potential effects on weight, risk of hypoglycemia, and comorbidities such as atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease.2
HbA1c level reflects the mean blood glucose over the previous 3 months and serves as an indication of diabetes control. In patients with diabetes, it is recommended that HbA1c is checked ≥ 2 times annually for those meeting treatment goals, or more often if the patient needs to adjust medications to reach their HbA1c goal. The goal HbA1c level for most adults with diabetes is < 7%.3 This target can be adjusted based on age, comorbidities, or other patient factors. It is generally recommended that frequent glucose monitoring is not needed for patients with T2DM who are only taking oral agents and/or noninsulin injectables. However, for those on insulin regimens, it is advised to monitor glucose closely, with even more frequent testing for those with an intensive insulin regimen.3
Most patients with diabetes use fingerstick testing to self-monitor their blood glucose. However, continuous glucose monitors (CGMs) are becoming widely available and offer a solution to those who do not have the ability to check their glucose multiple times a day and throughout the night. The American Diabetes Association recommends that the frequency and timing of blood glucose monitoring, or the consideration of CGM use, should be based on the specific needs and goals of each patient.3 Guidelines also encourage those on intensive insulin regimens to check glucose levels when fasting, before and after meals, prior to exercise, and when hypoglycemia or hyperglycemia is suspected. Frequent testing can become a burden for patients, whereas once a CGM sensor is placed, it can be worn for 10 to 14 days. CGMs are also capable of transmitting glucose readings every 1 to 15 minutes to a receiver or mobile phone, allowing for further adaptability to a patient’s lifestyle.3
CGMs work by measuring the interstitial glucose with a small filament sensor and have demonstrated accuracy when compared to blood glucose readings. The ability of a CGM to accurately reflect HbA1c levels is a potential benefit, reducing the need for frequent testing to determine whether patients have achieved glycemic control.4 Another benefit of a CGM is the ease of sharing data; patient accounts can be linked with a health care site, allowing clinicians to access glucose data even if the patient is not able to be seen in clinic. This allows health care practitioners (HCPs) to more efficiently tailor medications and optimize regimens based on patient-specific data that was not available by fingerstick testing alone.
Vigersky and colleagues provided one of the few studies on the long-term effects of CGM in patients managing T2DM through diet and exercise alone, oral medications, or basal insulin and found significant improvement in HbA1c after only 3 months of CGM use.5
An important aspect of CGM use is the ability to alert the patient to low blood glucose readings, which can be dangerous for those unaware of hypoglycemia. Many studies have investigated the association between CGM use and acute metabolic events, demonstrating the potential for CGMs to prevent these emergencies. Karter and colleagues found a reduction in emergency department visits and hospitalizations for hypoglycemia associated with the use of CGMs in patients with type 1 DM (T1DM) and T2DM.6
There have been few studies on the use of CGM in veterans. Langford and colleagues found a reduction of HbA1c among veterans with T2DM using CGMs. However, > 50% of the patients in the study were not receiving insulin therapy, which currently is a US Department of Veterans Affairs (VA) CGM criteria for use.7 While current studies provide evidence that supports improvement in HbA1c levels with the use of CGMs, data are lacking for veterans with T2DM taking insulin. There is also minimal research that indicates which patients should be offered a CGM. The objective of this study was to evaluate glycemic control in veterans with T2DM on insulin using a CGM who were previously monitoring blood glucose with fingerstick testing. Secondary endpoints were explored to identify subgroups that may benefit from a CGM and other potential advantages of CGMs.
Methods
This was a retrospective study of veterans who transitioned from fingerstick testing to CGM for glucose monitoring. Each veteran served as their own control to limit confounding variables when comparing HbA1c levels. Veterans with an active or suspended CGM order were identified by reviewing outpatient prescription data. All data collection and analysis were done within the Veterans Affairs Sioux Falls Health Care System.
The primary objective of this study was to assess glycemic control from the use of a CGM by evaluating the change in HbA1c after transitioning to a CGM compared to the change in HbA1c with standard fingerstick monitoring. Three HbA1c values were collected for each veteran: before starting CGM, at initiation, and following CGM initiation (Figure 1). CGM start date was the date the CGM prescription order was placed. The pre-CGM HbA1c level was ≥ 1 year prior to the CGM start date or the HbA1c closest to 1 year. The start CGM HbA1c level was within 3 months before or 1 month after the CGM start date. The post-CGM HbA1c level was the most recent time of data collection and at least 6 months after CGM initiation. The change in HbA1c from fingerstick glucose monitoring was the difference between the pre-CGM and start CGM values. The change in HbA1c from use of a CGM was the difference between start CGM and post-CGM values, which were compared to determine HbA1c reduction from CGM use.
This study also explored secondary outcomes including changes in HbA1c by prescriber type, differences in HbA1c reduction based on age, and changes in diabetes medications, including total daily insulin doses. For secondary outcomes, diabetes medication information and the total daily dose of insulin were gathered at the start of CGM use and at the time of data collection. The most recent CGM order prescribed was also collected.
Veterans were included if they were aged ≥ 18 years, had an active order for a CGM, T2DM diagnosis, an insulin prescription, and previously used test strips for glucose monitoring. Patients with T1DM, those who accessed CGMs or care in the community, and patients without HbA1c values pre-CGM, were excluded.
Statistical Analysis
The primary endpoint of change in HbA1c level before and after CGM use was compared using a paired t test. A 0.5% change in HbA1c was considered clinically significant, as suggested in other studies.8,9P < .05 was considered statistically significant. Analysis for continuous baseline characteristics, including age and total daily insulin, were reported as mean values. Nominal characteristics including sex, race, diabetes medications, and prescriber type are reported as percentages.
Results
A total of 402 veterans were identified with an active CGM at the time of initial data collection in January 2024 and 175 met inclusion criteria. Sixty patients were excluded due to diabetes managed through a community HCP, 38 had T1DM, and 129 lacked HbA1c within all specified time periods. The 175 veterans were randomized, and 150 were selected to perform a chart review for data collection. The mean age was 70 years, most were male and identified as White (Table 1). The majority of patients were managed by endocrinology (53.3%), followed by primary care (24.0%), and pharmacy (22.7%) (Table 2). The mean baseline HbA1c was 8.6%.
The difference in HbA1c before and after use of CGM was -0.97% (P = .0001). Prior to use of a CGM the change in HbA1c was minimal, with an increase of 0.003% with the use of selfmonitoring glucose. After use of a CGM, HbA1c decreased by 0.971%. This reduction in HbA1c would also be considered clinically significant as the change was > 0.5%. The mean pre-, at start, and post-CGM HbA1c levels were 8.6%, 8.6%, and 7.6%, respectively (Figure 2). Pharmacy prescribers had a 0.7% reduction in HbA1c post-CGM, the least of all prescribers. While most age groups saw a reduction in HbA1c, those aged ≥ 80 years had an increase of 0.18% (Table 3). There was an overall mean reduction in insulin of 22 units, which was similar between all prescribers.
Discussion
The primary endpoint of difference in change of HbA1c before and after CGM use was found to be statistically and clinically significant, with a nearly 1% reduction in HbA1c, which was similar to the reduction found by Vigersky and colleagues. 5 Across all prescribers, post-CGM HbA1c levels were similar; however, patients with CGM prescribed by pharmacists had the smallest change in HbA1c. VA pharmacists primarily assess veterans taking insulin who have HbA1c levels that are below the goal with the aim of decreasing insulin to reduce the risk of hypoglycemia, which could result in increased HbA1c levels. This may also explain the observed increase in post-CGM HbA1c levels in patients aged ≥ 80 years. Patients under the care of pharmacists also had baseline mean HbA1c levels that were lower than primary care and endocrinology prescribers and were closer to their HbA1c goal at baseline, which likely was reflected in the smaller reduction in post-CGM HbA1c level.
While there was a decrease in HbA1c levels with CGM use, there were also changes to medications during this timeframe that also may have impacted HbA1c levels. The most common diabetes medications started during CGM use were GLP-1 agonists and SGLT2-inhibitors. Additionally, there was a reduction in the total daily dose of insulin in the study population. These results demonstrate the potential benefits of CGMs for prescribers who take advantage of the CGM glucose data available to assist with medication adjustments. Another consideration for differences in changes of HbA1c among prescriber types is the opportunity for more frequent follow- up visits with pharmacy or endocrinology compared with primary care. If veterans are followed more closely, it may be associated with improved HbA1c control. Further research investigating changes in HbA1c levels based on followup frequency may be useful.
Strengths and Limitations
The crossover design was a strength of this study. This design reduced confounding variables by having veterans serve as their own controls. In addition, the collection of multiple secondary outcomes adds to the knowledge base for future studies. This study focused on a unique population of veterans with T2DM who were taking insulin, an area that previously had very little data available to determine the benefits of CGM use.
Although the use of a CGM showed statistical significance in lowering HbA1c, many veterans were started on new diabetes medication during the period of CGM use, which also likely contributed to the reduction in HbA1c and may have confounded the results. The study was limited by its small population size due to time constraints of chart reviews and the limited generalizability of results outside of the VA system. The majority of patients were from a single site, male and identified as White, which may not be reflective of other VA and community health care systems. It was also noted that the time from the initiation of CGM use to the most recent HbA1c level varied from 6 months to several years. Additionally, veterans managed by community-based HCPs with complex diabetes cases were excluded.
Conclusions
This study demonstrated a clinically and statistically significant reduction in HbA1c with the use of a CGM compared to fingerstick monitoring in veterans with T2DM who were being treated with insulin. The change in post-CGM HbA1c levels across prescribers was similar. In the subgroup analysis of change in HbA1c among age groups, there was a lower HbA1c reduction in individuals aged ≥ 80 years. The results from this study support the idea that CGM use may be beneficial for patients who require a reduction in HbA1c by allowing more precise adjustments to medications and optimization of therapy, as well as the potential to reduce insulin requirements, which is especially valuable in the older adult veteran population.
- US Department of Veterans Affairs. VA supports veterans who have type 2 diabetes. VA News. Accessed September 30, 2024. https://news.va.gov/107579/va-supports-veterans-who-have-type-2-diabetes/
- ElSayed NA, Aleppo G, Aroda VR, et al. 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S140- S157. doi:10.2337/dc23-S009
- ElSayed NA, Aleppo G, Aroda VR, et al. 6. Glycemic targets: standards of care in diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S97-S110. doi:10.2337/dc23-S006
- Miller E, Gavin JR, Kruger DF, Brunton SA. Continuous glucose monitoring: optimizing diabetes care: executive summary. Clin Diabetes. 2022;40(4):394-398. doi:10.2337/cd22-0043
- Vigersky RA, Fonda SJ, Chellappa M, Walker MS, Ehrhardt NM. Short- and long-term effects of real-time continuous glucose monitoring in patients with type 2 diabetes. Diabetes Care. 2012;35(1):32-38. doi:10.2337/dc11-1438
- Karter AJ, Parker MM, Moffet HH, Gilliam LK, Dlott R. Association of real-time continuous glucose monitoring with glycemic control and acute metabolic events among patients with insulin-treated diabetes. JAMA. 2021;325(22):2273-2284. doi:10.1001/JAMA.2021.6530
- Langford SN, Lane M, Karounos D. Continuous blood glucose monitoring outcomes in veterans with type 2 diabetes. Fed Pract. 2021;38(Suppl 4):S14-S17. doi:10.12788/fp.0189
- Radin MS. Pitfalls in hemoglobin A1c measurement: when results may be misleading. J Gen Intern Med. 2014;29(2):388-394. doi:10.1007/s11606-013-2595-x.
- Little RR, Rohlfing CL, Sacks DB; National Glycohemoglobin Standardization Program (NGSP) steering committee. Status of hemoglobin A1c measurement and goals for improvement: from chaos to order for improving diabetes care. Clin Chem. 2011;57(2):205-214. doi:10.1373/clinchem.2010.148841
- US Department of Veterans Affairs. VA supports veterans who have type 2 diabetes. VA News. Accessed September 30, 2024. https://news.va.gov/107579/va-supports-veterans-who-have-type-2-diabetes/
- ElSayed NA, Aleppo G, Aroda VR, et al. 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S140- S157. doi:10.2337/dc23-S009
- ElSayed NA, Aleppo G, Aroda VR, et al. 6. Glycemic targets: standards of care in diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S97-S110. doi:10.2337/dc23-S006
- Miller E, Gavin JR, Kruger DF, Brunton SA. Continuous glucose monitoring: optimizing diabetes care: executive summary. Clin Diabetes. 2022;40(4):394-398. doi:10.2337/cd22-0043
- Vigersky RA, Fonda SJ, Chellappa M, Walker MS, Ehrhardt NM. Short- and long-term effects of real-time continuous glucose monitoring in patients with type 2 diabetes. Diabetes Care. 2012;35(1):32-38. doi:10.2337/dc11-1438
- Karter AJ, Parker MM, Moffet HH, Gilliam LK, Dlott R. Association of real-time continuous glucose monitoring with glycemic control and acute metabolic events among patients with insulin-treated diabetes. JAMA. 2021;325(22):2273-2284. doi:10.1001/JAMA.2021.6530
- Langford SN, Lane M, Karounos D. Continuous blood glucose monitoring outcomes in veterans with type 2 diabetes. Fed Pract. 2021;38(Suppl 4):S14-S17. doi:10.12788/fp.0189
- Radin MS. Pitfalls in hemoglobin A1c measurement: when results may be misleading. J Gen Intern Med. 2014;29(2):388-394. doi:10.1007/s11606-013-2595-x.
- Little RR, Rohlfing CL, Sacks DB; National Glycohemoglobin Standardization Program (NGSP) steering committee. Status of hemoglobin A1c measurement and goals for improvement: from chaos to order for improving diabetes care. Clin Chem. 2011;57(2):205-214. doi:10.1373/clinchem.2010.148841
VA Cancer Clinical Trials as a Strategy for Increasing Accrual of Racial and Ethnic Underrepresented Groups
Background
Cancer clinical trials (CCTs) are central to improving cancer care. However, generalizability of findings from CCTs is difficult due to the lack of diversity in most United States CCTs. Clinical trial accrual of underrepresented groups, is low throughout the United States and is approximately 4-5% in most CCTs. Reasons for low accrual in this population are multifactorial. Despite numerous factors related to accruing racial and ethnic underrepresented groups, many institutions have sought to address these barriers. We conducted a scoping review to identify evidence-based approaches to increase participation in cancer treatment clinical trials.
Methods
We reviewed the Salisbury VA Medical Center Oncology clinical trial database from October 2019 to June 2024. The participants in these clinical trials required consent. These clinical trials included treatment interventional as well as non-treatment interventional. Fifteen studies were included and over 260 Veterans participated.
Results
Key themes emerged that included a focus on patient education, cultural competency, and building capacity in the clinics to care for the Veteran population at three separate sites in the Salisbury VA system. The Black Veteran accrual rate of 29% was achieved. This accrual rate is representative of our VA catchment population of 33% for Black Veterans, and is five times the national average.
Conclusions
The research team’s success in enrolling Black Veterans in clinical trials is attributed to several factors. The demographic composition of Veterans served by the Salisbury, Charlotte, and Kernersville VA provided a diverse population that included a 33% Black group. The type of clinical trials focused on patients who were most impacted by the disease. The VA did afford less barriers to access to health care.
Background
Cancer clinical trials (CCTs) are central to improving cancer care. However, generalizability of findings from CCTs is difficult due to the lack of diversity in most United States CCTs. Clinical trial accrual of underrepresented groups, is low throughout the United States and is approximately 4-5% in most CCTs. Reasons for low accrual in this population are multifactorial. Despite numerous factors related to accruing racial and ethnic underrepresented groups, many institutions have sought to address these barriers. We conducted a scoping review to identify evidence-based approaches to increase participation in cancer treatment clinical trials.
Methods
We reviewed the Salisbury VA Medical Center Oncology clinical trial database from October 2019 to June 2024. The participants in these clinical trials required consent. These clinical trials included treatment interventional as well as non-treatment interventional. Fifteen studies were included and over 260 Veterans participated.
Results
Key themes emerged that included a focus on patient education, cultural competency, and building capacity in the clinics to care for the Veteran population at three separate sites in the Salisbury VA system. The Black Veteran accrual rate of 29% was achieved. This accrual rate is representative of our VA catchment population of 33% for Black Veterans, and is five times the national average.
Conclusions
The research team’s success in enrolling Black Veterans in clinical trials is attributed to several factors. The demographic composition of Veterans served by the Salisbury, Charlotte, and Kernersville VA provided a diverse population that included a 33% Black group. The type of clinical trials focused on patients who were most impacted by the disease. The VA did afford less barriers to access to health care.
Background
Cancer clinical trials (CCTs) are central to improving cancer care. However, generalizability of findings from CCTs is difficult due to the lack of diversity in most United States CCTs. Clinical trial accrual of underrepresented groups, is low throughout the United States and is approximately 4-5% in most CCTs. Reasons for low accrual in this population are multifactorial. Despite numerous factors related to accruing racial and ethnic underrepresented groups, many institutions have sought to address these barriers. We conducted a scoping review to identify evidence-based approaches to increase participation in cancer treatment clinical trials.
Methods
We reviewed the Salisbury VA Medical Center Oncology clinical trial database from October 2019 to June 2024. The participants in these clinical trials required consent. These clinical trials included treatment interventional as well as non-treatment interventional. Fifteen studies were included and over 260 Veterans participated.
Results
Key themes emerged that included a focus on patient education, cultural competency, and building capacity in the clinics to care for the Veteran population at three separate sites in the Salisbury VA system. The Black Veteran accrual rate of 29% was achieved. This accrual rate is representative of our VA catchment population of 33% for Black Veterans, and is five times the national average.
Conclusions
The research team’s success in enrolling Black Veterans in clinical trials is attributed to several factors. The demographic composition of Veterans served by the Salisbury, Charlotte, and Kernersville VA provided a diverse population that included a 33% Black group. The type of clinical trials focused on patients who were most impacted by the disease. The VA did afford less barriers to access to health care.
Anti-Tumor Necrosis Factor Treatment for Glomerulopathy: Case Report and Review of Literature
Podocytes are terminally differentiated, highly specialized cells located in juxtaposition to the basement membrane over the abluminal surfaces of endothelial cells within the glomerular tuft. This triad structure is the site of the filtration barrier, which forms highly delicate and tightly regulated architecture to carry out the ultrafiltration function of the kidney.1 The filtration barrier is characterized by foot processes that are connected by specialized junctions called slit diaphragms.
Insults to components of the filtration barrier can initiate cascading events and perpetuate structural alterations that may eventually result in sclerotic changes.2 Common causes among children include minimal change disease (MCD) with the collapse of foot processes resulting in proteinuria, Alport syndrome due to mutation of collagen fibers within the basement membrane leading to hematuria and proteinuria, immune complex mediated nephropathy following common infections or autoimmune diseases, and focal segmental glomerulosclerosis (FSGS) that can show variable histopathology toward eventual glomerular scarring.3,4 These children often clinically have minimal, if any, signs of systemic inflammation.3-5 This has been a limiting factor for the commitment to immunomodulatory treatment, except for steroids for the treatment of MCD.6 Although prolonged steroid treatment may be efficacious, adverse effects are significant in a growing child. Alternative treatments, such as tacrolimus and rituximab have been suggested as second-line steroid-sparing agents.7,8 Not uncommonly, however, these cases are managed by supportive measures only during the progression of the natural course of the disease, which may eventually lead to renal failure, requiring transplant for survival.8,9
This case report highlights a child with a variant of uncertain significance (VUS) in genes involved in Alport syndrome and FSGS who developed an abrupt onset of proteinuria and hematuria after a respiratory illness. To our knowledge, he represents the youngest case demonstrating the benefit of targeted treatment against tumor necrosis factor-α (TNF-α) for glomerulopathy using biologic response modifiers.
Case Description
This is currently a 7-year-old male patient who was born at 39 weeks gestation to gravida 3 para 3 following induced labor due to elevated maternal blood pressure. During the first 2 years of life, his growth and development were normal and his immunizations were up to date. The patient's medical history included upper respiratory tract infections (URIs), respiratory syncytial virus, as well as 3 bouts of pneumonia and multiple otitis media that resulted in 18 rounds of antibiotics. The child was also allergic to nuts and milk protein. The patient’s parents are of Northern European and Native American descent. There is no known family history of eye, ear, or kidney diseases.
Renal concerns were first noted at the age of 2 years and 6 months when he presented to an emergency department in Fall 2019 (week 0) for several weeks of intermittent dark-colored urine. His mother reported that the discoloration recently progressed in intensity to cola-colored, along with the onset of persistent vomiting without any fever or diarrhea. On physical examination, the patient had normal vitals: weight 14.8 kg (68th percentile), height 91 cm (24th percentile), and body surface area 0.6 m2. There was no edema, rash, or lymphadenopathy, but he appeared pale.
The patient’s initial laboratory results included: complete blood count with white blood cells (WBC) 10 x 103/L (reference range, 4.5-13.5 x 103/L); differential lymphocytes 69%; neutrophils 21%; hemoglobin 10 g/dL (reference range, 12-16 g/dL); hematocrit, 30%; (reference range, 37%-45%); platelets 437 103/L (reference range, 150-450 x 103/L); serum creatinine 0.46 mg/dL (reference range, 0.5-0.9 mg/dL); and albumin 3.1 g/dL (reference range, 3.5-5.2 g/dL). Serum electrolyte levels and liver enzymes were normal. A urine analysis revealed 3+ protein and 3+ blood with dysmorphic red blood cells (RBC) and RBC casts without WBC. The patient's spot urine protein-to-creatinine ratio was 4.3 and his renal ultrasound was normal. The patient was referred to Nephrology.
During the next 2 weeks, his protein-to-creatinine ratio progressed to 5.9 and serum albumin fell to 2.7 g/dL. His urine remained red colored, and a microscopic examination with RBC > 500 and WBC up to 10 on a high powered field. His workup was negative for antinuclear antibodies, antineutrophil cytoplasmic antibody, antistreptolysin-O (ASO) and anti-DNase B. Serum C3 was low at 81 mg/dL (reference range, 90-180 mg/dL), C4 was 13.3 mg/dL (reference range, 10-40 mg/dL), and immunoglobulin G was low at 452 mg/dL (reference range 719-1475 mg/dL). A baseline audiology test revealed normal hearing.
Percutaneous renal biopsy yielded about 12 glomeruli, all exhibiting mild mesangial matrix expansion and hypercellularity (Figure 1). One glomerulus had prominent parietal epithelial cells without endocapillary hypercellularity or crescent formation. There was no interstitial fibrosis or tubular atrophy. Immunofluorescence studies showed no evidence of immune complex deposition with negative staining for immunoglobulin heavy and light chains, C3 and C1q. Staining for α 2 and α 5 units of collagen was normal. Electron microscopy showed patchy areas of severe basement membrane thinning with frequent foci of mild to moderate lamina densa splitting and associated visceral epithelial cell foot process effacement (Figure 2).
These were reported as concerning findings for possible Alport syndrome by 3 independent pathology teams. The genetic testing was submitted at a commercial laboratory to screen 17 mutations, including COL4A3, COL4A4, and COL4A5. Results showed the presence of a heterozygous VUS in the COL4A4 gene (c.1055C > T; p.Pro352Leu; dbSNP ID: rs371717486; PolyPhen-2: Probably Damaging; SIFT: Deleterious) as well as the presence of a heterozygous VUS in TRPC6 gene (c2463A>T; p.Lys821Asn; dbSNP ID: rs199948731; PolyPhen-2: Benign; SIFT: Tolerated). Further genetic investigation by whole exome sequencing on approximately 20,000 genes through MNG Laboratories showed a new heterozygous VUS in the OSGEP gene [c.328T>C; p.Cys110Arg]. Additional studies ruled out mitochondrial disease, CoQ10 deficiency, and metabolic disorders upon normal findings for mitochondrial DNA, urine amino acids, plasma acylcarnitine profile, orotic acid, ammonia, and homocysteine levels.
Figure 3 summarizes the patient’s treatment response during 170 weeks of follow-up (Fall 2019 to Summer 2023). The patient was started on enalapril 0.6 mg/kg daily at week 3, which continued throughout treatment. Following a rheumatology consult at week 30, the patient was started on prednisolone 3 mg/mL to assess the role of inflammation through the treatment response. An initial dose of 2 mg/kg daily (9 mL) for 1 month was followed by every other day treatment that was tapered off by week 48. To control mild but noticeably increasing proteinuria in the interim, subcutaneous anakinra 50 mg (3 mg/kg daily) was added as a steroid
DISCUSSION
This case describes a child with rapidly progressive proteinuria and hematuria following a URI who was found to have VUS mutations in 3 different genes associated with chronic kidney disease. Serology tests on the patient were negative for streptococcal antibodies and antinuclear antibodies, ruling out poststreptococcal glomerulonephritis, or systemic lupus erythematosus. His renal biopsy findings were concerning for altered podocytes, mesangial cells, and basement membrane without inflammatory infiltrate, immune complex, complements, immunoglobulin A, or vasculopathy. His blood inflammatory markers, erythrocyte sedimentation rate, C-reactive protein, and ferritin were normal when his care team initiated daily steroids.
Overall, the patient’s clinical presentation and histopathology findings were suggestive of Alport syndrome or thin basement membrane nephropathy with a high potential to progress into FSGS.10-12 Alport syndrome affects 1 in 5000 to 10,000 children annually due to S-linked inheritance of COL4A5, or autosomal recessive inheritance of COL4A3 or COL4A4 genes. It presents with hematuria and hearing loss.10 Our patient had a single copy COL4A4 gene mutation that was classified as VUS. He also had 2 additional VUS affecting the TRPC6 and OSGEP genes. TRPC6 gene mutation can be associated with FSGS through autosomal dominant inheritance. Both COL4A4 and TRPC6 gene mutations were paternally inherited. Although the patient’s father not having renal disease argues against the clinical significance of these findings, there is literature on the potential role of heterozygous COL4A4 variant mimicking thin basement membrane nephropathy that can lead to renal impairment upon copresence of superimposed conditions.13 The patient’s rapidly progressing hematuria and changes in the basement membrane were worrisome for emerging FSGS. Furthermore, VUS of TRPC6 has been reported in late onset autosomal dominant FSGS and can be associated with early onset steroid-resistant nephrotic syndrome (NS) in children.14 This concern was voiced by 3 nephrology consultants during the initial evaluation, leading to the consensus that steroid treatment for podocytopathy would not alter the patient’s long-term outcomes (ie, progression to FSGS).
Immunomodulation
Our rationale for immunomodulatory treatment was based on the abrupt onset of renal concerns following a URI, suggesting the importance of an inflammatory trigger causing altered homeostasis in a genetically susceptible host. Preclinical models show that microbial products such as lipopolysaccharides can lead to podocytopathy by several mechanisms through activation of toll-like receptor signaling. It can directly cause apoptosis by downregulation of the intracellular Akt survival pathway.15 Lipopolysaccharide can also activate the NF-αB pathway and upregulate the production of interleukin-1 (IL-1) and TNF-α in mesangial cells.16,17
Both cytokines can promote mesangial cell proliferation.18 Through autocrine and paracrine mechanisms, proinflammatory cytokines can further perpetuate somatic tissue changes and contribute to the development of podocytopathy. For instance, TNF-α can promote podocyte injury and proteinuria by downregulation of the slit diaphragm protein expression (ie, nephrin, ezrin, or podocin), and disruption of podocyte cytoskeleton.19,20 TNF-α promotes the influx and activation of macrophages and inflammatory cells. It is actively involved in chronic alterations within the glomeruli by the upregulation of matrix metalloproteases by integrins, as well as activation of myofibroblast progenitors and extracellular matrix deposition in crosstalk with transforming growth factor and other key mediators.17,21,22
For the patient described in this case report, initial improvement on steroids encouraged the pursuit of additional treatment to downregulate inflammatory pathways within the glomerular milieu. However, within the COVID-19 environment, escalating the patient’s treatment using traditional immunomodulators (ie, calcineurin inhibitors or mycophenolate mofetil) was not favored due to the risk of infection. Initially, anakinra, a recombinant IL-1 receptor antagonist, was preferred as a steroid-sparing agent for its short life and safety profile during the pandemic. At first, the patient responded well to anakinra and was allowed a steroid wean when the dose was titrated up to 6 mg/kg daily. However, anakinra did not prevent the escalation of proteinuria following a URI. After the treatment was changed to adalimumab, a fully humanized monoclonal antibody to TNF-α, the patient continued to improve and reach full remission despite experiencing a cold and the flu in the following months.
Literature Review
There is a paucity of literature on applications of biological response modifiers for idiopathic NS and FSGS.23,24 Angeletti and colleagues reported that 3 patients with severe long-standing FSGS benefited from anakinra 4 mg/kg daily to reduce proteinuria and improve kidney function. All the patients had positive C3 staining in renal biopsy and treatment response, which supported the role of C3a in inducing podocyte injury through upregulated expression of IL-1 and IL-1R.23 Trachtman and colleagues reported on the phase II FONT trial that included 14 of 21 patients aged < 18 years with advanced FSGS who were treated with adalimumab 24 mg/m2, or ≤ 40 mg every other week.24 Although, during a 6-month period, none of the 7 patients met the endpoint of reduced proteinuria by ≥ 50%, and the authors suggested that careful patient selection may improve the treatment response in future trials.24
A recent study involving transcriptomics on renal tissue samples combined with available pathology (fibrosis), urinary markers, and clinical characteristics on 285 patients with MCD or FSGS from 3 different continents identified 3 distinct clusters. Patients with evidence of activated kidney TNF pathway (n = 72, aged > 18 years) were found to have poor clinical outcomes.25 The study identified 2 urine markers associated with the TNF pathway (ie, tissue inhibitor of metalloproteinases-1 and monocyte chemoattractant protein-1), which aligns with the preclinical findings previously mentioned.25
Conclusions
The patient’s condition in this case illustrates the complex nature of biologically predetermined cascading events in the emergence of glomerular disease upon environmental triggers under the influence of genetic factors.
Chronic kidney disease affects 7.7% of veterans annually, illustrating the need for new therapeutics.26 Based on our experience and literature review, upregulation of TNF-α is a root cause of glomerulopathy; further studies are warranted to evaluate the efficacy of anti-TNF biologic response modifiers for the treatment of these patients. Long-term postmarketing safety profile and steroid-sparing properties of adalimumab should allow inclusion of pediatric cases in future trials. Results may also contribute to identifying new predictive biomarkers related to the basement membrane when combined with precision nephrology to further advance patient selection and targeted treatment.25,27
Acknowledgments
The authors thank the patient’s mother for providing consent to allow publication of this case report.
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2. Garg PA. Review of podocyte biology. Am J Nephrol. 2018;47(suppl 1):3-13. doi:10.1159/000481633SUPPL
3. Warady BA, Agarwal R, Bangalore S, et al. Alport syndrome classification and management. Kidney Med. 2020;2(5):639-649. doi:10.1016/j.xkme.2020.05.014
4. Angioi A, Pani A. FSGS: from pathogenesis to the histological lesion. J Nephrol. 2016;29(4):517-523. doi:10.1007/s40620-016-0333-2
5. Roca N, Martinez C, Jatem E, Madrid A, Lopez M, Segarra A. Activation of the acute inflammatory phase response in idiopathic nephrotic syndrome: association with clinicopathological phenotypes and with response to corticosteroids. Clin Kidney J. 2021;14(4):1207-1215. doi:10.1093/ckj/sfaa247
6. Vivarelli M, Massella L, Ruggiero B, Emma F. Minimal change disease. Clin J Am Soc Nephrol. 2017;12(2):332-345.
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8. Ye Q, Lan B, Liu H, Persson PB, Lai EY, Mao J. A critical role of the podocyte cytoskeleton in the pathogenesis of glomerular proteinuria and autoimmune podocytopathies. Acta Physiol (Oxf). 2022;235(4):e13850. doi:10.1111/apha.13850
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10. Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol. 2021;36(3):711-719. doi:10.1007/s00467-020-04819-6
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12. Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2017; 12(3):502-517. doi:10.2215/CJN.05960616
13. Savige J. Should we diagnose autosomal dominant Alport syndrome when there is a pathogenic heterozygous COL4A3 or COL4A4 variant? Kidney Int Rep. 2018;3(6):1239-1241. doi:10.1016/j.ekir.2018.08.002
14. Gigante M, Caridi G, Montemurno E, et al. TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype. Clin J Am Soc Nephrol. 2011;6(7):1626-1634. doi:10.2215/CJN.07830910
15. Saurus P, Kuusela S, Lehtonen E, et al. Podocyte apoptosis is prevented by blocking the toll-like receptor pathway. Cell Death Dis. 2015;6(5):e1752. doi:10.1038/cddis.2015.125
16. Baud L, Oudinet JP, Bens M, et al. Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 1989;35(5):1111-1118. doi:10.1038/ki.1989.98
17. White S, Lin L, Hu K. NF-κB and tPA signaling in kidney and other diseases. Cells. 2020;9(6):1348. doi:10.3390/cells9061348
18. Tesch GH, Lan HY, Atkins RC, Nikolic-Paterson DJ. Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis. Am J Pathol. 1997;151(1):141-150.
19. Lai KN, Leung JCK, Chan LYY, et al. Podocyte injury induced by mesangial-derived cytokines in IgA Nephropathy. Nephrol Dial Transplant. 2009;24(1):62-72. doi:10.1093/ndt/gfn441
20. Saleem MA, Kobayashi Y. Cell biology and genetics of minimal change disease. F1000 Res. 2016;5: F1000 Faculty Rev-412. doi:10.12688/f1000research.7300.1
21. Kim KP, Williams CE, Lemmon CA. Cell-matrix interactions in renal fibrosis. Kidney Dial. 2022;2(4):607-624. doi:10.3390/kidneydial2040055
22. Zvaifler NJ. Relevance of the stroma and epithelial-mesenchymal transition (EMT) for the rheumatic diseases. Arthritis Res Ther. 2006;8(3):210. doi:10.1186/ar1963
23. Angeletti A, Magnasco A, Trivelli A, et al. Refractory minimal change disease and focal segmental glomerular sclerosis treated with Anakinra. Kidney Int Rep. 2021;7(1):121-124. doi:10.1016/j.ekir.2021.10.018
24. Trachtman H, Vento S, Herreshoff E, et al. Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group. BMC Nephrol. 2015;16:111. doi:10.1186/s12882-015-0094-5
25. Mariani LH, Eddy S, AlAkwaa FM, et al. Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis. Kidney Int. 2023;103(3):565-579. doi:10.1016/j.kint.2022.10.023
26. Korshak L, Washington DL, Powell J, Nylen E, Kokkinos P. Kidney Disease in Veterans. US Dept of Veterans Affairs, Office of Health Equity. Updated May 13, 2020. Accessed June 28, 2024. https://www.va.gov/HEALTHEQUITY/Kidney_Disease_In_Veterans.asp
27. Malone AF, Phelan PJ, Hall G, et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 2014;86(6):1253-1259. doi:10.1038/ki.2014.305
Podocytes are terminally differentiated, highly specialized cells located in juxtaposition to the basement membrane over the abluminal surfaces of endothelial cells within the glomerular tuft. This triad structure is the site of the filtration barrier, which forms highly delicate and tightly regulated architecture to carry out the ultrafiltration function of the kidney.1 The filtration barrier is characterized by foot processes that are connected by specialized junctions called slit diaphragms.
Insults to components of the filtration barrier can initiate cascading events and perpetuate structural alterations that may eventually result in sclerotic changes.2 Common causes among children include minimal change disease (MCD) with the collapse of foot processes resulting in proteinuria, Alport syndrome due to mutation of collagen fibers within the basement membrane leading to hematuria and proteinuria, immune complex mediated nephropathy following common infections or autoimmune diseases, and focal segmental glomerulosclerosis (FSGS) that can show variable histopathology toward eventual glomerular scarring.3,4 These children often clinically have minimal, if any, signs of systemic inflammation.3-5 This has been a limiting factor for the commitment to immunomodulatory treatment, except for steroids for the treatment of MCD.6 Although prolonged steroid treatment may be efficacious, adverse effects are significant in a growing child. Alternative treatments, such as tacrolimus and rituximab have been suggested as second-line steroid-sparing agents.7,8 Not uncommonly, however, these cases are managed by supportive measures only during the progression of the natural course of the disease, which may eventually lead to renal failure, requiring transplant for survival.8,9
This case report highlights a child with a variant of uncertain significance (VUS) in genes involved in Alport syndrome and FSGS who developed an abrupt onset of proteinuria and hematuria after a respiratory illness. To our knowledge, he represents the youngest case demonstrating the benefit of targeted treatment against tumor necrosis factor-α (TNF-α) for glomerulopathy using biologic response modifiers.
Case Description
This is currently a 7-year-old male patient who was born at 39 weeks gestation to gravida 3 para 3 following induced labor due to elevated maternal blood pressure. During the first 2 years of life, his growth and development were normal and his immunizations were up to date. The patient's medical history included upper respiratory tract infections (URIs), respiratory syncytial virus, as well as 3 bouts of pneumonia and multiple otitis media that resulted in 18 rounds of antibiotics. The child was also allergic to nuts and milk protein. The patient’s parents are of Northern European and Native American descent. There is no known family history of eye, ear, or kidney diseases.
Renal concerns were first noted at the age of 2 years and 6 months when he presented to an emergency department in Fall 2019 (week 0) for several weeks of intermittent dark-colored urine. His mother reported that the discoloration recently progressed in intensity to cola-colored, along with the onset of persistent vomiting without any fever or diarrhea. On physical examination, the patient had normal vitals: weight 14.8 kg (68th percentile), height 91 cm (24th percentile), and body surface area 0.6 m2. There was no edema, rash, or lymphadenopathy, but he appeared pale.
The patient’s initial laboratory results included: complete blood count with white blood cells (WBC) 10 x 103/L (reference range, 4.5-13.5 x 103/L); differential lymphocytes 69%; neutrophils 21%; hemoglobin 10 g/dL (reference range, 12-16 g/dL); hematocrit, 30%; (reference range, 37%-45%); platelets 437 103/L (reference range, 150-450 x 103/L); serum creatinine 0.46 mg/dL (reference range, 0.5-0.9 mg/dL); and albumin 3.1 g/dL (reference range, 3.5-5.2 g/dL). Serum electrolyte levels and liver enzymes were normal. A urine analysis revealed 3+ protein and 3+ blood with dysmorphic red blood cells (RBC) and RBC casts without WBC. The patient's spot urine protein-to-creatinine ratio was 4.3 and his renal ultrasound was normal. The patient was referred to Nephrology.
During the next 2 weeks, his protein-to-creatinine ratio progressed to 5.9 and serum albumin fell to 2.7 g/dL. His urine remained red colored, and a microscopic examination with RBC > 500 and WBC up to 10 on a high powered field. His workup was negative for antinuclear antibodies, antineutrophil cytoplasmic antibody, antistreptolysin-O (ASO) and anti-DNase B. Serum C3 was low at 81 mg/dL (reference range, 90-180 mg/dL), C4 was 13.3 mg/dL (reference range, 10-40 mg/dL), and immunoglobulin G was low at 452 mg/dL (reference range 719-1475 mg/dL). A baseline audiology test revealed normal hearing.
Percutaneous renal biopsy yielded about 12 glomeruli, all exhibiting mild mesangial matrix expansion and hypercellularity (Figure 1). One glomerulus had prominent parietal epithelial cells without endocapillary hypercellularity or crescent formation. There was no interstitial fibrosis or tubular atrophy. Immunofluorescence studies showed no evidence of immune complex deposition with negative staining for immunoglobulin heavy and light chains, C3 and C1q. Staining for α 2 and α 5 units of collagen was normal. Electron microscopy showed patchy areas of severe basement membrane thinning with frequent foci of mild to moderate lamina densa splitting and associated visceral epithelial cell foot process effacement (Figure 2).
These were reported as concerning findings for possible Alport syndrome by 3 independent pathology teams. The genetic testing was submitted at a commercial laboratory to screen 17 mutations, including COL4A3, COL4A4, and COL4A5. Results showed the presence of a heterozygous VUS in the COL4A4 gene (c.1055C > T; p.Pro352Leu; dbSNP ID: rs371717486; PolyPhen-2: Probably Damaging; SIFT: Deleterious) as well as the presence of a heterozygous VUS in TRPC6 gene (c2463A>T; p.Lys821Asn; dbSNP ID: rs199948731; PolyPhen-2: Benign; SIFT: Tolerated). Further genetic investigation by whole exome sequencing on approximately 20,000 genes through MNG Laboratories showed a new heterozygous VUS in the OSGEP gene [c.328T>C; p.Cys110Arg]. Additional studies ruled out mitochondrial disease, CoQ10 deficiency, and metabolic disorders upon normal findings for mitochondrial DNA, urine amino acids, plasma acylcarnitine profile, orotic acid, ammonia, and homocysteine levels.
Figure 3 summarizes the patient’s treatment response during 170 weeks of follow-up (Fall 2019 to Summer 2023). The patient was started on enalapril 0.6 mg/kg daily at week 3, which continued throughout treatment. Following a rheumatology consult at week 30, the patient was started on prednisolone 3 mg/mL to assess the role of inflammation through the treatment response. An initial dose of 2 mg/kg daily (9 mL) for 1 month was followed by every other day treatment that was tapered off by week 48. To control mild but noticeably increasing proteinuria in the interim, subcutaneous anakinra 50 mg (3 mg/kg daily) was added as a steroid
DISCUSSION
This case describes a child with rapidly progressive proteinuria and hematuria following a URI who was found to have VUS mutations in 3 different genes associated with chronic kidney disease. Serology tests on the patient were negative for streptococcal antibodies and antinuclear antibodies, ruling out poststreptococcal glomerulonephritis, or systemic lupus erythematosus. His renal biopsy findings were concerning for altered podocytes, mesangial cells, and basement membrane without inflammatory infiltrate, immune complex, complements, immunoglobulin A, or vasculopathy. His blood inflammatory markers, erythrocyte sedimentation rate, C-reactive protein, and ferritin were normal when his care team initiated daily steroids.
Overall, the patient’s clinical presentation and histopathology findings were suggestive of Alport syndrome or thin basement membrane nephropathy with a high potential to progress into FSGS.10-12 Alport syndrome affects 1 in 5000 to 10,000 children annually due to S-linked inheritance of COL4A5, or autosomal recessive inheritance of COL4A3 or COL4A4 genes. It presents with hematuria and hearing loss.10 Our patient had a single copy COL4A4 gene mutation that was classified as VUS. He also had 2 additional VUS affecting the TRPC6 and OSGEP genes. TRPC6 gene mutation can be associated with FSGS through autosomal dominant inheritance. Both COL4A4 and TRPC6 gene mutations were paternally inherited. Although the patient’s father not having renal disease argues against the clinical significance of these findings, there is literature on the potential role of heterozygous COL4A4 variant mimicking thin basement membrane nephropathy that can lead to renal impairment upon copresence of superimposed conditions.13 The patient’s rapidly progressing hematuria and changes in the basement membrane were worrisome for emerging FSGS. Furthermore, VUS of TRPC6 has been reported in late onset autosomal dominant FSGS and can be associated with early onset steroid-resistant nephrotic syndrome (NS) in children.14 This concern was voiced by 3 nephrology consultants during the initial evaluation, leading to the consensus that steroid treatment for podocytopathy would not alter the patient’s long-term outcomes (ie, progression to FSGS).
Immunomodulation
Our rationale for immunomodulatory treatment was based on the abrupt onset of renal concerns following a URI, suggesting the importance of an inflammatory trigger causing altered homeostasis in a genetically susceptible host. Preclinical models show that microbial products such as lipopolysaccharides can lead to podocytopathy by several mechanisms through activation of toll-like receptor signaling. It can directly cause apoptosis by downregulation of the intracellular Akt survival pathway.15 Lipopolysaccharide can also activate the NF-αB pathway and upregulate the production of interleukin-1 (IL-1) and TNF-α in mesangial cells.16,17
Both cytokines can promote mesangial cell proliferation.18 Through autocrine and paracrine mechanisms, proinflammatory cytokines can further perpetuate somatic tissue changes and contribute to the development of podocytopathy. For instance, TNF-α can promote podocyte injury and proteinuria by downregulation of the slit diaphragm protein expression (ie, nephrin, ezrin, or podocin), and disruption of podocyte cytoskeleton.19,20 TNF-α promotes the influx and activation of macrophages and inflammatory cells. It is actively involved in chronic alterations within the glomeruli by the upregulation of matrix metalloproteases by integrins, as well as activation of myofibroblast progenitors and extracellular matrix deposition in crosstalk with transforming growth factor and other key mediators.17,21,22
For the patient described in this case report, initial improvement on steroids encouraged the pursuit of additional treatment to downregulate inflammatory pathways within the glomerular milieu. However, within the COVID-19 environment, escalating the patient’s treatment using traditional immunomodulators (ie, calcineurin inhibitors or mycophenolate mofetil) was not favored due to the risk of infection. Initially, anakinra, a recombinant IL-1 receptor antagonist, was preferred as a steroid-sparing agent for its short life and safety profile during the pandemic. At first, the patient responded well to anakinra and was allowed a steroid wean when the dose was titrated up to 6 mg/kg daily. However, anakinra did not prevent the escalation of proteinuria following a URI. After the treatment was changed to adalimumab, a fully humanized monoclonal antibody to TNF-α, the patient continued to improve and reach full remission despite experiencing a cold and the flu in the following months.
Literature Review
There is a paucity of literature on applications of biological response modifiers for idiopathic NS and FSGS.23,24 Angeletti and colleagues reported that 3 patients with severe long-standing FSGS benefited from anakinra 4 mg/kg daily to reduce proteinuria and improve kidney function. All the patients had positive C3 staining in renal biopsy and treatment response, which supported the role of C3a in inducing podocyte injury through upregulated expression of IL-1 and IL-1R.23 Trachtman and colleagues reported on the phase II FONT trial that included 14 of 21 patients aged < 18 years with advanced FSGS who were treated with adalimumab 24 mg/m2, or ≤ 40 mg every other week.24 Although, during a 6-month period, none of the 7 patients met the endpoint of reduced proteinuria by ≥ 50%, and the authors suggested that careful patient selection may improve the treatment response in future trials.24
A recent study involving transcriptomics on renal tissue samples combined with available pathology (fibrosis), urinary markers, and clinical characteristics on 285 patients with MCD or FSGS from 3 different continents identified 3 distinct clusters. Patients with evidence of activated kidney TNF pathway (n = 72, aged > 18 years) were found to have poor clinical outcomes.25 The study identified 2 urine markers associated with the TNF pathway (ie, tissue inhibitor of metalloproteinases-1 and monocyte chemoattractant protein-1), which aligns with the preclinical findings previously mentioned.25
Conclusions
The patient’s condition in this case illustrates the complex nature of biologically predetermined cascading events in the emergence of glomerular disease upon environmental triggers under the influence of genetic factors.
Chronic kidney disease affects 7.7% of veterans annually, illustrating the need for new therapeutics.26 Based on our experience and literature review, upregulation of TNF-α is a root cause of glomerulopathy; further studies are warranted to evaluate the efficacy of anti-TNF biologic response modifiers for the treatment of these patients. Long-term postmarketing safety profile and steroid-sparing properties of adalimumab should allow inclusion of pediatric cases in future trials. Results may also contribute to identifying new predictive biomarkers related to the basement membrane when combined with precision nephrology to further advance patient selection and targeted treatment.25,27
Acknowledgments
The authors thank the patient’s mother for providing consent to allow publication of this case report.
Podocytes are terminally differentiated, highly specialized cells located in juxtaposition to the basement membrane over the abluminal surfaces of endothelial cells within the glomerular tuft. This triad structure is the site of the filtration barrier, which forms highly delicate and tightly regulated architecture to carry out the ultrafiltration function of the kidney.1 The filtration barrier is characterized by foot processes that are connected by specialized junctions called slit diaphragms.
Insults to components of the filtration barrier can initiate cascading events and perpetuate structural alterations that may eventually result in sclerotic changes.2 Common causes among children include minimal change disease (MCD) with the collapse of foot processes resulting in proteinuria, Alport syndrome due to mutation of collagen fibers within the basement membrane leading to hematuria and proteinuria, immune complex mediated nephropathy following common infections or autoimmune diseases, and focal segmental glomerulosclerosis (FSGS) that can show variable histopathology toward eventual glomerular scarring.3,4 These children often clinically have minimal, if any, signs of systemic inflammation.3-5 This has been a limiting factor for the commitment to immunomodulatory treatment, except for steroids for the treatment of MCD.6 Although prolonged steroid treatment may be efficacious, adverse effects are significant in a growing child. Alternative treatments, such as tacrolimus and rituximab have been suggested as second-line steroid-sparing agents.7,8 Not uncommonly, however, these cases are managed by supportive measures only during the progression of the natural course of the disease, which may eventually lead to renal failure, requiring transplant for survival.8,9
This case report highlights a child with a variant of uncertain significance (VUS) in genes involved in Alport syndrome and FSGS who developed an abrupt onset of proteinuria and hematuria after a respiratory illness. To our knowledge, he represents the youngest case demonstrating the benefit of targeted treatment against tumor necrosis factor-α (TNF-α) for glomerulopathy using biologic response modifiers.
Case Description
This is currently a 7-year-old male patient who was born at 39 weeks gestation to gravida 3 para 3 following induced labor due to elevated maternal blood pressure. During the first 2 years of life, his growth and development were normal and his immunizations were up to date. The patient's medical history included upper respiratory tract infections (URIs), respiratory syncytial virus, as well as 3 bouts of pneumonia and multiple otitis media that resulted in 18 rounds of antibiotics. The child was also allergic to nuts and milk protein. The patient’s parents are of Northern European and Native American descent. There is no known family history of eye, ear, or kidney diseases.
Renal concerns were first noted at the age of 2 years and 6 months when he presented to an emergency department in Fall 2019 (week 0) for several weeks of intermittent dark-colored urine. His mother reported that the discoloration recently progressed in intensity to cola-colored, along with the onset of persistent vomiting without any fever or diarrhea. On physical examination, the patient had normal vitals: weight 14.8 kg (68th percentile), height 91 cm (24th percentile), and body surface area 0.6 m2. There was no edema, rash, or lymphadenopathy, but he appeared pale.
The patient’s initial laboratory results included: complete blood count with white blood cells (WBC) 10 x 103/L (reference range, 4.5-13.5 x 103/L); differential lymphocytes 69%; neutrophils 21%; hemoglobin 10 g/dL (reference range, 12-16 g/dL); hematocrit, 30%; (reference range, 37%-45%); platelets 437 103/L (reference range, 150-450 x 103/L); serum creatinine 0.46 mg/dL (reference range, 0.5-0.9 mg/dL); and albumin 3.1 g/dL (reference range, 3.5-5.2 g/dL). Serum electrolyte levels and liver enzymes were normal. A urine analysis revealed 3+ protein and 3+ blood with dysmorphic red blood cells (RBC) and RBC casts without WBC. The patient's spot urine protein-to-creatinine ratio was 4.3 and his renal ultrasound was normal. The patient was referred to Nephrology.
During the next 2 weeks, his protein-to-creatinine ratio progressed to 5.9 and serum albumin fell to 2.7 g/dL. His urine remained red colored, and a microscopic examination with RBC > 500 and WBC up to 10 on a high powered field. His workup was negative for antinuclear antibodies, antineutrophil cytoplasmic antibody, antistreptolysin-O (ASO) and anti-DNase B. Serum C3 was low at 81 mg/dL (reference range, 90-180 mg/dL), C4 was 13.3 mg/dL (reference range, 10-40 mg/dL), and immunoglobulin G was low at 452 mg/dL (reference range 719-1475 mg/dL). A baseline audiology test revealed normal hearing.
Percutaneous renal biopsy yielded about 12 glomeruli, all exhibiting mild mesangial matrix expansion and hypercellularity (Figure 1). One glomerulus had prominent parietal epithelial cells without endocapillary hypercellularity or crescent formation. There was no interstitial fibrosis or tubular atrophy. Immunofluorescence studies showed no evidence of immune complex deposition with negative staining for immunoglobulin heavy and light chains, C3 and C1q. Staining for α 2 and α 5 units of collagen was normal. Electron microscopy showed patchy areas of severe basement membrane thinning with frequent foci of mild to moderate lamina densa splitting and associated visceral epithelial cell foot process effacement (Figure 2).
These were reported as concerning findings for possible Alport syndrome by 3 independent pathology teams. The genetic testing was submitted at a commercial laboratory to screen 17 mutations, including COL4A3, COL4A4, and COL4A5. Results showed the presence of a heterozygous VUS in the COL4A4 gene (c.1055C > T; p.Pro352Leu; dbSNP ID: rs371717486; PolyPhen-2: Probably Damaging; SIFT: Deleterious) as well as the presence of a heterozygous VUS in TRPC6 gene (c2463A>T; p.Lys821Asn; dbSNP ID: rs199948731; PolyPhen-2: Benign; SIFT: Tolerated). Further genetic investigation by whole exome sequencing on approximately 20,000 genes through MNG Laboratories showed a new heterozygous VUS in the OSGEP gene [c.328T>C; p.Cys110Arg]. Additional studies ruled out mitochondrial disease, CoQ10 deficiency, and metabolic disorders upon normal findings for mitochondrial DNA, urine amino acids, plasma acylcarnitine profile, orotic acid, ammonia, and homocysteine levels.
Figure 3 summarizes the patient’s treatment response during 170 weeks of follow-up (Fall 2019 to Summer 2023). The patient was started on enalapril 0.6 mg/kg daily at week 3, which continued throughout treatment. Following a rheumatology consult at week 30, the patient was started on prednisolone 3 mg/mL to assess the role of inflammation through the treatment response. An initial dose of 2 mg/kg daily (9 mL) for 1 month was followed by every other day treatment that was tapered off by week 48. To control mild but noticeably increasing proteinuria in the interim, subcutaneous anakinra 50 mg (3 mg/kg daily) was added as a steroid
DISCUSSION
This case describes a child with rapidly progressive proteinuria and hematuria following a URI who was found to have VUS mutations in 3 different genes associated with chronic kidney disease. Serology tests on the patient were negative for streptococcal antibodies and antinuclear antibodies, ruling out poststreptococcal glomerulonephritis, or systemic lupus erythematosus. His renal biopsy findings were concerning for altered podocytes, mesangial cells, and basement membrane without inflammatory infiltrate, immune complex, complements, immunoglobulin A, or vasculopathy. His blood inflammatory markers, erythrocyte sedimentation rate, C-reactive protein, and ferritin were normal when his care team initiated daily steroids.
Overall, the patient’s clinical presentation and histopathology findings were suggestive of Alport syndrome or thin basement membrane nephropathy with a high potential to progress into FSGS.10-12 Alport syndrome affects 1 in 5000 to 10,000 children annually due to S-linked inheritance of COL4A5, or autosomal recessive inheritance of COL4A3 or COL4A4 genes. It presents with hematuria and hearing loss.10 Our patient had a single copy COL4A4 gene mutation that was classified as VUS. He also had 2 additional VUS affecting the TRPC6 and OSGEP genes. TRPC6 gene mutation can be associated with FSGS through autosomal dominant inheritance. Both COL4A4 and TRPC6 gene mutations were paternally inherited. Although the patient’s father not having renal disease argues against the clinical significance of these findings, there is literature on the potential role of heterozygous COL4A4 variant mimicking thin basement membrane nephropathy that can lead to renal impairment upon copresence of superimposed conditions.13 The patient’s rapidly progressing hematuria and changes in the basement membrane were worrisome for emerging FSGS. Furthermore, VUS of TRPC6 has been reported in late onset autosomal dominant FSGS and can be associated with early onset steroid-resistant nephrotic syndrome (NS) in children.14 This concern was voiced by 3 nephrology consultants during the initial evaluation, leading to the consensus that steroid treatment for podocytopathy would not alter the patient’s long-term outcomes (ie, progression to FSGS).
Immunomodulation
Our rationale for immunomodulatory treatment was based on the abrupt onset of renal concerns following a URI, suggesting the importance of an inflammatory trigger causing altered homeostasis in a genetically susceptible host. Preclinical models show that microbial products such as lipopolysaccharides can lead to podocytopathy by several mechanisms through activation of toll-like receptor signaling. It can directly cause apoptosis by downregulation of the intracellular Akt survival pathway.15 Lipopolysaccharide can also activate the NF-αB pathway and upregulate the production of interleukin-1 (IL-1) and TNF-α in mesangial cells.16,17
Both cytokines can promote mesangial cell proliferation.18 Through autocrine and paracrine mechanisms, proinflammatory cytokines can further perpetuate somatic tissue changes and contribute to the development of podocytopathy. For instance, TNF-α can promote podocyte injury and proteinuria by downregulation of the slit diaphragm protein expression (ie, nephrin, ezrin, or podocin), and disruption of podocyte cytoskeleton.19,20 TNF-α promotes the influx and activation of macrophages and inflammatory cells. It is actively involved in chronic alterations within the glomeruli by the upregulation of matrix metalloproteases by integrins, as well as activation of myofibroblast progenitors and extracellular matrix deposition in crosstalk with transforming growth factor and other key mediators.17,21,22
For the patient described in this case report, initial improvement on steroids encouraged the pursuit of additional treatment to downregulate inflammatory pathways within the glomerular milieu. However, within the COVID-19 environment, escalating the patient’s treatment using traditional immunomodulators (ie, calcineurin inhibitors or mycophenolate mofetil) was not favored due to the risk of infection. Initially, anakinra, a recombinant IL-1 receptor antagonist, was preferred as a steroid-sparing agent for its short life and safety profile during the pandemic. At first, the patient responded well to anakinra and was allowed a steroid wean when the dose was titrated up to 6 mg/kg daily. However, anakinra did not prevent the escalation of proteinuria following a URI. After the treatment was changed to adalimumab, a fully humanized monoclonal antibody to TNF-α, the patient continued to improve and reach full remission despite experiencing a cold and the flu in the following months.
Literature Review
There is a paucity of literature on applications of biological response modifiers for idiopathic NS and FSGS.23,24 Angeletti and colleagues reported that 3 patients with severe long-standing FSGS benefited from anakinra 4 mg/kg daily to reduce proteinuria and improve kidney function. All the patients had positive C3 staining in renal biopsy and treatment response, which supported the role of C3a in inducing podocyte injury through upregulated expression of IL-1 and IL-1R.23 Trachtman and colleagues reported on the phase II FONT trial that included 14 of 21 patients aged < 18 years with advanced FSGS who were treated with adalimumab 24 mg/m2, or ≤ 40 mg every other week.24 Although, during a 6-month period, none of the 7 patients met the endpoint of reduced proteinuria by ≥ 50%, and the authors suggested that careful patient selection may improve the treatment response in future trials.24
A recent study involving transcriptomics on renal tissue samples combined with available pathology (fibrosis), urinary markers, and clinical characteristics on 285 patients with MCD or FSGS from 3 different continents identified 3 distinct clusters. Patients with evidence of activated kidney TNF pathway (n = 72, aged > 18 years) were found to have poor clinical outcomes.25 The study identified 2 urine markers associated with the TNF pathway (ie, tissue inhibitor of metalloproteinases-1 and monocyte chemoattractant protein-1), which aligns with the preclinical findings previously mentioned.25
Conclusions
The patient’s condition in this case illustrates the complex nature of biologically predetermined cascading events in the emergence of glomerular disease upon environmental triggers under the influence of genetic factors.
Chronic kidney disease affects 7.7% of veterans annually, illustrating the need for new therapeutics.26 Based on our experience and literature review, upregulation of TNF-α is a root cause of glomerulopathy; further studies are warranted to evaluate the efficacy of anti-TNF biologic response modifiers for the treatment of these patients. Long-term postmarketing safety profile and steroid-sparing properties of adalimumab should allow inclusion of pediatric cases in future trials. Results may also contribute to identifying new predictive biomarkers related to the basement membrane when combined with precision nephrology to further advance patient selection and targeted treatment.25,27
Acknowledgments
The authors thank the patient’s mother for providing consent to allow publication of this case report.
1. Arif E, Nihalani D. Glomerular filtration barrier assembly: an insight. Postdoc J. 2013;1(4):33-45.
2. Garg PA. Review of podocyte biology. Am J Nephrol. 2018;47(suppl 1):3-13. doi:10.1159/000481633SUPPL
3. Warady BA, Agarwal R, Bangalore S, et al. Alport syndrome classification and management. Kidney Med. 2020;2(5):639-649. doi:10.1016/j.xkme.2020.05.014
4. Angioi A, Pani A. FSGS: from pathogenesis to the histological lesion. J Nephrol. 2016;29(4):517-523. doi:10.1007/s40620-016-0333-2
5. Roca N, Martinez C, Jatem E, Madrid A, Lopez M, Segarra A. Activation of the acute inflammatory phase response in idiopathic nephrotic syndrome: association with clinicopathological phenotypes and with response to corticosteroids. Clin Kidney J. 2021;14(4):1207-1215. doi:10.1093/ckj/sfaa247
6. Vivarelli M, Massella L, Ruggiero B, Emma F. Minimal change disease. Clin J Am Soc Nephrol. 2017;12(2):332-345.
7. Medjeral-Thomas NR, Lawrence C, Condon M, et al. Randomized, controlled trial of tacrolimus and prednisolone monotherapy for adults with De Novo minimal change disease: a multicenter, randomized, controlled trial. Clin J Am Soc Nephrol. 2020;15(2):209-218. doi:10.2215/CJN.06290420
8. Ye Q, Lan B, Liu H, Persson PB, Lai EY, Mao J. A critical role of the podocyte cytoskeleton in the pathogenesis of glomerular proteinuria and autoimmune podocytopathies. Acta Physiol (Oxf). 2022;235(4):e13850. doi:10.1111/apha.13850
9. Trautmann A, Schnaidt S, Lipska-Ziμtkiewicz BS, et al. Long-term outcome of steroid-resistant nephrotic syndrome in children. J Am Soc Nephrol. 2017;28:3055-3065. doi:10.1681/ASN.2016101121
10. Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol. 2021;36(3):711-719. doi:10.1007/s00467-020-04819-6
11. Savige J, Rana K, Tonna S, Buzza M, Dagher H, Wang YY. Thin basement membrane nephropathy. Kidney Int. 2003;64(4):1169-78. doi:10.1046/j.1523-1755.2003.00234.x
12. Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2017; 12(3):502-517. doi:10.2215/CJN.05960616
13. Savige J. Should we diagnose autosomal dominant Alport syndrome when there is a pathogenic heterozygous COL4A3 or COL4A4 variant? Kidney Int Rep. 2018;3(6):1239-1241. doi:10.1016/j.ekir.2018.08.002
14. Gigante M, Caridi G, Montemurno E, et al. TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype. Clin J Am Soc Nephrol. 2011;6(7):1626-1634. doi:10.2215/CJN.07830910
15. Saurus P, Kuusela S, Lehtonen E, et al. Podocyte apoptosis is prevented by blocking the toll-like receptor pathway. Cell Death Dis. 2015;6(5):e1752. doi:10.1038/cddis.2015.125
16. Baud L, Oudinet JP, Bens M, et al. Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 1989;35(5):1111-1118. doi:10.1038/ki.1989.98
17. White S, Lin L, Hu K. NF-κB and tPA signaling in kidney and other diseases. Cells. 2020;9(6):1348. doi:10.3390/cells9061348
18. Tesch GH, Lan HY, Atkins RC, Nikolic-Paterson DJ. Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis. Am J Pathol. 1997;151(1):141-150.
19. Lai KN, Leung JCK, Chan LYY, et al. Podocyte injury induced by mesangial-derived cytokines in IgA Nephropathy. Nephrol Dial Transplant. 2009;24(1):62-72. doi:10.1093/ndt/gfn441
20. Saleem MA, Kobayashi Y. Cell biology and genetics of minimal change disease. F1000 Res. 2016;5: F1000 Faculty Rev-412. doi:10.12688/f1000research.7300.1
21. Kim KP, Williams CE, Lemmon CA. Cell-matrix interactions in renal fibrosis. Kidney Dial. 2022;2(4):607-624. doi:10.3390/kidneydial2040055
22. Zvaifler NJ. Relevance of the stroma and epithelial-mesenchymal transition (EMT) for the rheumatic diseases. Arthritis Res Ther. 2006;8(3):210. doi:10.1186/ar1963
23. Angeletti A, Magnasco A, Trivelli A, et al. Refractory minimal change disease and focal segmental glomerular sclerosis treated with Anakinra. Kidney Int Rep. 2021;7(1):121-124. doi:10.1016/j.ekir.2021.10.018
24. Trachtman H, Vento S, Herreshoff E, et al. Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group. BMC Nephrol. 2015;16:111. doi:10.1186/s12882-015-0094-5
25. Mariani LH, Eddy S, AlAkwaa FM, et al. Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis. Kidney Int. 2023;103(3):565-579. doi:10.1016/j.kint.2022.10.023
26. Korshak L, Washington DL, Powell J, Nylen E, Kokkinos P. Kidney Disease in Veterans. US Dept of Veterans Affairs, Office of Health Equity. Updated May 13, 2020. Accessed June 28, 2024. https://www.va.gov/HEALTHEQUITY/Kidney_Disease_In_Veterans.asp
27. Malone AF, Phelan PJ, Hall G, et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 2014;86(6):1253-1259. doi:10.1038/ki.2014.305
1. Arif E, Nihalani D. Glomerular filtration barrier assembly: an insight. Postdoc J. 2013;1(4):33-45.
2. Garg PA. Review of podocyte biology. Am J Nephrol. 2018;47(suppl 1):3-13. doi:10.1159/000481633SUPPL
3. Warady BA, Agarwal R, Bangalore S, et al. Alport syndrome classification and management. Kidney Med. 2020;2(5):639-649. doi:10.1016/j.xkme.2020.05.014
4. Angioi A, Pani A. FSGS: from pathogenesis to the histological lesion. J Nephrol. 2016;29(4):517-523. doi:10.1007/s40620-016-0333-2
5. Roca N, Martinez C, Jatem E, Madrid A, Lopez M, Segarra A. Activation of the acute inflammatory phase response in idiopathic nephrotic syndrome: association with clinicopathological phenotypes and with response to corticosteroids. Clin Kidney J. 2021;14(4):1207-1215. doi:10.1093/ckj/sfaa247
6. Vivarelli M, Massella L, Ruggiero B, Emma F. Minimal change disease. Clin J Am Soc Nephrol. 2017;12(2):332-345.
7. Medjeral-Thomas NR, Lawrence C, Condon M, et al. Randomized, controlled trial of tacrolimus and prednisolone monotherapy for adults with De Novo minimal change disease: a multicenter, randomized, controlled trial. Clin J Am Soc Nephrol. 2020;15(2):209-218. doi:10.2215/CJN.06290420
8. Ye Q, Lan B, Liu H, Persson PB, Lai EY, Mao J. A critical role of the podocyte cytoskeleton in the pathogenesis of glomerular proteinuria and autoimmune podocytopathies. Acta Physiol (Oxf). 2022;235(4):e13850. doi:10.1111/apha.13850
9. Trautmann A, Schnaidt S, Lipska-Ziμtkiewicz BS, et al. Long-term outcome of steroid-resistant nephrotic syndrome in children. J Am Soc Nephrol. 2017;28:3055-3065. doi:10.1681/ASN.2016101121
10. Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol. 2021;36(3):711-719. doi:10.1007/s00467-020-04819-6
11. Savige J, Rana K, Tonna S, Buzza M, Dagher H, Wang YY. Thin basement membrane nephropathy. Kidney Int. 2003;64(4):1169-78. doi:10.1046/j.1523-1755.2003.00234.x
12. Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2017; 12(3):502-517. doi:10.2215/CJN.05960616
13. Savige J. Should we diagnose autosomal dominant Alport syndrome when there is a pathogenic heterozygous COL4A3 or COL4A4 variant? Kidney Int Rep. 2018;3(6):1239-1241. doi:10.1016/j.ekir.2018.08.002
14. Gigante M, Caridi G, Montemurno E, et al. TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype. Clin J Am Soc Nephrol. 2011;6(7):1626-1634. doi:10.2215/CJN.07830910
15. Saurus P, Kuusela S, Lehtonen E, et al. Podocyte apoptosis is prevented by blocking the toll-like receptor pathway. Cell Death Dis. 2015;6(5):e1752. doi:10.1038/cddis.2015.125
16. Baud L, Oudinet JP, Bens M, et al. Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 1989;35(5):1111-1118. doi:10.1038/ki.1989.98
17. White S, Lin L, Hu K. NF-κB and tPA signaling in kidney and other diseases. Cells. 2020;9(6):1348. doi:10.3390/cells9061348
18. Tesch GH, Lan HY, Atkins RC, Nikolic-Paterson DJ. Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis. Am J Pathol. 1997;151(1):141-150.
19. Lai KN, Leung JCK, Chan LYY, et al. Podocyte injury induced by mesangial-derived cytokines in IgA Nephropathy. Nephrol Dial Transplant. 2009;24(1):62-72. doi:10.1093/ndt/gfn441
20. Saleem MA, Kobayashi Y. Cell biology and genetics of minimal change disease. F1000 Res. 2016;5: F1000 Faculty Rev-412. doi:10.12688/f1000research.7300.1
21. Kim KP, Williams CE, Lemmon CA. Cell-matrix interactions in renal fibrosis. Kidney Dial. 2022;2(4):607-624. doi:10.3390/kidneydial2040055
22. Zvaifler NJ. Relevance of the stroma and epithelial-mesenchymal transition (EMT) for the rheumatic diseases. Arthritis Res Ther. 2006;8(3):210. doi:10.1186/ar1963
23. Angeletti A, Magnasco A, Trivelli A, et al. Refractory minimal change disease and focal segmental glomerular sclerosis treated with Anakinra. Kidney Int Rep. 2021;7(1):121-124. doi:10.1016/j.ekir.2021.10.018
24. Trachtman H, Vento S, Herreshoff E, et al. Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group. BMC Nephrol. 2015;16:111. doi:10.1186/s12882-015-0094-5
25. Mariani LH, Eddy S, AlAkwaa FM, et al. Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis. Kidney Int. 2023;103(3):565-579. doi:10.1016/j.kint.2022.10.023
26. Korshak L, Washington DL, Powell J, Nylen E, Kokkinos P. Kidney Disease in Veterans. US Dept of Veterans Affairs, Office of Health Equity. Updated May 13, 2020. Accessed June 28, 2024. https://www.va.gov/HEALTHEQUITY/Kidney_Disease_In_Veterans.asp
27. Malone AF, Phelan PJ, Hall G, et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 2014;86(6):1253-1259. doi:10.1038/ki.2014.305
Improving Colorectal Cancer Screening via Mailed Fecal Immunochemical Testing in a Veterans Affairs Health System
Colorectal cancer (CRC) is among the most common cancers and causes of cancer-related deaths in the United States.1 Reflective of a nationwide trend, CRC screening rates at the Veterans Affairs Connecticut Healthcare System (VACHS) decreased during the COVID-19 pandemic.2-5 Contributing factors to this decrease included cancellations of elective colonoscopies during the initial phase of the pandemic and concurrent turnover of endoscopists. In 2021, the US Preventive Services Task Force lowered the recommended initial CRC screening age from 50 years to 45 years, further increasing the backlog of unscreened patients.6
Fecal immunochemical testing (FIT) is a noninvasive screening method in which antibodies are used to detect hemoglobin in the stool. The sensitivity and specificity of 1-time FIT are 79% to 80% and 94%, respectively, for the detection of CRC, with sensitivity improving with successive testing.7,8 Annual FIT is recognized as a tier 1 preferred screening method by the US Multi-Society Task Force on Colorectal Cancer.7,9 Programs that mail FIT kits to eligible patients outside of physician visits have been successfully implemented in health care systems.10,11
The VACHS designed and implemented a mailed FIT program using existing infrastructure and staffing.
Program Description
A team of local stakeholders comprised of VACHS leadership, primary care, nursing, and gastroenterology staff, as well as representatives from laboratory, informatics, mail services, and group practice management, was established to execute the project. The team met monthly to plan the project.
The team developed a dataset consisting of patients aged 45 to 75 years who were at average risk for CRC and due for CRC screening. Patients were defined as due for CRC screening if they had not had a colonoscopy in the previous 9 years or a FIT or fecal occult blood test in the previous 11 months. Average risk for CRC was defined by excluding patients with associated diagnosis codes for CRC, colectomy, inflammatory bowel disease, and anemia. The program also excluded patients with diagnosis codes associated with dementia, deferring discussions about cancer screening to their primary care practitioners (PCPs). Patients with invalid mailing addresses were also excluded, as well as those whose PCPs had indicated in the electronic health record that the patient received CRC screening outside the US Department of Veterans Affairs (VA) system.
Letter Templates
Two patient letter electronic health record templates were developed. The first was a primer letter, which was mailed to patients 2 to 3 weeks before the mailed FIT kit as an introduction to the program.12 The purpose of the primer letter was to give advance notice to patients that they could expect a FIT kit to arrive in the mail. The goal was to prepare patients to complete FIT when the kit arrived and prompt them to call the VA to opt out of the mailed FIT program if they were up to date with CRC screening or if they had a condition which made them at high risk for CRC.
The second FIT letter arrived with the FIT kit, introduced FIT and described the importance of CRC screening. The letter detailed instructions for completing FIT and automatically created a FIT order. It also included a list of common conditions that may exclude patients, with a recommendation for patients to contact their medical team if they felt they were not candidates for FIT.
Staff Education
A previous VACHS pilot project demonstrated the success of a mailed FIT program to increase FIT use. Implemented as part of the pilot program, staff education consisted of a session for clinicians about the role of FIT in CRC screening and an all-staff education session. An additional education session about CRC and FIT for all staff was repeated with the program launch.
Program Launch
The mailed FIT program was introduced during a VACHS primary care all-staff meeting. After the meeting, each patient aligned care team (PACT) received an encrypted email that included a list of the patients on their team who were candidates for the program, a patient-facing FIT instruction sheet, detailed instructions on how to send the FIT primer letter, and a FIT package consisting of the labeled FIT kit, FIT letter, and patient instruction sheet. A reminder letter was sent to each patient 3 weeks after the FIT package was mailed. The patient lists were populated into a shared, encrypted Microsoft Teams folder that was edited in real time by PACT teams and viewed by VACHS leadership to track progress.
Program Metrics
At program launch, the VACHS had 4642 patients due for CRC screening who were eligible for the mailed FIT program. On March 7, 2023, the data consisting of FIT tests ordered between December 2022 and May 2023—3 months before and after the launch of the program—were reviewed and categorized. In the 3 months before program launch, 1528 FIT were ordered and 714 were returned (46.7%). In the 3 months after the launch of the program, 4383 FIT were ordered and 1712 were returned (39.1%) (Figure). Test orders increased 287% from the preintervention to the postintervention period. The mean (SD) number of monthly FIT tests prelaunch was 509 (32.7), which increased to 1461 (331.6) postlaunch.
At the VACHS, 61.4% of patients aged 45 to 75 years were up to date with CRC screening before the program launch. In the 3 months after program launch, the rate increased to 63.8% among patients aged 45 to 75 years, the highest rate in our Veterans Integrated Services Network and exceeding the VA national average CRC screening rate, according to unpublished VA Monthly Management Report data.
In the 3 months following the program launch, 139 FIT kits tested positive for potential CRC. Of these, 79 (56.8%) patients had completed a diagnostic colonoscopy. PACT PCPs and nurses received reports on patients with positive FIT tests and those with no colonoscopy scheduled or completed and were asked to follow up.
Discussion
Through a proactive, population-based CRC screening program centered on mailed FIT kits outside of the traditional patient visit, the VACHS increased the use of FIT and rates of CRC screening. The numbers of FIT kits ordered and completed substantially increased in the 3 months after program launch.
Compared to mailed FIT programs described in the literature that rely on centralized processes in that a separate team operates the mailed FIT program for the entire organization, this program used existing PACT infrastructure and staff.10,11 This strategy allowed VACHS to design and implement the program in several months. Not needing to hire new staff or create a central team for the sole purpose of implementing the program allowed us to save on any organizational funding and efforts that would have accompanied the additional staff. The program described in this article may be more attainable for primary care practices or smaller health systems that do not have the capacity for the creation of a centralized process.
Limitations
Although the total number of FIT completions substantially increased during the program, the rate of FIT completion during the mailed FIT program was lower than the rate of completion prior to program launch. This decreased rate of FIT kit completion may be related to separation from a patient visit and potential loss of real-time education with a clinician. The program’s decentralized design increased the existing workload for primary care staff, and as a result, consideration must be given to local staffing levels. Additionally, the report of eligible patients depended on diagnosis codes and may have captured patients with higher-than-average risk of CRC, such as patients with prior history of adenomatous polyps, family history of CRC, or other medical or genetic conditions. We attempted to mitigate this by including a list of conditions that would exclude patients from FIT eligibility in the FIT letter and giving them the option to opt out.
Conclusions
CRC screening rates improved following implementation of a primary care team-centered quality improvement process to proactively identify patients appropriate for FIT and mail them FIT kits. This project highlights that population-health interventions around CRC screening via use of FIT can be successful within a primary care patient-centered medical home model, considering the increases in both CRC screening rates and increase in FIT tests ordered.
1. American Cancer Society. Key statistics for colorectal cancer. Revised January 29, 2024. Accessed June 11, 2024. https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html
2. Chen RC, Haynes K, Du S, Barron J, Katz AJ. Association of cancer screening deficit in the United States with the COVID-19 pandemic. JAMA Oncol. 2021;7(6):878-884. doi:10.1001/jamaoncol.2021.0884
3. Mazidimoradi A, Tiznobaik A, Salehiniya H. Impact of the COVID-19 pandemic on colorectal cancer screening: a systematic review. J Gastrointest Cancer. 2022;53(3):730-744. doi:10.1007/s12029-021-00679-x
4. Adams MA, Kurlander JE, Gao Y, Yankey N, Saini SD. Impact of coronavirus disease 2019 on screening colonoscopy utilization in a large integrated health system. Gastroenterology. 2022;162(7):2098-2100.e2. doi:10.1053/j.gastro.2022.02.034
5. Sundaram S, Olson S, Sharma P, Rajendra S. A review of the impact of the COVID-19 pandemic on colorectal cancer screening: implications and solutions. Pathogens. 2021;10(11):558. doi:10.3390/pathogens10111508
6. US Preventive Services Task Force. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965-1977. doi:10.1001/jama.2021.6238
7. Robertson DJ, Lee JK, Boland CR, et al. Recommendations on fecal immunochemical testing to screen for colorectal neoplasia: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc. 2017;85(1):2-21.e3. doi:10.1016/j.gie.2016.09.025
8. Lee JK, Liles EG, Bent S, Levin TR, Corley DA. Accuracy of fecal immunochemical tests for colorectal cancer: systematic review and meta-analysis. Ann Intern Med. 2014;160(3):171. doi:10.7326/M13-1484
9. Rex DK, Boland CR, Dominitz JA, et al. Colorectal cancer screening: recommendations for physicians and patients from the U.S. Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2017;153(1):307-323. doi:10.1053/j.gastro.2017.05.013
10. Deeds SA, Moore CB, Gunnink EJ, et al. Implementation of a mailed faecal immunochemical test programme for colorectal cancer screening among veterans. BMJ Open Qual. 2022;11(4):e001927. doi:10.1136/bmjoq-2022-001927
11. Selby K, Jensen CD, Levin TR, et al. Program components and results from an organized colorectal cancer screening program using annual fecal immunochemical testing. Clin Gastroenterol Hepatol. 2022;20(1):145-152. doi:10.1016/j.cgh.2020.09.042
12. Deeds S, Liu T, Schuttner L, et al. A postcard primer prior to mailed fecal immunochemical test among veterans: a randomized controlled trial. J Gen Intern Med. 2023:38(14):3235-3241. doi:10.1007/s11606-023-08248-7
Colorectal cancer (CRC) is among the most common cancers and causes of cancer-related deaths in the United States.1 Reflective of a nationwide trend, CRC screening rates at the Veterans Affairs Connecticut Healthcare System (VACHS) decreased during the COVID-19 pandemic.2-5 Contributing factors to this decrease included cancellations of elective colonoscopies during the initial phase of the pandemic and concurrent turnover of endoscopists. In 2021, the US Preventive Services Task Force lowered the recommended initial CRC screening age from 50 years to 45 years, further increasing the backlog of unscreened patients.6
Fecal immunochemical testing (FIT) is a noninvasive screening method in which antibodies are used to detect hemoglobin in the stool. The sensitivity and specificity of 1-time FIT are 79% to 80% and 94%, respectively, for the detection of CRC, with sensitivity improving with successive testing.7,8 Annual FIT is recognized as a tier 1 preferred screening method by the US Multi-Society Task Force on Colorectal Cancer.7,9 Programs that mail FIT kits to eligible patients outside of physician visits have been successfully implemented in health care systems.10,11
The VACHS designed and implemented a mailed FIT program using existing infrastructure and staffing.
Program Description
A team of local stakeholders comprised of VACHS leadership, primary care, nursing, and gastroenterology staff, as well as representatives from laboratory, informatics, mail services, and group practice management, was established to execute the project. The team met monthly to plan the project.
The team developed a dataset consisting of patients aged 45 to 75 years who were at average risk for CRC and due for CRC screening. Patients were defined as due for CRC screening if they had not had a colonoscopy in the previous 9 years or a FIT or fecal occult blood test in the previous 11 months. Average risk for CRC was defined by excluding patients with associated diagnosis codes for CRC, colectomy, inflammatory bowel disease, and anemia. The program also excluded patients with diagnosis codes associated with dementia, deferring discussions about cancer screening to their primary care practitioners (PCPs). Patients with invalid mailing addresses were also excluded, as well as those whose PCPs had indicated in the electronic health record that the patient received CRC screening outside the US Department of Veterans Affairs (VA) system.
Letter Templates
Two patient letter electronic health record templates were developed. The first was a primer letter, which was mailed to patients 2 to 3 weeks before the mailed FIT kit as an introduction to the program.12 The purpose of the primer letter was to give advance notice to patients that they could expect a FIT kit to arrive in the mail. The goal was to prepare patients to complete FIT when the kit arrived and prompt them to call the VA to opt out of the mailed FIT program if they were up to date with CRC screening or if they had a condition which made them at high risk for CRC.
The second FIT letter arrived with the FIT kit, introduced FIT and described the importance of CRC screening. The letter detailed instructions for completing FIT and automatically created a FIT order. It also included a list of common conditions that may exclude patients, with a recommendation for patients to contact their medical team if they felt they were not candidates for FIT.
Staff Education
A previous VACHS pilot project demonstrated the success of a mailed FIT program to increase FIT use. Implemented as part of the pilot program, staff education consisted of a session for clinicians about the role of FIT in CRC screening and an all-staff education session. An additional education session about CRC and FIT for all staff was repeated with the program launch.
Program Launch
The mailed FIT program was introduced during a VACHS primary care all-staff meeting. After the meeting, each patient aligned care team (PACT) received an encrypted email that included a list of the patients on their team who were candidates for the program, a patient-facing FIT instruction sheet, detailed instructions on how to send the FIT primer letter, and a FIT package consisting of the labeled FIT kit, FIT letter, and patient instruction sheet. A reminder letter was sent to each patient 3 weeks after the FIT package was mailed. The patient lists were populated into a shared, encrypted Microsoft Teams folder that was edited in real time by PACT teams and viewed by VACHS leadership to track progress.
Program Metrics
At program launch, the VACHS had 4642 patients due for CRC screening who were eligible for the mailed FIT program. On March 7, 2023, the data consisting of FIT tests ordered between December 2022 and May 2023—3 months before and after the launch of the program—were reviewed and categorized. In the 3 months before program launch, 1528 FIT were ordered and 714 were returned (46.7%). In the 3 months after the launch of the program, 4383 FIT were ordered and 1712 were returned (39.1%) (Figure). Test orders increased 287% from the preintervention to the postintervention period. The mean (SD) number of monthly FIT tests prelaunch was 509 (32.7), which increased to 1461 (331.6) postlaunch.
At the VACHS, 61.4% of patients aged 45 to 75 years were up to date with CRC screening before the program launch. In the 3 months after program launch, the rate increased to 63.8% among patients aged 45 to 75 years, the highest rate in our Veterans Integrated Services Network and exceeding the VA national average CRC screening rate, according to unpublished VA Monthly Management Report data.
In the 3 months following the program launch, 139 FIT kits tested positive for potential CRC. Of these, 79 (56.8%) patients had completed a diagnostic colonoscopy. PACT PCPs and nurses received reports on patients with positive FIT tests and those with no colonoscopy scheduled or completed and were asked to follow up.
Discussion
Through a proactive, population-based CRC screening program centered on mailed FIT kits outside of the traditional patient visit, the VACHS increased the use of FIT and rates of CRC screening. The numbers of FIT kits ordered and completed substantially increased in the 3 months after program launch.
Compared to mailed FIT programs described in the literature that rely on centralized processes in that a separate team operates the mailed FIT program for the entire organization, this program used existing PACT infrastructure and staff.10,11 This strategy allowed VACHS to design and implement the program in several months. Not needing to hire new staff or create a central team for the sole purpose of implementing the program allowed us to save on any organizational funding and efforts that would have accompanied the additional staff. The program described in this article may be more attainable for primary care practices or smaller health systems that do not have the capacity for the creation of a centralized process.
Limitations
Although the total number of FIT completions substantially increased during the program, the rate of FIT completion during the mailed FIT program was lower than the rate of completion prior to program launch. This decreased rate of FIT kit completion may be related to separation from a patient visit and potential loss of real-time education with a clinician. The program’s decentralized design increased the existing workload for primary care staff, and as a result, consideration must be given to local staffing levels. Additionally, the report of eligible patients depended on diagnosis codes and may have captured patients with higher-than-average risk of CRC, such as patients with prior history of adenomatous polyps, family history of CRC, or other medical or genetic conditions. We attempted to mitigate this by including a list of conditions that would exclude patients from FIT eligibility in the FIT letter and giving them the option to opt out.
Conclusions
CRC screening rates improved following implementation of a primary care team-centered quality improvement process to proactively identify patients appropriate for FIT and mail them FIT kits. This project highlights that population-health interventions around CRC screening via use of FIT can be successful within a primary care patient-centered medical home model, considering the increases in both CRC screening rates and increase in FIT tests ordered.
Colorectal cancer (CRC) is among the most common cancers and causes of cancer-related deaths in the United States.1 Reflective of a nationwide trend, CRC screening rates at the Veterans Affairs Connecticut Healthcare System (VACHS) decreased during the COVID-19 pandemic.2-5 Contributing factors to this decrease included cancellations of elective colonoscopies during the initial phase of the pandemic and concurrent turnover of endoscopists. In 2021, the US Preventive Services Task Force lowered the recommended initial CRC screening age from 50 years to 45 years, further increasing the backlog of unscreened patients.6
Fecal immunochemical testing (FIT) is a noninvasive screening method in which antibodies are used to detect hemoglobin in the stool. The sensitivity and specificity of 1-time FIT are 79% to 80% and 94%, respectively, for the detection of CRC, with sensitivity improving with successive testing.7,8 Annual FIT is recognized as a tier 1 preferred screening method by the US Multi-Society Task Force on Colorectal Cancer.7,9 Programs that mail FIT kits to eligible patients outside of physician visits have been successfully implemented in health care systems.10,11
The VACHS designed and implemented a mailed FIT program using existing infrastructure and staffing.
Program Description
A team of local stakeholders comprised of VACHS leadership, primary care, nursing, and gastroenterology staff, as well as representatives from laboratory, informatics, mail services, and group practice management, was established to execute the project. The team met monthly to plan the project.
The team developed a dataset consisting of patients aged 45 to 75 years who were at average risk for CRC and due for CRC screening. Patients were defined as due for CRC screening if they had not had a colonoscopy in the previous 9 years or a FIT or fecal occult blood test in the previous 11 months. Average risk for CRC was defined by excluding patients with associated diagnosis codes for CRC, colectomy, inflammatory bowel disease, and anemia. The program also excluded patients with diagnosis codes associated with dementia, deferring discussions about cancer screening to their primary care practitioners (PCPs). Patients with invalid mailing addresses were also excluded, as well as those whose PCPs had indicated in the electronic health record that the patient received CRC screening outside the US Department of Veterans Affairs (VA) system.
Letter Templates
Two patient letter electronic health record templates were developed. The first was a primer letter, which was mailed to patients 2 to 3 weeks before the mailed FIT kit as an introduction to the program.12 The purpose of the primer letter was to give advance notice to patients that they could expect a FIT kit to arrive in the mail. The goal was to prepare patients to complete FIT when the kit arrived and prompt them to call the VA to opt out of the mailed FIT program if they were up to date with CRC screening or if they had a condition which made them at high risk for CRC.
The second FIT letter arrived with the FIT kit, introduced FIT and described the importance of CRC screening. The letter detailed instructions for completing FIT and automatically created a FIT order. It also included a list of common conditions that may exclude patients, with a recommendation for patients to contact their medical team if they felt they were not candidates for FIT.
Staff Education
A previous VACHS pilot project demonstrated the success of a mailed FIT program to increase FIT use. Implemented as part of the pilot program, staff education consisted of a session for clinicians about the role of FIT in CRC screening and an all-staff education session. An additional education session about CRC and FIT for all staff was repeated with the program launch.
Program Launch
The mailed FIT program was introduced during a VACHS primary care all-staff meeting. After the meeting, each patient aligned care team (PACT) received an encrypted email that included a list of the patients on their team who were candidates for the program, a patient-facing FIT instruction sheet, detailed instructions on how to send the FIT primer letter, and a FIT package consisting of the labeled FIT kit, FIT letter, and patient instruction sheet. A reminder letter was sent to each patient 3 weeks after the FIT package was mailed. The patient lists were populated into a shared, encrypted Microsoft Teams folder that was edited in real time by PACT teams and viewed by VACHS leadership to track progress.
Program Metrics
At program launch, the VACHS had 4642 patients due for CRC screening who were eligible for the mailed FIT program. On March 7, 2023, the data consisting of FIT tests ordered between December 2022 and May 2023—3 months before and after the launch of the program—were reviewed and categorized. In the 3 months before program launch, 1528 FIT were ordered and 714 were returned (46.7%). In the 3 months after the launch of the program, 4383 FIT were ordered and 1712 were returned (39.1%) (Figure). Test orders increased 287% from the preintervention to the postintervention period. The mean (SD) number of monthly FIT tests prelaunch was 509 (32.7), which increased to 1461 (331.6) postlaunch.
At the VACHS, 61.4% of patients aged 45 to 75 years were up to date with CRC screening before the program launch. In the 3 months after program launch, the rate increased to 63.8% among patients aged 45 to 75 years, the highest rate in our Veterans Integrated Services Network and exceeding the VA national average CRC screening rate, according to unpublished VA Monthly Management Report data.
In the 3 months following the program launch, 139 FIT kits tested positive for potential CRC. Of these, 79 (56.8%) patients had completed a diagnostic colonoscopy. PACT PCPs and nurses received reports on patients with positive FIT tests and those with no colonoscopy scheduled or completed and were asked to follow up.
Discussion
Through a proactive, population-based CRC screening program centered on mailed FIT kits outside of the traditional patient visit, the VACHS increased the use of FIT and rates of CRC screening. The numbers of FIT kits ordered and completed substantially increased in the 3 months after program launch.
Compared to mailed FIT programs described in the literature that rely on centralized processes in that a separate team operates the mailed FIT program for the entire organization, this program used existing PACT infrastructure and staff.10,11 This strategy allowed VACHS to design and implement the program in several months. Not needing to hire new staff or create a central team for the sole purpose of implementing the program allowed us to save on any organizational funding and efforts that would have accompanied the additional staff. The program described in this article may be more attainable for primary care practices or smaller health systems that do not have the capacity for the creation of a centralized process.
Limitations
Although the total number of FIT completions substantially increased during the program, the rate of FIT completion during the mailed FIT program was lower than the rate of completion prior to program launch. This decreased rate of FIT kit completion may be related to separation from a patient visit and potential loss of real-time education with a clinician. The program’s decentralized design increased the existing workload for primary care staff, and as a result, consideration must be given to local staffing levels. Additionally, the report of eligible patients depended on diagnosis codes and may have captured patients with higher-than-average risk of CRC, such as patients with prior history of adenomatous polyps, family history of CRC, or other medical or genetic conditions. We attempted to mitigate this by including a list of conditions that would exclude patients from FIT eligibility in the FIT letter and giving them the option to opt out.
Conclusions
CRC screening rates improved following implementation of a primary care team-centered quality improvement process to proactively identify patients appropriate for FIT and mail them FIT kits. This project highlights that population-health interventions around CRC screening via use of FIT can be successful within a primary care patient-centered medical home model, considering the increases in both CRC screening rates and increase in FIT tests ordered.
1. American Cancer Society. Key statistics for colorectal cancer. Revised January 29, 2024. Accessed June 11, 2024. https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html
2. Chen RC, Haynes K, Du S, Barron J, Katz AJ. Association of cancer screening deficit in the United States with the COVID-19 pandemic. JAMA Oncol. 2021;7(6):878-884. doi:10.1001/jamaoncol.2021.0884
3. Mazidimoradi A, Tiznobaik A, Salehiniya H. Impact of the COVID-19 pandemic on colorectal cancer screening: a systematic review. J Gastrointest Cancer. 2022;53(3):730-744. doi:10.1007/s12029-021-00679-x
4. Adams MA, Kurlander JE, Gao Y, Yankey N, Saini SD. Impact of coronavirus disease 2019 on screening colonoscopy utilization in a large integrated health system. Gastroenterology. 2022;162(7):2098-2100.e2. doi:10.1053/j.gastro.2022.02.034
5. Sundaram S, Olson S, Sharma P, Rajendra S. A review of the impact of the COVID-19 pandemic on colorectal cancer screening: implications and solutions. Pathogens. 2021;10(11):558. doi:10.3390/pathogens10111508
6. US Preventive Services Task Force. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965-1977. doi:10.1001/jama.2021.6238
7. Robertson DJ, Lee JK, Boland CR, et al. Recommendations on fecal immunochemical testing to screen for colorectal neoplasia: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc. 2017;85(1):2-21.e3. doi:10.1016/j.gie.2016.09.025
8. Lee JK, Liles EG, Bent S, Levin TR, Corley DA. Accuracy of fecal immunochemical tests for colorectal cancer: systematic review and meta-analysis. Ann Intern Med. 2014;160(3):171. doi:10.7326/M13-1484
9. Rex DK, Boland CR, Dominitz JA, et al. Colorectal cancer screening: recommendations for physicians and patients from the U.S. Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2017;153(1):307-323. doi:10.1053/j.gastro.2017.05.013
10. Deeds SA, Moore CB, Gunnink EJ, et al. Implementation of a mailed faecal immunochemical test programme for colorectal cancer screening among veterans. BMJ Open Qual. 2022;11(4):e001927. doi:10.1136/bmjoq-2022-001927
11. Selby K, Jensen CD, Levin TR, et al. Program components and results from an organized colorectal cancer screening program using annual fecal immunochemical testing. Clin Gastroenterol Hepatol. 2022;20(1):145-152. doi:10.1016/j.cgh.2020.09.042
12. Deeds S, Liu T, Schuttner L, et al. A postcard primer prior to mailed fecal immunochemical test among veterans: a randomized controlled trial. J Gen Intern Med. 2023:38(14):3235-3241. doi:10.1007/s11606-023-08248-7
1. American Cancer Society. Key statistics for colorectal cancer. Revised January 29, 2024. Accessed June 11, 2024. https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html
2. Chen RC, Haynes K, Du S, Barron J, Katz AJ. Association of cancer screening deficit in the United States with the COVID-19 pandemic. JAMA Oncol. 2021;7(6):878-884. doi:10.1001/jamaoncol.2021.0884
3. Mazidimoradi A, Tiznobaik A, Salehiniya H. Impact of the COVID-19 pandemic on colorectal cancer screening: a systematic review. J Gastrointest Cancer. 2022;53(3):730-744. doi:10.1007/s12029-021-00679-x
4. Adams MA, Kurlander JE, Gao Y, Yankey N, Saini SD. Impact of coronavirus disease 2019 on screening colonoscopy utilization in a large integrated health system. Gastroenterology. 2022;162(7):2098-2100.e2. doi:10.1053/j.gastro.2022.02.034
5. Sundaram S, Olson S, Sharma P, Rajendra S. A review of the impact of the COVID-19 pandemic on colorectal cancer screening: implications and solutions. Pathogens. 2021;10(11):558. doi:10.3390/pathogens10111508
6. US Preventive Services Task Force. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965-1977. doi:10.1001/jama.2021.6238
7. Robertson DJ, Lee JK, Boland CR, et al. Recommendations on fecal immunochemical testing to screen for colorectal neoplasia: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc. 2017;85(1):2-21.e3. doi:10.1016/j.gie.2016.09.025
8. Lee JK, Liles EG, Bent S, Levin TR, Corley DA. Accuracy of fecal immunochemical tests for colorectal cancer: systematic review and meta-analysis. Ann Intern Med. 2014;160(3):171. doi:10.7326/M13-1484
9. Rex DK, Boland CR, Dominitz JA, et al. Colorectal cancer screening: recommendations for physicians and patients from the U.S. Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2017;153(1):307-323. doi:10.1053/j.gastro.2017.05.013
10. Deeds SA, Moore CB, Gunnink EJ, et al. Implementation of a mailed faecal immunochemical test programme for colorectal cancer screening among veterans. BMJ Open Qual. 2022;11(4):e001927. doi:10.1136/bmjoq-2022-001927
11. Selby K, Jensen CD, Levin TR, et al. Program components and results from an organized colorectal cancer screening program using annual fecal immunochemical testing. Clin Gastroenterol Hepatol. 2022;20(1):145-152. doi:10.1016/j.cgh.2020.09.042
12. Deeds S, Liu T, Schuttner L, et al. A postcard primer prior to mailed fecal immunochemical test among veterans: a randomized controlled trial. J Gen Intern Med. 2023:38(14):3235-3241. doi:10.1007/s11606-023-08248-7
Follow our continuing CROI coverage
Keep up to date with the Conference on Retroviruses and Opportunistic Infections home page for the latest in ID Practitioner's continuing reporting from the CROI meeting and our follow-ups afterward. You can also check out our archival coverage from last year's meeting.
Keep up to date with the Conference on Retroviruses and Opportunistic Infections home page for the latest in ID Practitioner's continuing reporting from the CROI meeting and our follow-ups afterward. You can also check out our archival coverage from last year's meeting.
Keep up to date with the Conference on Retroviruses and Opportunistic Infections home page for the latest in ID Practitioner's continuing reporting from the CROI meeting and our follow-ups afterward. You can also check out our archival coverage from last year's meeting.
New SVS Task Force Explores Vascular Certification Program
The Society for Vascular Surgery (SVS) executive board has established a task force to explore developing a vascular certification program for inpatient and outpatient care settings.
Noting the shift in professional reimbursement from payment for volume to payment for quality, along with a surge in outpatient endovascular care, “The SVS executive board believes that it is a critical time for vascular surgery to set standards based on quality improvement, efficiency and appropriateness,” said Dr. R. Clement Darling III, SVS president.
Task force chair Dr. Tony Sidawy will oversee two subcommittees, one for inpatient and one for office-based endovascular care (OBEC). Dr. Krishna Jain has been appointed chair of the OBEC subcommittee. A chair for the inpatient subcommittee has yet to be named.
“Vascular surgeons represented by the SVS should take the lead in defining quality and value standards for vascular care before they are defined for us,” said Dr. Sidawy.
“Offering an SVS-led certification process will inspire the most appropriate, high-quality vascular care and optimal outcomes for all patients,” Dr. Jain added.
Many SVS members are pioneers in the design and delivery of care in office-based practice settings, and they have been fierce advocates for this effort, said Dr. Darling. “We have heard our members loud and clear. They want SVS to play a major role in shaping the future of the office-based endovascular center, setting the bar for appropriateness and quality and helping all practitioners achieve it.
“We feel that to provide the best vascular care in a data-driven, quality-based system, the SVS needs to be actively involved in this process," he added. "Vascular surgeons have a long history of making data-driven decisions about which patients need an intervention, and since we treat patients medically as well as by endovascular or open techniques, we have a unique perspective."
A data registry is a critical component and will be provided by the SVS Patient Safety Organization and Vascular Quality Initiative (SVS VQI). VQI registries are already used in more than 430 vascular care settings, ranging from academic to community practice. VQI data can be used to benchmark performance and improve the quality of vascular care.
“Given that the SVS VQI has already been adopted by all types of facilities, including OBECs and vein centers, the SVS VQI is well positioned to help assess and improve quality of care,” said Dr. Jens Eldrup-Jorgensen, SVS PSO medical director.
The process will include discussions and potential collaboration with partners such as the American College of Surgeons, the Outpatient Endovascular and Interventional Society and the Intersociety Accreditation Council, Dr. Darling said, as well as societies such as the American Venous Forum, the Society for Vascular Ultrasound, and the Society for Vascular Nursing.
If established, a pilot program would be launched in 2018 with a full launch planned in 2019.
The Society for Vascular Surgery (SVS) executive board has established a task force to explore developing a vascular certification program for inpatient and outpatient care settings.
Noting the shift in professional reimbursement from payment for volume to payment for quality, along with a surge in outpatient endovascular care, “The SVS executive board believes that it is a critical time for vascular surgery to set standards based on quality improvement, efficiency and appropriateness,” said Dr. R. Clement Darling III, SVS president.
Task force chair Dr. Tony Sidawy will oversee two subcommittees, one for inpatient and one for office-based endovascular care (OBEC). Dr. Krishna Jain has been appointed chair of the OBEC subcommittee. A chair for the inpatient subcommittee has yet to be named.
“Vascular surgeons represented by the SVS should take the lead in defining quality and value standards for vascular care before they are defined for us,” said Dr. Sidawy.
“Offering an SVS-led certification process will inspire the most appropriate, high-quality vascular care and optimal outcomes for all patients,” Dr. Jain added.
Many SVS members are pioneers in the design and delivery of care in office-based practice settings, and they have been fierce advocates for this effort, said Dr. Darling. “We have heard our members loud and clear. They want SVS to play a major role in shaping the future of the office-based endovascular center, setting the bar for appropriateness and quality and helping all practitioners achieve it.
“We feel that to provide the best vascular care in a data-driven, quality-based system, the SVS needs to be actively involved in this process," he added. "Vascular surgeons have a long history of making data-driven decisions about which patients need an intervention, and since we treat patients medically as well as by endovascular or open techniques, we have a unique perspective."
A data registry is a critical component and will be provided by the SVS Patient Safety Organization and Vascular Quality Initiative (SVS VQI). VQI registries are already used in more than 430 vascular care settings, ranging from academic to community practice. VQI data can be used to benchmark performance and improve the quality of vascular care.
“Given that the SVS VQI has already been adopted by all types of facilities, including OBECs and vein centers, the SVS VQI is well positioned to help assess and improve quality of care,” said Dr. Jens Eldrup-Jorgensen, SVS PSO medical director.
The process will include discussions and potential collaboration with partners such as the American College of Surgeons, the Outpatient Endovascular and Interventional Society and the Intersociety Accreditation Council, Dr. Darling said, as well as societies such as the American Venous Forum, the Society for Vascular Ultrasound, and the Society for Vascular Nursing.
If established, a pilot program would be launched in 2018 with a full launch planned in 2019.
The Society for Vascular Surgery (SVS) executive board has established a task force to explore developing a vascular certification program for inpatient and outpatient care settings.
Noting the shift in professional reimbursement from payment for volume to payment for quality, along with a surge in outpatient endovascular care, “The SVS executive board believes that it is a critical time for vascular surgery to set standards based on quality improvement, efficiency and appropriateness,” said Dr. R. Clement Darling III, SVS president.
Task force chair Dr. Tony Sidawy will oversee two subcommittees, one for inpatient and one for office-based endovascular care (OBEC). Dr. Krishna Jain has been appointed chair of the OBEC subcommittee. A chair for the inpatient subcommittee has yet to be named.
“Vascular surgeons represented by the SVS should take the lead in defining quality and value standards for vascular care before they are defined for us,” said Dr. Sidawy.
“Offering an SVS-led certification process will inspire the most appropriate, high-quality vascular care and optimal outcomes for all patients,” Dr. Jain added.
Many SVS members are pioneers in the design and delivery of care in office-based practice settings, and they have been fierce advocates for this effort, said Dr. Darling. “We have heard our members loud and clear. They want SVS to play a major role in shaping the future of the office-based endovascular center, setting the bar for appropriateness and quality and helping all practitioners achieve it.
“We feel that to provide the best vascular care in a data-driven, quality-based system, the SVS needs to be actively involved in this process," he added. "Vascular surgeons have a long history of making data-driven decisions about which patients need an intervention, and since we treat patients medically as well as by endovascular or open techniques, we have a unique perspective."
A data registry is a critical component and will be provided by the SVS Patient Safety Organization and Vascular Quality Initiative (SVS VQI). VQI registries are already used in more than 430 vascular care settings, ranging from academic to community practice. VQI data can be used to benchmark performance and improve the quality of vascular care.
“Given that the SVS VQI has already been adopted by all types of facilities, including OBECs and vein centers, the SVS VQI is well positioned to help assess and improve quality of care,” said Dr. Jens Eldrup-Jorgensen, SVS PSO medical director.
The process will include discussions and potential collaboration with partners such as the American College of Surgeons, the Outpatient Endovascular and Interventional Society and the Intersociety Accreditation Council, Dr. Darling said, as well as societies such as the American Venous Forum, the Society for Vascular Ultrasound, and the Society for Vascular Nursing.
If established, a pilot program would be launched in 2018 with a full launch planned in 2019.
VA Choice Bill Defeated in the House
A U.S. House of Representatives appropriation to fund the Veterans Choice Program surprisingly went down to defeat on Monday. The VA Choice Program is set to run out of money in September, and VA officials have been calling for Congress to provide additional funding for the program. Republican leaders, hoping to expedite the bill’s passage and thinking that it was not controversial, submitted the bill in a process that required the votes of two-thirds of the representatives. The 219-186 vote fell well short of the necessary two-thirds, and voting fell largely along party lines.
Many veterans service organizations (VSOs) were critical of the bill and called on the House to make substantial changes to it. Seven VSOs signed a joint statement calling for the bill’s defeat. “As organizations who represent and support the interests of America’s 21 million veterans, and in fulfillment of our mandate to ensure that the men and women who served are able to receive the health care and benefits they need and deserve, we are calling on Members of Congress to defeat the House vote on unacceptable choice funding legislation (S. 114, with amendments),” the statement read.
AMVETS, Disabled American Veterans , Military Officers Association of America, Military Order of the Purple Heart, Veterans of Foreign Wars, Vietnam Veterans of America, and Wounded Warrior Project all signed on to the statement. The chief complaint was that the legislation “includes funding only for the ‘choice’ program which provides additional community care options, but makes no investment in VA and uses ‘savings’ from other veterans benefits or services to ‘pay’ for the ‘choice’ program.”
The bill would have allocated $2 billion for the Veterans Choice Program, taken funding for veteran housing loan fees, and would reduce the pensions for some veterans living in nursing facilities that also could be paid for under the Medicaid program.
The fate of the bill and funding for the Veterans Choice Program remains unclear. Senate and House veterans committees seem to be far apart on how to fund the program and for efforts to make more substantive changes to the program. Although House Republicans eventually may be able to pass a bill without Democrats, in the Senate, they will need the support of at least a handful of Democrats to move the bill to the President’s desk.
A U.S. House of Representatives appropriation to fund the Veterans Choice Program surprisingly went down to defeat on Monday. The VA Choice Program is set to run out of money in September, and VA officials have been calling for Congress to provide additional funding for the program. Republican leaders, hoping to expedite the bill’s passage and thinking that it was not controversial, submitted the bill in a process that required the votes of two-thirds of the representatives. The 219-186 vote fell well short of the necessary two-thirds, and voting fell largely along party lines.
Many veterans service organizations (VSOs) were critical of the bill and called on the House to make substantial changes to it. Seven VSOs signed a joint statement calling for the bill’s defeat. “As organizations who represent and support the interests of America’s 21 million veterans, and in fulfillment of our mandate to ensure that the men and women who served are able to receive the health care and benefits they need and deserve, we are calling on Members of Congress to defeat the House vote on unacceptable choice funding legislation (S. 114, with amendments),” the statement read.
AMVETS, Disabled American Veterans , Military Officers Association of America, Military Order of the Purple Heart, Veterans of Foreign Wars, Vietnam Veterans of America, and Wounded Warrior Project all signed on to the statement. The chief complaint was that the legislation “includes funding only for the ‘choice’ program which provides additional community care options, but makes no investment in VA and uses ‘savings’ from other veterans benefits or services to ‘pay’ for the ‘choice’ program.”
The bill would have allocated $2 billion for the Veterans Choice Program, taken funding for veteran housing loan fees, and would reduce the pensions for some veterans living in nursing facilities that also could be paid for under the Medicaid program.
The fate of the bill and funding for the Veterans Choice Program remains unclear. Senate and House veterans committees seem to be far apart on how to fund the program and for efforts to make more substantive changes to the program. Although House Republicans eventually may be able to pass a bill without Democrats, in the Senate, they will need the support of at least a handful of Democrats to move the bill to the President’s desk.
A U.S. House of Representatives appropriation to fund the Veterans Choice Program surprisingly went down to defeat on Monday. The VA Choice Program is set to run out of money in September, and VA officials have been calling for Congress to provide additional funding for the program. Republican leaders, hoping to expedite the bill’s passage and thinking that it was not controversial, submitted the bill in a process that required the votes of two-thirds of the representatives. The 219-186 vote fell well short of the necessary two-thirds, and voting fell largely along party lines.
Many veterans service organizations (VSOs) were critical of the bill and called on the House to make substantial changes to it. Seven VSOs signed a joint statement calling for the bill’s defeat. “As organizations who represent and support the interests of America’s 21 million veterans, and in fulfillment of our mandate to ensure that the men and women who served are able to receive the health care and benefits they need and deserve, we are calling on Members of Congress to defeat the House vote on unacceptable choice funding legislation (S. 114, with amendments),” the statement read.
AMVETS, Disabled American Veterans , Military Officers Association of America, Military Order of the Purple Heart, Veterans of Foreign Wars, Vietnam Veterans of America, and Wounded Warrior Project all signed on to the statement. The chief complaint was that the legislation “includes funding only for the ‘choice’ program which provides additional community care options, but makes no investment in VA and uses ‘savings’ from other veterans benefits or services to ‘pay’ for the ‘choice’ program.”
The bill would have allocated $2 billion for the Veterans Choice Program, taken funding for veteran housing loan fees, and would reduce the pensions for some veterans living in nursing facilities that also could be paid for under the Medicaid program.
The fate of the bill and funding for the Veterans Choice Program remains unclear. Senate and House veterans committees seem to be far apart on how to fund the program and for efforts to make more substantive changes to the program. Although House Republicans eventually may be able to pass a bill without Democrats, in the Senate, they will need the support of at least a handful of Democrats to move the bill to the President’s desk.
Three Anomalies and a Complication: Ruptured Noncoronary Sinus of Valsalva Aneurysm, Atrial Septal Aneurysm, and Patent Foramen Ovale
A 53 year-old white male with a past medical history of hypertension, hyperlipidemia, and former tobacco use was referred to the Dayton VAMC in Ohio for symptoms that included shortness of breath and a recent abnormal stress test. The patient reported no history of known coronary artery disease (CAD), congestive heart failure, or other cardiovascular diseases. The patient also reported no recent fever, bacterial blood infection, syphilis infection, recreational drug use, or chest trauma.
A physical examination was remarkable for grade 3/6 continuous murmur at the 5th interspace to the left of the sternum and a loud “pistol shot” sound heard over the femoral artery. The patient had jugular venous distension and 2+ leg edema bilaterally. His vital signs were normal, and laboratory blood tests showed normal hemoglobin level and kidney function.
An electrocardiogram showed nonspecific ST segment changes and a transthoracic echocardiogram (TTE) revealed a high-velocity jet in the right atrium (RA) above the tricuspid valve concerning for sinus of Valsalva aneurysm (SVA).
Right heart catheterization revealed elevated RA pressures with positive shunt study showing oxygen saturation step-up in the RA (Figure 3). Left heart hemodynamic measurement from an aortic approach to the distal part of the noncoronary cusp SVA revealed an RA pressure-tracing pattern consistent with rupture of the noncoronary SVA into the RA (Figure 4).
The primary diagnosis was of acute heart failure secondary to ruptured aneurysm of the noncoronary SVA into RA. The patient also received a secondary diagnosis of atrial septal aneurysm and PFO.
Treatment & Outcome
The patient was treated with aggressive diuresis and responded well to therapy. Considering the high mortality rate associated with a ruptured SVA, the patient was referred to a tertiary care center for surgical evaluation. He underwent repair of aorto-right atrial communication with a Cormatrix patch (Roswell, GA) from the aortic side and with primary closure from the right atrial side with resection of the windsock tract; coronary artery bypass graft x1 with right internal mammary artery to the right coronary artery; closure of the PFO with the Cormatrix patch.
The postoperative TEE confirmed preserved LV and RV function, no shunts, no aortic or tricuspid insufficiency. Biopsy of the tissue resected showed intimal fibroplasia. A TTE completed 1 year after surgery showed normal valvular function and without any structural abnormalities. The patient had improvement in symptoms and an uneventful year after surgical intervention followed by 24 session of cardiac rehabilitation.
Discussion
Sinus of Valsalva aneurysm is a dilation of the aortic wall between the aortic valve and the sinotubular junction that is caused by the lack of continuity between the middle layer of the aortic wall and the aortic valve.1 Cases of SVA are rare cardiac anomalies with prevalence of 1% in patients undergoing open-heart surgery.2 Between 65% and 85% of SVA cases originate from the right coronary sinus, 10% to 20% from the noncoronary sinus, and < 5% from the left coronary sinus.3
Sinus of Valsalva aneurysm is usually congenital, although cases associated with syphilis, bacterial endocarditis, trauma, Behçet disease, and aortic dissection have been reported. Structural defects associated with congenital SVAs include ventricular septal defect, bicuspid aortic valve, and aortic regurgitation. It is less commonly associated with pulmonary stenosis, coarctation of the aorta, patent ductus arteriosus, tricuspid regurgitation, and atrial septal defects.
The most common complication of the SVA is rupture into another cardiac chamber, frequently the right ventricle (60%) or RA (29%) and less frequently into left atrium (6%), left ventricle (4%), or pericardium (1%).1 Patients with ruptured SVA mainly develop dyspnea and chest pain, but cough, fatigue, peripheral edema, and continuous murmur have been reported.1
Atrial septal aneurysm is an uncommon finding in adults, with an incidence of 2.2 % in the general population, and it is often associated with atrial septal defect and PFO.1,4 Although ASA formation can be secondary to interatrial differences in pressures, it can be a primary malformation involving the region of the fossa ovalis or the entire atrial septum.4 Atrial septal aneurysm may be an isolated anomaly, but often is found in association with other structural cardiac anomalies, including SVA and PFO.4,5
Conclusion
Although coexistence of SVA and ASA has been reported previously, the case reported here, a ruptured noncoronary SVA that was associated with a large ASA and a PFO, has not been previously documented in the English literature. This patient’s anomalies are most likely congenital in origin. Progressive dyspnea and chest pain in the presence of a continuous loud murmur should raise the suspicion of ruptured sinus of Valsalva. Although no significant aortic regurgitation was noted on echocardiography, the pistol shot sound heard over the femoral artery was believed to be due to the rapid diastolic runoff into the RA through the ruptured SVA.
The significant increase in the RA pressure made the ASA and PFO more prominent. A TEE, left and right heart catheterizations with shunt study are vital for the diagnosis of SVA. If left untreated, SVA has an ominous prognosis. Surgical repair of ruptured SVA has an accepted risk and good prognosis with 10-year survival rate of 90%, whereas the mean survival of untreated ruptured SVA is about 4 years.6,7 Hence, the patient in this study was referred to a tertiary care center for surgical intervention.
1. Galicia-Tornell MM, Marín-Solís B, Mercado-Astorga O, Espinoza-Anguiano S, Martínez-Martínez M, Villalpando-Mendoza E. Sinus of Valsalva aneurysm with rupture. Case report and literature review. Cir Cir. 2009;77(6):441-445.
2. Takach TJ, Reul GJ, Duncan JM, et al. Sinus of Valsalva aneurysm or fistula: management and outcome. Ann Thorac Surg. 1999;68(5):1573-1577.
3. Meier JH, Seward JB, Miller FA Jr, Oh JK, Enriquez-Sarano M. Aneurysms in the left ventricular outflow tract: clinical presentation, causes, and echocardiographic features. J Am Soc Echocardiogr. 1998;11(7):729-745.
4. Mügge A, Daniel WG, Angermann C et al. Atrial septal aneurysm in adult patients: a multicenter study using transthoracic and transesophageal echocardiography. Circulation. 1995;91(11):2785-2792.
5. Silver MD, Dorsey JS. Aneurysms of the septum primum in adults. Arch Pathol Lab Med. 1978;102(2):62-65.
6. Wang ZJ, Zou CW, Li DC, et al. Surgical repair of sinus of Valsalva aneurysm in Asian patients. Ann Thorac Surg. 2007;84(1):156-160.
7. Yan F, Huo Q, Qiao J, Murat V, Ma SF. Surgery for sinus of valsalva aneurysm: 27-year experience with 100 patients. Asian Cardiovasc Thorac Ann. 2008;16(5):361-365.
A 53 year-old white male with a past medical history of hypertension, hyperlipidemia, and former tobacco use was referred to the Dayton VAMC in Ohio for symptoms that included shortness of breath and a recent abnormal stress test. The patient reported no history of known coronary artery disease (CAD), congestive heart failure, or other cardiovascular diseases. The patient also reported no recent fever, bacterial blood infection, syphilis infection, recreational drug use, or chest trauma.
A physical examination was remarkable for grade 3/6 continuous murmur at the 5th interspace to the left of the sternum and a loud “pistol shot” sound heard over the femoral artery. The patient had jugular venous distension and 2+ leg edema bilaterally. His vital signs were normal, and laboratory blood tests showed normal hemoglobin level and kidney function.
An electrocardiogram showed nonspecific ST segment changes and a transthoracic echocardiogram (TTE) revealed a high-velocity jet in the right atrium (RA) above the tricuspid valve concerning for sinus of Valsalva aneurysm (SVA).
Right heart catheterization revealed elevated RA pressures with positive shunt study showing oxygen saturation step-up in the RA (Figure 3). Left heart hemodynamic measurement from an aortic approach to the distal part of the noncoronary cusp SVA revealed an RA pressure-tracing pattern consistent with rupture of the noncoronary SVA into the RA (Figure 4).
The primary diagnosis was of acute heart failure secondary to ruptured aneurysm of the noncoronary SVA into RA. The patient also received a secondary diagnosis of atrial septal aneurysm and PFO.
Treatment & Outcome
The patient was treated with aggressive diuresis and responded well to therapy. Considering the high mortality rate associated with a ruptured SVA, the patient was referred to a tertiary care center for surgical evaluation. He underwent repair of aorto-right atrial communication with a Cormatrix patch (Roswell, GA) from the aortic side and with primary closure from the right atrial side with resection of the windsock tract; coronary artery bypass graft x1 with right internal mammary artery to the right coronary artery; closure of the PFO with the Cormatrix patch.
The postoperative TEE confirmed preserved LV and RV function, no shunts, no aortic or tricuspid insufficiency. Biopsy of the tissue resected showed intimal fibroplasia. A TTE completed 1 year after surgery showed normal valvular function and without any structural abnormalities. The patient had improvement in symptoms and an uneventful year after surgical intervention followed by 24 session of cardiac rehabilitation.
Discussion
Sinus of Valsalva aneurysm is a dilation of the aortic wall between the aortic valve and the sinotubular junction that is caused by the lack of continuity between the middle layer of the aortic wall and the aortic valve.1 Cases of SVA are rare cardiac anomalies with prevalence of 1% in patients undergoing open-heart surgery.2 Between 65% and 85% of SVA cases originate from the right coronary sinus, 10% to 20% from the noncoronary sinus, and < 5% from the left coronary sinus.3
Sinus of Valsalva aneurysm is usually congenital, although cases associated with syphilis, bacterial endocarditis, trauma, Behçet disease, and aortic dissection have been reported. Structural defects associated with congenital SVAs include ventricular septal defect, bicuspid aortic valve, and aortic regurgitation. It is less commonly associated with pulmonary stenosis, coarctation of the aorta, patent ductus arteriosus, tricuspid regurgitation, and atrial septal defects.
The most common complication of the SVA is rupture into another cardiac chamber, frequently the right ventricle (60%) or RA (29%) and less frequently into left atrium (6%), left ventricle (4%), or pericardium (1%).1 Patients with ruptured SVA mainly develop dyspnea and chest pain, but cough, fatigue, peripheral edema, and continuous murmur have been reported.1
Atrial septal aneurysm is an uncommon finding in adults, with an incidence of 2.2 % in the general population, and it is often associated with atrial septal defect and PFO.1,4 Although ASA formation can be secondary to interatrial differences in pressures, it can be a primary malformation involving the region of the fossa ovalis or the entire atrial septum.4 Atrial septal aneurysm may be an isolated anomaly, but often is found in association with other structural cardiac anomalies, including SVA and PFO.4,5
Conclusion
Although coexistence of SVA and ASA has been reported previously, the case reported here, a ruptured noncoronary SVA that was associated with a large ASA and a PFO, has not been previously documented in the English literature. This patient’s anomalies are most likely congenital in origin. Progressive dyspnea and chest pain in the presence of a continuous loud murmur should raise the suspicion of ruptured sinus of Valsalva. Although no significant aortic regurgitation was noted on echocardiography, the pistol shot sound heard over the femoral artery was believed to be due to the rapid diastolic runoff into the RA through the ruptured SVA.
The significant increase in the RA pressure made the ASA and PFO more prominent. A TEE, left and right heart catheterizations with shunt study are vital for the diagnosis of SVA. If left untreated, SVA has an ominous prognosis. Surgical repair of ruptured SVA has an accepted risk and good prognosis with 10-year survival rate of 90%, whereas the mean survival of untreated ruptured SVA is about 4 years.6,7 Hence, the patient in this study was referred to a tertiary care center for surgical intervention.
A 53 year-old white male with a past medical history of hypertension, hyperlipidemia, and former tobacco use was referred to the Dayton VAMC in Ohio for symptoms that included shortness of breath and a recent abnormal stress test. The patient reported no history of known coronary artery disease (CAD), congestive heart failure, or other cardiovascular diseases. The patient also reported no recent fever, bacterial blood infection, syphilis infection, recreational drug use, or chest trauma.
A physical examination was remarkable for grade 3/6 continuous murmur at the 5th interspace to the left of the sternum and a loud “pistol shot” sound heard over the femoral artery. The patient had jugular venous distension and 2+ leg edema bilaterally. His vital signs were normal, and laboratory blood tests showed normal hemoglobin level and kidney function.
An electrocardiogram showed nonspecific ST segment changes and a transthoracic echocardiogram (TTE) revealed a high-velocity jet in the right atrium (RA) above the tricuspid valve concerning for sinus of Valsalva aneurysm (SVA).
Right heart catheterization revealed elevated RA pressures with positive shunt study showing oxygen saturation step-up in the RA (Figure 3). Left heart hemodynamic measurement from an aortic approach to the distal part of the noncoronary cusp SVA revealed an RA pressure-tracing pattern consistent with rupture of the noncoronary SVA into the RA (Figure 4).
The primary diagnosis was of acute heart failure secondary to ruptured aneurysm of the noncoronary SVA into RA. The patient also received a secondary diagnosis of atrial septal aneurysm and PFO.
Treatment & Outcome
The patient was treated with aggressive diuresis and responded well to therapy. Considering the high mortality rate associated with a ruptured SVA, the patient was referred to a tertiary care center for surgical evaluation. He underwent repair of aorto-right atrial communication with a Cormatrix patch (Roswell, GA) from the aortic side and with primary closure from the right atrial side with resection of the windsock tract; coronary artery bypass graft x1 with right internal mammary artery to the right coronary artery; closure of the PFO with the Cormatrix patch.
The postoperative TEE confirmed preserved LV and RV function, no shunts, no aortic or tricuspid insufficiency. Biopsy of the tissue resected showed intimal fibroplasia. A TTE completed 1 year after surgery showed normal valvular function and without any structural abnormalities. The patient had improvement in symptoms and an uneventful year after surgical intervention followed by 24 session of cardiac rehabilitation.
Discussion
Sinus of Valsalva aneurysm is a dilation of the aortic wall between the aortic valve and the sinotubular junction that is caused by the lack of continuity between the middle layer of the aortic wall and the aortic valve.1 Cases of SVA are rare cardiac anomalies with prevalence of 1% in patients undergoing open-heart surgery.2 Between 65% and 85% of SVA cases originate from the right coronary sinus, 10% to 20% from the noncoronary sinus, and < 5% from the left coronary sinus.3
Sinus of Valsalva aneurysm is usually congenital, although cases associated with syphilis, bacterial endocarditis, trauma, Behçet disease, and aortic dissection have been reported. Structural defects associated with congenital SVAs include ventricular septal defect, bicuspid aortic valve, and aortic regurgitation. It is less commonly associated with pulmonary stenosis, coarctation of the aorta, patent ductus arteriosus, tricuspid regurgitation, and atrial septal defects.
The most common complication of the SVA is rupture into another cardiac chamber, frequently the right ventricle (60%) or RA (29%) and less frequently into left atrium (6%), left ventricle (4%), or pericardium (1%).1 Patients with ruptured SVA mainly develop dyspnea and chest pain, but cough, fatigue, peripheral edema, and continuous murmur have been reported.1
Atrial septal aneurysm is an uncommon finding in adults, with an incidence of 2.2 % in the general population, and it is often associated with atrial septal defect and PFO.1,4 Although ASA formation can be secondary to interatrial differences in pressures, it can be a primary malformation involving the region of the fossa ovalis or the entire atrial septum.4 Atrial septal aneurysm may be an isolated anomaly, but often is found in association with other structural cardiac anomalies, including SVA and PFO.4,5
Conclusion
Although coexistence of SVA and ASA has been reported previously, the case reported here, a ruptured noncoronary SVA that was associated with a large ASA and a PFO, has not been previously documented in the English literature. This patient’s anomalies are most likely congenital in origin. Progressive dyspnea and chest pain in the presence of a continuous loud murmur should raise the suspicion of ruptured sinus of Valsalva. Although no significant aortic regurgitation was noted on echocardiography, the pistol shot sound heard over the femoral artery was believed to be due to the rapid diastolic runoff into the RA through the ruptured SVA.
The significant increase in the RA pressure made the ASA and PFO more prominent. A TEE, left and right heart catheterizations with shunt study are vital for the diagnosis of SVA. If left untreated, SVA has an ominous prognosis. Surgical repair of ruptured SVA has an accepted risk and good prognosis with 10-year survival rate of 90%, whereas the mean survival of untreated ruptured SVA is about 4 years.6,7 Hence, the patient in this study was referred to a tertiary care center for surgical intervention.
1. Galicia-Tornell MM, Marín-Solís B, Mercado-Astorga O, Espinoza-Anguiano S, Martínez-Martínez M, Villalpando-Mendoza E. Sinus of Valsalva aneurysm with rupture. Case report and literature review. Cir Cir. 2009;77(6):441-445.
2. Takach TJ, Reul GJ, Duncan JM, et al. Sinus of Valsalva aneurysm or fistula: management and outcome. Ann Thorac Surg. 1999;68(5):1573-1577.
3. Meier JH, Seward JB, Miller FA Jr, Oh JK, Enriquez-Sarano M. Aneurysms in the left ventricular outflow tract: clinical presentation, causes, and echocardiographic features. J Am Soc Echocardiogr. 1998;11(7):729-745.
4. Mügge A, Daniel WG, Angermann C et al. Atrial septal aneurysm in adult patients: a multicenter study using transthoracic and transesophageal echocardiography. Circulation. 1995;91(11):2785-2792.
5. Silver MD, Dorsey JS. Aneurysms of the septum primum in adults. Arch Pathol Lab Med. 1978;102(2):62-65.
6. Wang ZJ, Zou CW, Li DC, et al. Surgical repair of sinus of Valsalva aneurysm in Asian patients. Ann Thorac Surg. 2007;84(1):156-160.
7. Yan F, Huo Q, Qiao J, Murat V, Ma SF. Surgery for sinus of valsalva aneurysm: 27-year experience with 100 patients. Asian Cardiovasc Thorac Ann. 2008;16(5):361-365.
1. Galicia-Tornell MM, Marín-Solís B, Mercado-Astorga O, Espinoza-Anguiano S, Martínez-Martínez M, Villalpando-Mendoza E. Sinus of Valsalva aneurysm with rupture. Case report and literature review. Cir Cir. 2009;77(6):441-445.
2. Takach TJ, Reul GJ, Duncan JM, et al. Sinus of Valsalva aneurysm or fistula: management and outcome. Ann Thorac Surg. 1999;68(5):1573-1577.
3. Meier JH, Seward JB, Miller FA Jr, Oh JK, Enriquez-Sarano M. Aneurysms in the left ventricular outflow tract: clinical presentation, causes, and echocardiographic features. J Am Soc Echocardiogr. 1998;11(7):729-745.
4. Mügge A, Daniel WG, Angermann C et al. Atrial septal aneurysm in adult patients: a multicenter study using transthoracic and transesophageal echocardiography. Circulation. 1995;91(11):2785-2792.
5. Silver MD, Dorsey JS. Aneurysms of the septum primum in adults. Arch Pathol Lab Med. 1978;102(2):62-65.
6. Wang ZJ, Zou CW, Li DC, et al. Surgical repair of sinus of Valsalva aneurysm in Asian patients. Ann Thorac Surg. 2007;84(1):156-160.
7. Yan F, Huo Q, Qiao J, Murat V, Ma SF. Surgery for sinus of valsalva aneurysm: 27-year experience with 100 patients. Asian Cardiovasc Thorac Ann. 2008;16(5):361-365.
Special Report II: Tackling Burnout
Last month, we introduced the epidemic of burnout and the adverse consequences for both our vascular surgery patients and ourselves. Today we will outline a framework for addressing these issues. The foundation of this framework is informed by the social and neurosciences.
From the perspective of the social scientist: Christina Maslach, the originator of the widely used Maslach Burnout Inventory, theorized that burnout arises from a chronic mismatch between people and their work setting in some or all of the following domains: Workload (too much, wrong kind); control (lack of autonomy, or insufficient control over resources); reward (insufficient financial or social rewards commensurate with achievements); community (loss of positive connection with others); fairness (lack of perceived fairness, inequity of work, pay, or promotion); and values (conflict of personal and organizational values). The reality of practicing medicine in today’s business milieu – of achieving service efficiencies by meeting performance targets – brings many of these mismatches into sharp focus.
From the perspective of the neuroscientist: Recent advances, including functional MRI, have demonstrated that the human brain is hard wired for compassion. Compassion is the deep feeling that arises when confronted with another’s suffering, coupled with a strong desire to alleviate that suffering. There are at least two neural pathways: one activated during empathy, having us experience another’s pain; and the other activated during compassion, resulting in our sense of reward. Thus, burnout is thought to occur when you know what your patient needs but you are unable to deliver it. Compassionate medical care is purposeful work, which promotes a sense of reward and mitigates burnout.
Because burnout affects all caregivers (anyone who touches the patient), a successful program addressing workforce well-being must be comprehensive and organization wide, similar to successful patient safety, CPI [continuous process improvement] and LEAN [Six Sigma] initiatives.
There are no shortcuts. Creating a culture of compassionate, collaborative care requires an understanding of the interrelationships between the individual provider, the unit or team, and organizational leadership.
1) The individual provider: There is evidence to support the use of programs that build personal resilience. A recently published meta-analysis by West and colleagues concluded that while no specific physician burnout intervention has been shown to be better than other types of interventions, mindfulness, stress management, and small-group discussions can be effective approaches to reducing burnout scores. Strategies to build individual resilience, such as mindfulness and meditation, are easy to teach but place the burden for success on the individual. No amount of resilience can withstand an unsupportive or toxic workplace environment, so both individual and organizational strategies in combination are necessary.
2) The unit or team: Scheduling time for open and honest discussion of social and emotional issues that arise in caring for patients helps nourish caregiver to caregiver compassion. The Schwartz Center for Compassionate Healthcare is a national nonprofit leading the movement to bring compassion to every patient-caregiver interaction. More than 425 health care organization are Schwartz Center members and conduct Schwartz Rounds™ to bring doctors, nurses, and other caregivers together to discuss the human side of health care. (www.theschwartzcenter.org). Team member to team member support is essential for navigating the stressors of practice. With having lunch in front of your computer being the norm, and the disappearance of traditional spaces for colleagues to connect (for example, nurses’ lounge, physician dining rooms), the opportunity for caregivers to have a safe place to escape, a place to have their own humanity reaffirmed, a place to offer support to their peers, has been eliminated.
3) Organizational Leadership: Making compassion a core value, articulating it, and establishing metrics whereby it can be measured, is a good start. The barriers to a culture of compassion are related to our systems of care. There are burgeoning administrative and documentation tasks to be performed, and productivity expectations that turn our clinics and hospitals into assembly lines. No, we cannot expect the EMR [electronic medical records] to be eliminated, but workforce well-being cannot be sustainable in the context of inadequate resources. A culture of compassionate collaborative care requires programs and policies that are implemented by the organization itself. Examples of organization-wide initiatives that support workforce well-being and provider engagement include: screening for caregiver burnout, establishing policies for managing adverse events with an eye toward the second victim, and most importantly, supporting systems that preserve work control autonomy of physicians and nurses in clinical settings. The business sector has long recognized that workplace stress is a function of how demanding a person’s job is and how much control that person has over his or her responsibilities. The business community has also recognized that the experience of the worker (provider) drives the experience of the customer (patient). In a study of hospital compassionate practices and HCAHPS [the Hospital Consumer Assessment of Healthcare Providers and Systems], McClelland and Vogus reported that how well a hospital compassionately supports it employees and rewards compassionate acts is significantly and positively is associated with that hospital’s ratings and likelihood of patients recommending it.
How does the Society of Vascular Surgery, or any professional medical/nursing society for that matter, fit into this model?
We propose that the SVS find ways to empower their members to be agents for culture change within their own health care organizations. How might this be done:
- Teach organizational leadership skills, starting with the SVS Board of Directors, the presidential line, and the chairs of committees. Offer leadership courses at the Annual Meeting.
- Develop a community of caregivers committed to creating a compassionate collaborative culture. The SVS is a founding member of the Schwartz Center Healthcare Society Leadership Council, and you, as members of the SVS benefit from reduced registration at the Annual Compassion in Action Healthcare Conference, June 24-27, 2017 in Boston. (http://compassioninactionconference.org) This conference is designed to be highly experiential, using a hands-on “how to do it” model.
- The SVS should make improving the overall wellness of its members a specific goal and find specific metrics to monitor our progress towards this goal. Members can be provided with the tools to identify, monitor, and measure burnout and compassion. Each committee and council of the SVS can reexamine their objectives through the lens of reducing burnout and improving the wellness of vascular surgeons.
- Provide members with evidence-based programs that build personal resilience. This will not be a successful initiative unless our surgeons recognize and acknowledge the symptoms of burnout, and are willing to admit vulnerability. Without doing so, it is difficult to reach out for help.
- Redesign postgraduate resident and fellowship education. Standardizing clinical care may reduce variation and promote efficiency. However, when processes such as time-limited appointment scheduling, EMR templates, and protocols that drive physician-patient interactions are embedded in Resident and Fellowship education, the result may well be inflexibility in practice, reduced face time with patients, and interactions that lack compassion; all leading to burnout. Graduate Medical Education leaders must develop programs that support the learner’s ability to connect with patients and families, cultivate and role-model skills and behaviors that strengthen compassionate interactions, and strive to develop clinical practice models that increase Resident and Fellow work control autonomy.
The SVS should work proactively to optimize workload, fairness, and reward on a larger scale for its members as it relates to the EMR, reimbursement, and systems coverage. While we may be relatively small in size, as leaders, we are perfectly poised to address these larger, global issues. Perhaps working within the current system (i.e., PAC and APM task force) and considering innovative solutions at a national leadership scale, the SVS can direct real change!
Changing culture is not easy, nor quick, nor does it have an easy-to-follow blueprint. The first step is recognizing the need. The second is taking a leadership role. The third is thinking deeply about implementation.
*The authors extend their thanks and appreciation for the guidance, resources and support of Michael Goldberg, MD, scholar in residence, Schwartz Center for Compassionate Care, Boston and clinical professor of orthopedics at Seattle Children’s Hospital.
REFERENCES
1. J Managerial Psychol. (2007) 22:309-28
2. Annu Rev Neurosci. (2012) 35:1-23
3. Medicine. (2016) 44:583-5
4. J Health Organization Manag. (2015) 29:973-87
5. De Zulueta P Developing compassionate leadership in health care: an integrative review. J Healthcare Leadership. (2016) 8:1-10
6. Dolan ED, Morh D, Lempa M et al. Using a single item to measure burnout in primary care staff: A psychometry evaluation. J Gen Intern Med. (2015) 30:582-7
7. Karasek RA Job demands, job decision latitude, and mental strain: implications for job design. Administrative Sciences Quarterly (1979) 24: 285-308
8. Lee VS, Miller T, Daniels C, et al. Creating the exceptional patient experience in one academic health system. Acad Med. (2016) 91:338-44
9. Linzer M, Levine R, Meltzer D, et al. 10 bold steps to prevent burnout in general internal medicine. J Gen Intern Med. (2013) 29:18-20
10. Lown BA, Manning CF The Schwartz Center Rounds: Evaluation of an interdisciplinary approach to enhancing patient-centered communication, teamwork, and provider support. Acad Med. (2010) 85:1073-81
11. Lown BA, Muncer SJ, Chadwick R Can compassionate healthcare be measured? The Schwartz Center Compassionate Care Scale. Patient Education and Counseling (2015) 98:1005-10
12. Lown BA, McIntosh S, Gaines ME, et. al. Integrating compassionate collaborative care (“the Triple C”) into health professional education to advance the triple aim of health care. Acad Med (2016) 91:1-7
13. Lown BA A social neuroscience-informed model for teaching and practicing compassion in health care. Medical Education (2016) 50: 332-342
14. Maslach C, Schaufeli WG, Leiter MP Job burnout. Annu Rev Psychol (2001) 52:397-422
15. McClelland LE, Vogus TJ Compassion practices and HCAHPS: Does rewarding and supporting workplace compassion influence patient perceptions? HSR: Health Serv Res. (2014) 49:1670-83
16. Shanafelt TD, Noseworthy JH Executive leadership and physician well-being: Nine organizational strategies to promote engagement and reduce burnout. Mayo Clin Proc. (2016) 6:1-18
17. Shanafelt TD, Dyrbye LN, West CP Addressing physician burnout: the way forward. JAMA (2017) 317:901-2
18. Singer T, Klimecki OM Empathy and compassion Curr Biol. (2014) 24: R875-8
19. West CP, Dyrbye LN, Satele DV et. al. Concurrent validity of single-item measures of emotional exhaustion and depersonalization in burnout assessment. J Gen Intern Med. (2012) 27:1445-52
20. West CP, Dyrbye LN, Erwin PJ, et al. Interventions to address and reduce physician burnout: a systematic review and meta-analysis. Lancet. (2016) 388:2272-81
21. Wuest TK, Goldberg MJ, Kelly JD Clinical faceoff: Physician burnout-Fact, fantasy, or the fourth component of the triple aim? Clin Orthop Relat Res. (2016) doi: 10.1007/5-11999-016-5193-5
Last month, we introduced the epidemic of burnout and the adverse consequences for both our vascular surgery patients and ourselves. Today we will outline a framework for addressing these issues. The foundation of this framework is informed by the social and neurosciences.
From the perspective of the social scientist: Christina Maslach, the originator of the widely used Maslach Burnout Inventory, theorized that burnout arises from a chronic mismatch between people and their work setting in some or all of the following domains: Workload (too much, wrong kind); control (lack of autonomy, or insufficient control over resources); reward (insufficient financial or social rewards commensurate with achievements); community (loss of positive connection with others); fairness (lack of perceived fairness, inequity of work, pay, or promotion); and values (conflict of personal and organizational values). The reality of practicing medicine in today’s business milieu – of achieving service efficiencies by meeting performance targets – brings many of these mismatches into sharp focus.
From the perspective of the neuroscientist: Recent advances, including functional MRI, have demonstrated that the human brain is hard wired for compassion. Compassion is the deep feeling that arises when confronted with another’s suffering, coupled with a strong desire to alleviate that suffering. There are at least two neural pathways: one activated during empathy, having us experience another’s pain; and the other activated during compassion, resulting in our sense of reward. Thus, burnout is thought to occur when you know what your patient needs but you are unable to deliver it. Compassionate medical care is purposeful work, which promotes a sense of reward and mitigates burnout.
Because burnout affects all caregivers (anyone who touches the patient), a successful program addressing workforce well-being must be comprehensive and organization wide, similar to successful patient safety, CPI [continuous process improvement] and LEAN [Six Sigma] initiatives.
There are no shortcuts. Creating a culture of compassionate, collaborative care requires an understanding of the interrelationships between the individual provider, the unit or team, and organizational leadership.
1) The individual provider: There is evidence to support the use of programs that build personal resilience. A recently published meta-analysis by West and colleagues concluded that while no specific physician burnout intervention has been shown to be better than other types of interventions, mindfulness, stress management, and small-group discussions can be effective approaches to reducing burnout scores. Strategies to build individual resilience, such as mindfulness and meditation, are easy to teach but place the burden for success on the individual. No amount of resilience can withstand an unsupportive or toxic workplace environment, so both individual and organizational strategies in combination are necessary.
2) The unit or team: Scheduling time for open and honest discussion of social and emotional issues that arise in caring for patients helps nourish caregiver to caregiver compassion. The Schwartz Center for Compassionate Healthcare is a national nonprofit leading the movement to bring compassion to every patient-caregiver interaction. More than 425 health care organization are Schwartz Center members and conduct Schwartz Rounds™ to bring doctors, nurses, and other caregivers together to discuss the human side of health care. (www.theschwartzcenter.org). Team member to team member support is essential for navigating the stressors of practice. With having lunch in front of your computer being the norm, and the disappearance of traditional spaces for colleagues to connect (for example, nurses’ lounge, physician dining rooms), the opportunity for caregivers to have a safe place to escape, a place to have their own humanity reaffirmed, a place to offer support to their peers, has been eliminated.
3) Organizational Leadership: Making compassion a core value, articulating it, and establishing metrics whereby it can be measured, is a good start. The barriers to a culture of compassion are related to our systems of care. There are burgeoning administrative and documentation tasks to be performed, and productivity expectations that turn our clinics and hospitals into assembly lines. No, we cannot expect the EMR [electronic medical records] to be eliminated, but workforce well-being cannot be sustainable in the context of inadequate resources. A culture of compassionate collaborative care requires programs and policies that are implemented by the organization itself. Examples of organization-wide initiatives that support workforce well-being and provider engagement include: screening for caregiver burnout, establishing policies for managing adverse events with an eye toward the second victim, and most importantly, supporting systems that preserve work control autonomy of physicians and nurses in clinical settings. The business sector has long recognized that workplace stress is a function of how demanding a person’s job is and how much control that person has over his or her responsibilities. The business community has also recognized that the experience of the worker (provider) drives the experience of the customer (patient). In a study of hospital compassionate practices and HCAHPS [the Hospital Consumer Assessment of Healthcare Providers and Systems], McClelland and Vogus reported that how well a hospital compassionately supports it employees and rewards compassionate acts is significantly and positively is associated with that hospital’s ratings and likelihood of patients recommending it.
How does the Society of Vascular Surgery, or any professional medical/nursing society for that matter, fit into this model?
We propose that the SVS find ways to empower their members to be agents for culture change within their own health care organizations. How might this be done:
- Teach organizational leadership skills, starting with the SVS Board of Directors, the presidential line, and the chairs of committees. Offer leadership courses at the Annual Meeting.
- Develop a community of caregivers committed to creating a compassionate collaborative culture. The SVS is a founding member of the Schwartz Center Healthcare Society Leadership Council, and you, as members of the SVS benefit from reduced registration at the Annual Compassion in Action Healthcare Conference, June 24-27, 2017 in Boston. (http://compassioninactionconference.org) This conference is designed to be highly experiential, using a hands-on “how to do it” model.
- The SVS should make improving the overall wellness of its members a specific goal and find specific metrics to monitor our progress towards this goal. Members can be provided with the tools to identify, monitor, and measure burnout and compassion. Each committee and council of the SVS can reexamine their objectives through the lens of reducing burnout and improving the wellness of vascular surgeons.
- Provide members with evidence-based programs that build personal resilience. This will not be a successful initiative unless our surgeons recognize and acknowledge the symptoms of burnout, and are willing to admit vulnerability. Without doing so, it is difficult to reach out for help.
- Redesign postgraduate resident and fellowship education. Standardizing clinical care may reduce variation and promote efficiency. However, when processes such as time-limited appointment scheduling, EMR templates, and protocols that drive physician-patient interactions are embedded in Resident and Fellowship education, the result may well be inflexibility in practice, reduced face time with patients, and interactions that lack compassion; all leading to burnout. Graduate Medical Education leaders must develop programs that support the learner’s ability to connect with patients and families, cultivate and role-model skills and behaviors that strengthen compassionate interactions, and strive to develop clinical practice models that increase Resident and Fellow work control autonomy.
The SVS should work proactively to optimize workload, fairness, and reward on a larger scale for its members as it relates to the EMR, reimbursement, and systems coverage. While we may be relatively small in size, as leaders, we are perfectly poised to address these larger, global issues. Perhaps working within the current system (i.e., PAC and APM task force) and considering innovative solutions at a national leadership scale, the SVS can direct real change!
Changing culture is not easy, nor quick, nor does it have an easy-to-follow blueprint. The first step is recognizing the need. The second is taking a leadership role. The third is thinking deeply about implementation.
*The authors extend their thanks and appreciation for the guidance, resources and support of Michael Goldberg, MD, scholar in residence, Schwartz Center for Compassionate Care, Boston and clinical professor of orthopedics at Seattle Children’s Hospital.
REFERENCES
1. J Managerial Psychol. (2007) 22:309-28
2. Annu Rev Neurosci. (2012) 35:1-23
3. Medicine. (2016) 44:583-5
4. J Health Organization Manag. (2015) 29:973-87
5. De Zulueta P Developing compassionate leadership in health care: an integrative review. J Healthcare Leadership. (2016) 8:1-10
6. Dolan ED, Morh D, Lempa M et al. Using a single item to measure burnout in primary care staff: A psychometry evaluation. J Gen Intern Med. (2015) 30:582-7
7. Karasek RA Job demands, job decision latitude, and mental strain: implications for job design. Administrative Sciences Quarterly (1979) 24: 285-308
8. Lee VS, Miller T, Daniels C, et al. Creating the exceptional patient experience in one academic health system. Acad Med. (2016) 91:338-44
9. Linzer M, Levine R, Meltzer D, et al. 10 bold steps to prevent burnout in general internal medicine. J Gen Intern Med. (2013) 29:18-20
10. Lown BA, Manning CF The Schwartz Center Rounds: Evaluation of an interdisciplinary approach to enhancing patient-centered communication, teamwork, and provider support. Acad Med. (2010) 85:1073-81
11. Lown BA, Muncer SJ, Chadwick R Can compassionate healthcare be measured? The Schwartz Center Compassionate Care Scale. Patient Education and Counseling (2015) 98:1005-10
12. Lown BA, McIntosh S, Gaines ME, et. al. Integrating compassionate collaborative care (“the Triple C”) into health professional education to advance the triple aim of health care. Acad Med (2016) 91:1-7
13. Lown BA A social neuroscience-informed model for teaching and practicing compassion in health care. Medical Education (2016) 50: 332-342
14. Maslach C, Schaufeli WG, Leiter MP Job burnout. Annu Rev Psychol (2001) 52:397-422
15. McClelland LE, Vogus TJ Compassion practices and HCAHPS: Does rewarding and supporting workplace compassion influence patient perceptions? HSR: Health Serv Res. (2014) 49:1670-83
16. Shanafelt TD, Noseworthy JH Executive leadership and physician well-being: Nine organizational strategies to promote engagement and reduce burnout. Mayo Clin Proc. (2016) 6:1-18
17. Shanafelt TD, Dyrbye LN, West CP Addressing physician burnout: the way forward. JAMA (2017) 317:901-2
18. Singer T, Klimecki OM Empathy and compassion Curr Biol. (2014) 24: R875-8
19. West CP, Dyrbye LN, Satele DV et. al. Concurrent validity of single-item measures of emotional exhaustion and depersonalization in burnout assessment. J Gen Intern Med. (2012) 27:1445-52
20. West CP, Dyrbye LN, Erwin PJ, et al. Interventions to address and reduce physician burnout: a systematic review and meta-analysis. Lancet. (2016) 388:2272-81
21. Wuest TK, Goldberg MJ, Kelly JD Clinical faceoff: Physician burnout-Fact, fantasy, or the fourth component of the triple aim? Clin Orthop Relat Res. (2016) doi: 10.1007/5-11999-016-5193-5
Last month, we introduced the epidemic of burnout and the adverse consequences for both our vascular surgery patients and ourselves. Today we will outline a framework for addressing these issues. The foundation of this framework is informed by the social and neurosciences.
From the perspective of the social scientist: Christina Maslach, the originator of the widely used Maslach Burnout Inventory, theorized that burnout arises from a chronic mismatch between people and their work setting in some or all of the following domains: Workload (too much, wrong kind); control (lack of autonomy, or insufficient control over resources); reward (insufficient financial or social rewards commensurate with achievements); community (loss of positive connection with others); fairness (lack of perceived fairness, inequity of work, pay, or promotion); and values (conflict of personal and organizational values). The reality of practicing medicine in today’s business milieu – of achieving service efficiencies by meeting performance targets – brings many of these mismatches into sharp focus.
From the perspective of the neuroscientist: Recent advances, including functional MRI, have demonstrated that the human brain is hard wired for compassion. Compassion is the deep feeling that arises when confronted with another’s suffering, coupled with a strong desire to alleviate that suffering. There are at least two neural pathways: one activated during empathy, having us experience another’s pain; and the other activated during compassion, resulting in our sense of reward. Thus, burnout is thought to occur when you know what your patient needs but you are unable to deliver it. Compassionate medical care is purposeful work, which promotes a sense of reward and mitigates burnout.
Because burnout affects all caregivers (anyone who touches the patient), a successful program addressing workforce well-being must be comprehensive and organization wide, similar to successful patient safety, CPI [continuous process improvement] and LEAN [Six Sigma] initiatives.
There are no shortcuts. Creating a culture of compassionate, collaborative care requires an understanding of the interrelationships between the individual provider, the unit or team, and organizational leadership.
1) The individual provider: There is evidence to support the use of programs that build personal resilience. A recently published meta-analysis by West and colleagues concluded that while no specific physician burnout intervention has been shown to be better than other types of interventions, mindfulness, stress management, and small-group discussions can be effective approaches to reducing burnout scores. Strategies to build individual resilience, such as mindfulness and meditation, are easy to teach but place the burden for success on the individual. No amount of resilience can withstand an unsupportive or toxic workplace environment, so both individual and organizational strategies in combination are necessary.
2) The unit or team: Scheduling time for open and honest discussion of social and emotional issues that arise in caring for patients helps nourish caregiver to caregiver compassion. The Schwartz Center for Compassionate Healthcare is a national nonprofit leading the movement to bring compassion to every patient-caregiver interaction. More than 425 health care organization are Schwartz Center members and conduct Schwartz Rounds™ to bring doctors, nurses, and other caregivers together to discuss the human side of health care. (www.theschwartzcenter.org). Team member to team member support is essential for navigating the stressors of practice. With having lunch in front of your computer being the norm, and the disappearance of traditional spaces for colleagues to connect (for example, nurses’ lounge, physician dining rooms), the opportunity for caregivers to have a safe place to escape, a place to have their own humanity reaffirmed, a place to offer support to their peers, has been eliminated.
3) Organizational Leadership: Making compassion a core value, articulating it, and establishing metrics whereby it can be measured, is a good start. The barriers to a culture of compassion are related to our systems of care. There are burgeoning administrative and documentation tasks to be performed, and productivity expectations that turn our clinics and hospitals into assembly lines. No, we cannot expect the EMR [electronic medical records] to be eliminated, but workforce well-being cannot be sustainable in the context of inadequate resources. A culture of compassionate collaborative care requires programs and policies that are implemented by the organization itself. Examples of organization-wide initiatives that support workforce well-being and provider engagement include: screening for caregiver burnout, establishing policies for managing adverse events with an eye toward the second victim, and most importantly, supporting systems that preserve work control autonomy of physicians and nurses in clinical settings. The business sector has long recognized that workplace stress is a function of how demanding a person’s job is and how much control that person has over his or her responsibilities. The business community has also recognized that the experience of the worker (provider) drives the experience of the customer (patient). In a study of hospital compassionate practices and HCAHPS [the Hospital Consumer Assessment of Healthcare Providers and Systems], McClelland and Vogus reported that how well a hospital compassionately supports it employees and rewards compassionate acts is significantly and positively is associated with that hospital’s ratings and likelihood of patients recommending it.
How does the Society of Vascular Surgery, or any professional medical/nursing society for that matter, fit into this model?
We propose that the SVS find ways to empower their members to be agents for culture change within their own health care organizations. How might this be done:
- Teach organizational leadership skills, starting with the SVS Board of Directors, the presidential line, and the chairs of committees. Offer leadership courses at the Annual Meeting.
- Develop a community of caregivers committed to creating a compassionate collaborative culture. The SVS is a founding member of the Schwartz Center Healthcare Society Leadership Council, and you, as members of the SVS benefit from reduced registration at the Annual Compassion in Action Healthcare Conference, June 24-27, 2017 in Boston. (http://compassioninactionconference.org) This conference is designed to be highly experiential, using a hands-on “how to do it” model.
- The SVS should make improving the overall wellness of its members a specific goal and find specific metrics to monitor our progress towards this goal. Members can be provided with the tools to identify, monitor, and measure burnout and compassion. Each committee and council of the SVS can reexamine their objectives through the lens of reducing burnout and improving the wellness of vascular surgeons.
- Provide members with evidence-based programs that build personal resilience. This will not be a successful initiative unless our surgeons recognize and acknowledge the symptoms of burnout, and are willing to admit vulnerability. Without doing so, it is difficult to reach out for help.
- Redesign postgraduate resident and fellowship education. Standardizing clinical care may reduce variation and promote efficiency. However, when processes such as time-limited appointment scheduling, EMR templates, and protocols that drive physician-patient interactions are embedded in Resident and Fellowship education, the result may well be inflexibility in practice, reduced face time with patients, and interactions that lack compassion; all leading to burnout. Graduate Medical Education leaders must develop programs that support the learner’s ability to connect with patients and families, cultivate and role-model skills and behaviors that strengthen compassionate interactions, and strive to develop clinical practice models that increase Resident and Fellow work control autonomy.
The SVS should work proactively to optimize workload, fairness, and reward on a larger scale for its members as it relates to the EMR, reimbursement, and systems coverage. While we may be relatively small in size, as leaders, we are perfectly poised to address these larger, global issues. Perhaps working within the current system (i.e., PAC and APM task force) and considering innovative solutions at a national leadership scale, the SVS can direct real change!
Changing culture is not easy, nor quick, nor does it have an easy-to-follow blueprint. The first step is recognizing the need. The second is taking a leadership role. The third is thinking deeply about implementation.
*The authors extend their thanks and appreciation for the guidance, resources and support of Michael Goldberg, MD, scholar in residence, Schwartz Center for Compassionate Care, Boston and clinical professor of orthopedics at Seattle Children’s Hospital.
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7. Karasek RA Job demands, job decision latitude, and mental strain: implications for job design. Administrative Sciences Quarterly (1979) 24: 285-308
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VAM ’17 Will Be a ‘Spectacular Meeting’
Participants at the Vascular Annual Meeting (VAM) have lots more to look forward to than sunny skies, beaches and palm trees. A number of new program features are planned to add interest and value to the meeting, said Dr. Ron Dalman.
Dr. Dalman chairs the SVS Program Committee, which develops programming and content for VAM, the premiere meeting for vascular specialists.
The 2017 meeting will be May 31-June 3 in beautiful San Diego, with plenaries and exhibits set for June 1-3.
Changes for 2017 include:
• More and potentially longer sessions with collaborative specialty societies, such as the American Venous Forum, the Society for Vascular Ultrasound and the Society of Thoracic Surgeons. “These sessions provide a multi-disciplinary perspective on our common problems and showcase the SVS’ leadership role in vascular health and disease management,” said Dr. Dalman. Members provided positive feedback on last year’s partnership sessions, so this year, these program features will be significantly expanded.
• An educational review course highlighting some of the more frequently missed questions from the latest version of the Vascular Education Self-Assessment Program (VESAP3).
• Guideline summaries, organized by the SVS Document Oversight Committee and presented by the authorship group for each, on critical topics such as abdominal aortic aneurysms, aortic dissection, venous disease and more. These summaries will be incorporated into post-graduate programming. “It makes sense to cover current practice guidelines and consensus documents, as several high-profile efforts are being updated this year,” said Dr. Dalman. “We can give attendees an executive summary of current guidelines by their respective authors, and attendees will come away with unique insights into why the most impactful and significant changes were included in each respective document.”
• Sessions of potential interest to surgeons in community practice environments, marked in the schedule as such by the SVS Community Practice Committee.
“These improvements will increase the value of the Annual Meeting for all attendees,” Dr. Dalman said. “We’re emphasizing interactive education, not simply passive learning. It’s going to be very exciting – and different in both style and substance.”
A Californian himself, Dr. Dalman also is looking forward to showing off his state. “San Diego is a wonderful place to vacation and the meeting venue provides convenient access to the Gaslamp District, the waterfront and the world-famous beaches,” he said.
“We encourage our members to bring their families to San Diego and make a vacation out of it.”
With the programming additions, increased opportunities for participation, the educational activities planned plus the perfect location, he added, “This is going to be a spectacular meeting.”
Participants at the Vascular Annual Meeting (VAM) have lots more to look forward to than sunny skies, beaches and palm trees. A number of new program features are planned to add interest and value to the meeting, said Dr. Ron Dalman.
Dr. Dalman chairs the SVS Program Committee, which develops programming and content for VAM, the premiere meeting for vascular specialists.
The 2017 meeting will be May 31-June 3 in beautiful San Diego, with plenaries and exhibits set for June 1-3.
Changes for 2017 include:
• More and potentially longer sessions with collaborative specialty societies, such as the American Venous Forum, the Society for Vascular Ultrasound and the Society of Thoracic Surgeons. “These sessions provide a multi-disciplinary perspective on our common problems and showcase the SVS’ leadership role in vascular health and disease management,” said Dr. Dalman. Members provided positive feedback on last year’s partnership sessions, so this year, these program features will be significantly expanded.
• An educational review course highlighting some of the more frequently missed questions from the latest version of the Vascular Education Self-Assessment Program (VESAP3).
• Guideline summaries, organized by the SVS Document Oversight Committee and presented by the authorship group for each, on critical topics such as abdominal aortic aneurysms, aortic dissection, venous disease and more. These summaries will be incorporated into post-graduate programming. “It makes sense to cover current practice guidelines and consensus documents, as several high-profile efforts are being updated this year,” said Dr. Dalman. “We can give attendees an executive summary of current guidelines by their respective authors, and attendees will come away with unique insights into why the most impactful and significant changes were included in each respective document.”
• Sessions of potential interest to surgeons in community practice environments, marked in the schedule as such by the SVS Community Practice Committee.
“These improvements will increase the value of the Annual Meeting for all attendees,” Dr. Dalman said. “We’re emphasizing interactive education, not simply passive learning. It’s going to be very exciting – and different in both style and substance.”
A Californian himself, Dr. Dalman also is looking forward to showing off his state. “San Diego is a wonderful place to vacation and the meeting venue provides convenient access to the Gaslamp District, the waterfront and the world-famous beaches,” he said.
“We encourage our members to bring their families to San Diego and make a vacation out of it.”
With the programming additions, increased opportunities for participation, the educational activities planned plus the perfect location, he added, “This is going to be a spectacular meeting.”
Participants at the Vascular Annual Meeting (VAM) have lots more to look forward to than sunny skies, beaches and palm trees. A number of new program features are planned to add interest and value to the meeting, said Dr. Ron Dalman.
Dr. Dalman chairs the SVS Program Committee, which develops programming and content for VAM, the premiere meeting for vascular specialists.
The 2017 meeting will be May 31-June 3 in beautiful San Diego, with plenaries and exhibits set for June 1-3.
Changes for 2017 include:
• More and potentially longer sessions with collaborative specialty societies, such as the American Venous Forum, the Society for Vascular Ultrasound and the Society of Thoracic Surgeons. “These sessions provide a multi-disciplinary perspective on our common problems and showcase the SVS’ leadership role in vascular health and disease management,” said Dr. Dalman. Members provided positive feedback on last year’s partnership sessions, so this year, these program features will be significantly expanded.
• An educational review course highlighting some of the more frequently missed questions from the latest version of the Vascular Education Self-Assessment Program (VESAP3).
• Guideline summaries, organized by the SVS Document Oversight Committee and presented by the authorship group for each, on critical topics such as abdominal aortic aneurysms, aortic dissection, venous disease and more. These summaries will be incorporated into post-graduate programming. “It makes sense to cover current practice guidelines and consensus documents, as several high-profile efforts are being updated this year,” said Dr. Dalman. “We can give attendees an executive summary of current guidelines by their respective authors, and attendees will come away with unique insights into why the most impactful and significant changes were included in each respective document.”
• Sessions of potential interest to surgeons in community practice environments, marked in the schedule as such by the SVS Community Practice Committee.
“These improvements will increase the value of the Annual Meeting for all attendees,” Dr. Dalman said. “We’re emphasizing interactive education, not simply passive learning. It’s going to be very exciting – and different in both style and substance.”
A Californian himself, Dr. Dalman also is looking forward to showing off his state. “San Diego is a wonderful place to vacation and the meeting venue provides convenient access to the Gaslamp District, the waterfront and the world-famous beaches,” he said.
“We encourage our members to bring their families to San Diego and make a vacation out of it.”
With the programming additions, increased opportunities for participation, the educational activities planned plus the perfect location, he added, “This is going to be a spectacular meeting.”