Federal Practitioner

Metabolic modulation may represent a viable therapeutic strategy in pulmonary hypertension (PH), report researchers from the Veterans Affairs Atlanta Healthcare System. Metformin and thiazolidinedione (TZD) were associated with significantly improved survival in their recent retrospective study of 41,670 veterans with PH and diabetes mellitus (DM). Insulin, on the other hand, was associated with increased mortality.

PH is a complex condition that may combine pulmonary vascular disease, heart disease, lung disease, and chronic thromboembolism. More than one-third of veterans with PH also have DM. Veterans are more likely than nonveterans to have chronic cardiopulmonary disease, which may make them particularly susceptible to PH. Moreover, those who served in Iraq and Afghanistan may have respiratory issues that predispose them to PH.

Another study from the same researchers assessed the influence of DM and weight, both potentially modifiable risk factors, on PH outcomes in 110,495 veterans. Veterans with PH survived an average of 3.9 years after PH diagnosis. Roughly one-third had DM, which increased risk of death by 31%. The analysis showed that lower weight and DM were strong risk factors for mortality in PH.

The most striking finding in the current study, according to the researchers, was a consistent reduction of about 20% in mortality risk associated with metformin and a similar association of 18% lower risk with TZD. The contrast with the 28% higher mortality with insulin “likely reflects fundamental differences” in how these medications influence cellular energy metabolism, they reported.

Interactions were observed between drug effects and both renal function and PH comorbidities, with metformin's protective effect enhanced in patients with lower estimated glomerular filtration rate but attenuated in those with lung disease. The associations remained “robust across multiple analytical approaches,” the researchers note.

Hemoglobin A_1c was not associated with outcome, suggesting that these therapies' association with outcome may be irrespective of their glycemic effects. The researchers say this emphasizes the complex interplay between DM and PH pathobiology, known differences in mechanisms of action of antidiabetic medications, and potentially off target impacts of these metabolically active therapies.

Metabolic modulation may represent a viable therapeutic strategy in pulmonary hypertension (PH), report researchers from the Veterans Affairs Atlanta Healthcare System. Metformin and thiazolidinedione (TZD) were associated with significantly improved survival in their recent retrospective study of 41,670 veterans with PH and diabetes mellitus (DM). Insulin, on the other hand, was associated with increased mortality.

PH is a complex condition that may combine pulmonary vascular disease, heart disease, lung disease, and chronic thromboembolism. More than one-third of veterans with PH also have DM. Veterans are more likely than nonveterans to have chronic cardiopulmonary disease, which may make them particularly susceptible to PH. Moreover, those who served in Iraq and Afghanistan may have respiratory issues that predispose them to PH.

Another study from the same researchers assessed the influence of DM and weight, both potentially modifiable risk factors, on PH outcomes in 110,495 veterans. Veterans with PH survived an average of 3.9 years after PH diagnosis. Roughly one-third had DM, which increased risk of death by 31%. The analysis showed that lower weight and DM were strong risk factors for mortality in PH.

The most striking finding in the current study, according to the researchers, was a consistent reduction of about 20% in mortality risk associated with metformin and a similar association of 18% lower risk with TZD. The contrast with the 28% higher mortality with insulin “likely reflects fundamental differences” in how these medications influence cellular energy metabolism, they reported.

Interactions were observed between drug effects and both renal function and PH comorbidities, with metformin's protective effect enhanced in patients with lower estimated glomerular filtration rate but attenuated in those with lung disease. The associations remained “robust across multiple analytical approaches,” the researchers note.

Hemoglobin A_1c was not associated with outcome, suggesting that these therapies' association with outcome may be irrespective of their glycemic effects. The researchers say this emphasizes the complex interplay between DM and PH pathobiology, known differences in mechanisms of action of antidiabetic medications, and potentially off target impacts of these metabolically active therapies.

Metabolic modulation may represent a viable therapeutic strategy in pulmonary hypertension (PH), report researchers from the Veterans Affairs Atlanta Healthcare System. Metformin and thiazolidinedione (TZD) were associated with significantly improved survival in their recent retrospective study of 41,670 veterans with PH and diabetes mellitus (DM). Insulin, on the other hand, was associated with increased mortality.

PH is a complex condition that may combine pulmonary vascular disease, heart disease, lung disease, and chronic thromboembolism. More than one-third of veterans with PH also have DM. Veterans are more likely than nonveterans to have chronic cardiopulmonary disease, which may make them particularly susceptible to PH. Moreover, those who served in Iraq and Afghanistan may have respiratory issues that predispose them to PH.

Another study from the same researchers assessed the influence of DM and weight, both potentially modifiable risk factors, on PH outcomes in 110,495 veterans. Veterans with PH survived an average of 3.9 years after PH diagnosis. Roughly one-third had DM, which increased risk of death by 31%. The analysis showed that lower weight and DM were strong risk factors for mortality in PH.

The most striking finding in the current study, according to the researchers, was a consistent reduction of about 20% in mortality risk associated with metformin and a similar association of 18% lower risk with TZD. The contrast with the 28% higher mortality with insulin “likely reflects fundamental differences” in how these medications influence cellular energy metabolism, they reported.

Interactions were observed between drug effects and both renal function and PH comorbidities, with metformin's protective effect enhanced in patients with lower estimated glomerular filtration rate but attenuated in those with lung disease. The associations remained “robust across multiple analytical approaches,” the researchers note.

Hemoglobin A_1c was not associated with outcome, suggesting that these therapies' association with outcome may be irrespective of their glycemic effects. The researchers say this emphasizes the complex interplay between DM and PH pathobiology, known differences in mechanisms of action of antidiabetic medications, and potentially off target impacts of these metabolically active therapies.

A novel wearable wrist device was feasible and effective for identifying exposure to respiratory viruses in children with asthma, based on new data presented at the American Thoracic Society 2026 International Conference.

Upper respiratory infections are the main trigger of asthma exacerbations in children, and documented racial and ethnic disparities in upper respiratory infections likely contribute to similar disparities in asthma exacerbations, noted Darlene Bhavnani, PhD, MPH, of The University of Texas at Austin, et al in their abstract.

“Understanding differences in personal exposure to upper respiratory viruses in children with asthma may help to inform these differences in the risk of viral infection and viral-associated asthma exacerbations,” Bhavnani said.

The researchers hypothesized that the use of a wearable passive air sampler could monitor respiratory virus exposure as a way to identify children at increased risk for asthma exacerbations.

Wrist devices to measure respiratory virus exposure are an emerging technology and have not been tested in children, the researchers noted. In their study, the researchers identified 25 children aged 6 to 17 years with persistent asthma who were enrolled in the TexHALE study. Participants were given a Fresh Air Clip to station in their homes and were asked to wear a wristband with a Fresh Air Clip for about 5 consecutive days. The median age of the participants was 12 years, and 64% were male.

At the end of the study period, families reported the number of days the wristband was worn, and the researchers used droplet digital polymerase chain reaction tests to quantify exposure to rhinovirus, respiratory syncytial virus (RSV), influenza A, and influenza B.

A total of 24 clips and 24 wristbands were distributed; 23 clips and all 24 wristbands were recovered for analysis. A total of 22 participants (92%) wore the wristband over a median of 6 days. Overall, approximately one-third of the wristbands (33%) tested positive for any respiratory virus, defined as > 6 copies of viral RNA, with 5 positive tests for rhinovirus, 5 for influenza B, 2 for RSV, and none for influenza A. None of the stationary home-based clips tested positive for any respiratory virus.

The researchers were not sure what to expect from the study, as personal exposure to upper respiratory viruses has not been well studied in children, said Bhavnani.

“One third of the children in our pilot study were exposed to one or more upper respiratory viruses in their personal environments, which is a substantial portion of the population studied,” she noted. “Given that viral exposure is the first step in the pathway leading to a viral infection and viral-associated asthma exacerbations, understanding differences in viral exposure could help us to learn more about how to prevent viral infection and viral-associated asthma exacerbations in children with asthma,” she said.

The study was limited by the small sample size, and larger studies are needed. However, the finding the one-third of wristbands and zero stationary clips tested positive for upper respiratory viruses suggests that clips stationed in homes may not be optimal to detect household exposures, or and that exposure outside the home may be more important for monitoring exposure to respiratory viruses in this population, and the results support the feasibility of the devices, the researchers wrote.

“Fresh Air Clips in the form of wearables can be used to understand differences in personal viral exposure and to target interventions that ultimately, would reduce the burden of viral infection and viral-associated asthma exacerbations,” Bhavnani said.

New Role for New Technology

“New technology now allows us to quantitate exposure to specific respiratory viruses on wearable and stationary devices,” said Tim Joos, MD, who practices internal medicine and pediatrics at a community health center in Seattle.

The current study findings suggest that the majority of the exposure to respiratory viruses occurs outside the home, said Joos, who was not involved in the study. Consequently, technology that can detect community exposure could be useful, although the role it may play in public health and clinical practice is yet to be determined, Joos said.

The wristbands and clips were easy to deploy and recover, which supports their value, and potential applications include testing the effectiveness of infection control strategies such as social distancing, masking, and isolation in lowering viral exposures, Joos noted.

The study received no outside funding but was supported by core funds from the Dell Medical School at the University of Texas at Austin. The researchers had no financial conflicts to disclose. Joos had no financial conflicts to disclose.

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

A novel wearable wrist device was feasible and effective for identifying exposure to respiratory viruses in children with asthma, based on new data presented at the American Thoracic Society 2026 International Conference.

Upper respiratory infections are the main trigger of asthma exacerbations in children, and documented racial and ethnic disparities in upper respiratory infections likely contribute to similar disparities in asthma exacerbations, noted Darlene Bhavnani, PhD, MPH, of The University of Texas at Austin, et al in their abstract.

“Understanding differences in personal exposure to upper respiratory viruses in children with asthma may help to inform these differences in the risk of viral infection and viral-associated asthma exacerbations,” Bhavnani said.

The researchers hypothesized that the use of a wearable passive air sampler could monitor respiratory virus exposure as a way to identify children at increased risk for asthma exacerbations.

Wrist devices to measure respiratory virus exposure are an emerging technology and have not been tested in children, the researchers noted. In their study, the researchers identified 25 children aged 6 to 17 years with persistent asthma who were enrolled in the TexHALE study. Participants were given a Fresh Air Clip to station in their homes and were asked to wear a wristband with a Fresh Air Clip for about 5 consecutive days. The median age of the participants was 12 years, and 64% were male.

At the end of the study period, families reported the number of days the wristband was worn, and the researchers used droplet digital polymerase chain reaction tests to quantify exposure to rhinovirus, respiratory syncytial virus (RSV), influenza A, and influenza B.

A total of 24 clips and 24 wristbands were distributed; 23 clips and all 24 wristbands were recovered for analysis. A total of 22 participants (92%) wore the wristband over a median of 6 days. Overall, approximately one-third of the wristbands (33%) tested positive for any respiratory virus, defined as > 6 copies of viral RNA, with 5 positive tests for rhinovirus, 5 for influenza B, 2 for RSV, and none for influenza A. None of the stationary home-based clips tested positive for any respiratory virus.

The researchers were not sure what to expect from the study, as personal exposure to upper respiratory viruses has not been well studied in children, said Bhavnani.

“One third of the children in our pilot study were exposed to one or more upper respiratory viruses in their personal environments, which is a substantial portion of the population studied,” she noted. “Given that viral exposure is the first step in the pathway leading to a viral infection and viral-associated asthma exacerbations, understanding differences in viral exposure could help us to learn more about how to prevent viral infection and viral-associated asthma exacerbations in children with asthma,” she said.

The study was limited by the small sample size, and larger studies are needed. However, the finding the one-third of wristbands and zero stationary clips tested positive for upper respiratory viruses suggests that clips stationed in homes may not be optimal to detect household exposures, or and that exposure outside the home may be more important for monitoring exposure to respiratory viruses in this population, and the results support the feasibility of the devices, the researchers wrote.

“Fresh Air Clips in the form of wearables can be used to understand differences in personal viral exposure and to target interventions that ultimately, would reduce the burden of viral infection and viral-associated asthma exacerbations,” Bhavnani said.

New Role for New Technology

“New technology now allows us to quantitate exposure to specific respiratory viruses on wearable and stationary devices,” said Tim Joos, MD, who practices internal medicine and pediatrics at a community health center in Seattle.

The current study findings suggest that the majority of the exposure to respiratory viruses occurs outside the home, said Joos, who was not involved in the study. Consequently, technology that can detect community exposure could be useful, although the role it may play in public health and clinical practice is yet to be determined, Joos said.

The wristbands and clips were easy to deploy and recover, which supports their value, and potential applications include testing the effectiveness of infection control strategies such as social distancing, masking, and isolation in lowering viral exposures, Joos noted.

The study received no outside funding but was supported by core funds from the Dell Medical School at the University of Texas at Austin. The researchers had no financial conflicts to disclose. Joos had no financial conflicts to disclose.

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

A novel wearable wrist device was feasible and effective for identifying exposure to respiratory viruses in children with asthma, based on new data presented at the American Thoracic Society 2026 International Conference.

Upper respiratory infections are the main trigger of asthma exacerbations in children, and documented racial and ethnic disparities in upper respiratory infections likely contribute to similar disparities in asthma exacerbations, noted Darlene Bhavnani, PhD, MPH, of The University of Texas at Austin, et al in their abstract.

“Understanding differences in personal exposure to upper respiratory viruses in children with asthma may help to inform these differences in the risk of viral infection and viral-associated asthma exacerbations,” Bhavnani said.

The researchers hypothesized that the use of a wearable passive air sampler could monitor respiratory virus exposure as a way to identify children at increased risk for asthma exacerbations.

Wrist devices to measure respiratory virus exposure are an emerging technology and have not been tested in children, the researchers noted. In their study, the researchers identified 25 children aged 6 to 17 years with persistent asthma who were enrolled in the TexHALE study. Participants were given a Fresh Air Clip to station in their homes and were asked to wear a wristband with a Fresh Air Clip for about 5 consecutive days. The median age of the participants was 12 years, and 64% were male.

At the end of the study period, families reported the number of days the wristband was worn, and the researchers used droplet digital polymerase chain reaction tests to quantify exposure to rhinovirus, respiratory syncytial virus (RSV), influenza A, and influenza B.

A total of 24 clips and 24 wristbands were distributed; 23 clips and all 24 wristbands were recovered for analysis. A total of 22 participants (92%) wore the wristband over a median of 6 days. Overall, approximately one-third of the wristbands (33%) tested positive for any respiratory virus, defined as > 6 copies of viral RNA, with 5 positive tests for rhinovirus, 5 for influenza B, 2 for RSV, and none for influenza A. None of the stationary home-based clips tested positive for any respiratory virus.

The researchers were not sure what to expect from the study, as personal exposure to upper respiratory viruses has not been well studied in children, said Bhavnani.

“One third of the children in our pilot study were exposed to one or more upper respiratory viruses in their personal environments, which is a substantial portion of the population studied,” she noted. “Given that viral exposure is the first step in the pathway leading to a viral infection and viral-associated asthma exacerbations, understanding differences in viral exposure could help us to learn more about how to prevent viral infection and viral-associated asthma exacerbations in children with asthma,” she said.

The study was limited by the small sample size, and larger studies are needed. However, the finding the one-third of wristbands and zero stationary clips tested positive for upper respiratory viruses suggests that clips stationed in homes may not be optimal to detect household exposures, or and that exposure outside the home may be more important for monitoring exposure to respiratory viruses in this population, and the results support the feasibility of the devices, the researchers wrote.

“Fresh Air Clips in the form of wearables can be used to understand differences in personal viral exposure and to target interventions that ultimately, would reduce the burden of viral infection and viral-associated asthma exacerbations,” Bhavnani said.

New Role for New Technology

“New technology now allows us to quantitate exposure to specific respiratory viruses on wearable and stationary devices,” said Tim Joos, MD, who practices internal medicine and pediatrics at a community health center in Seattle.

The current study findings suggest that the majority of the exposure to respiratory viruses occurs outside the home, said Joos, who was not involved in the study. Consequently, technology that can detect community exposure could be useful, although the role it may play in public health and clinical practice is yet to be determined, Joos said.

The wristbands and clips were easy to deploy and recover, which supports their value, and potential applications include testing the effectiveness of infection control strategies such as social distancing, masking, and isolation in lowering viral exposures, Joos noted.

The study received no outside funding but was supported by core funds from the Dell Medical School at the University of Texas at Austin. The researchers had no financial conflicts to disclose. Joos had no financial conflicts to disclose.

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

Chronic obstructive pulmonary disease (COPD) affects about 25% of the veteran population and is the third-leading cause of death globally.^1,2 In patients with COPD, cigarette smoking leads to increased respiratory symptoms, a greater annual rate of decline in forced expiratory volume in 1 second (FEV₁), and an increase in COPD mortality rate vs nonsmokers.³ Veterans are at a higher risk of COPD due to increased prevalence of smoking within this population as well as military activities leading to environmental and occupational exposure.⁴

According to the 2024 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, the primary treatment goals of COPD therapy are to reduce symptoms and future risk of exacerbations.³ Bronchodilators are recommended for initial COPD pharmacotherapy, including long-acting muscarinic antagonists (LAMAs) and/or long-acting Β₂-agonists (LABAs). In some cases, treatment may include inhaled corticosteroids (ICS). Evidence supports ICS therapy in patients with COPD experiencing hospitalizations for exacerbations, ≥ 2 moderate exacerbations per year, blood eosinophil count ≥ 300 cells/μL or concomitant asthma.³

While the 2024 GOLD guidelines caution against the use of ICS outside of certain patient groups, previous GOLD guidelines recommended the use of ICS more broadly.⁵ Due to these changes, many patients may be using ICS therapy unnecessarily. At the Sioux Falls Veterans Affairs Health Care System (SFVAHCS), ICS overuse was identified as a driver of increased medication burden and potential adverse effects (AEs). To help reduce unnecessary ICS use, a data dashboard was created to identify potential candidates for ICS deprescribing. SFVAHCS clinical pharmacy practitioners are licensed pharmacists who work as independent practitioners with a scope of practice that allows them to initiate, modify, or discontinue medication therapy within medication management clinics. Pharmacists contacted dashboard patients to de-escalate ICS therapy when appropriate.

The SUNSET trial directly compared the continuation of triple therapy (tiotropium + salmeterol/fluticasone propionate) vs deprescribing to LABA/LAMA (indacaterol/ glycopyrronium) in patients with COPD.⁶ It evaluated whether LABA/LAMA was noninferior to LABA/LAMA/ICS therapy when comparing COPD exacerbations in patients whose COPD exacerbations were infrequent. Participants were randomized to triple therapy continuation or indacaterol/glycopyrronium and followed for 26 weeks. Patients on indacaterol/glycopyrronium did not have a significant difference in exacerbations than patients utilizing triple therapy.

The Implementation of a Targeted ICS De-Escalation in Patients with COPD in the Primary Care Setting trial evaluated the success of pharmacist-led ICS deprescribing in appropriate patients with COPD.⁷ Pharmacists followed GOLD guidelines to recommend ICS deprescribing and have risk vs benefit discussions with certain patients. Patients were considered for ICS deprescribing if they had a history of recurrent pneumonia or had no exacerbations within the previous year and eosinophils < 300 cells/μL (risk-benefit discussion if no eosinophil count available). This study found that 19.6% of patients were unable to tolerate ICS withdrawal and resumed either a standard or reduced dose of ICS therapy.⁷

Current guidelines and evidence recommend deprescribing ICS for appropriate patients. There is no current literature defining the impact of pharmacists on ICS deprescribing within the US Department of Veterans Affairs (VA) system. This study will allow for a quantifiable measure of pharmacists’ impact on reducing AEs associated with unnecessary ICS use.

Methods

This retrospective, single-center study was conducted at the SFVAHCS. Data were collected through manual chart review of SFVAHCS electronic health records. Veterans aged ≥ 18 years with a COPD diagnosis who underwent ICS deprescribing by a SFVAHCS pharmacist between February 2022 and December 2023 were included. Records were examined for 52 weeks prior to ICS withdrawal (baseline) and 52 weeks following withdrawal. Patients were excluded from the study if they had a history of asthma or ICS was used for < 52 weeks before deprescribing. Baseline characteristics were collected, including age, race, sex, current tobacco use, eosinophil count, COPD maintenance therapy, FEV₁/forced vital capacity (FVC) ratio, and mean postbronchodilator FEV₁ improvement.

The primary endpoint was number of COPD exacerbations at 52 weeks before vs after deprescribing. Secondary endpoints included the number of patients restarted on an ICS within 52 weeks of deprescribing, as well as ICS AEs, including pneumonia, oral candidiasis, and throat hoarseness.

Statistical Analysis

The primary endpoint was analyzed using the Wilcoxon signed rank test and secondary endpoints were analyzed using the McNemar exact test. Results with P < .05 were considered statistically significant for both tests.

Results

Seventy-six patients were included. Patients had a mean age of 75 years and 91% identified as White, which is representative of the SFVAHCS patient population (Table 1). Twenty-nine (38%) patients were current tobacco users and 55 patients (72%) used LAMA/LABA therapy (after ICS deprescribing) with an eosinophil count < 300 cells/μL. There was no significant difference in exacerbations before vs after ICS deprescribing (P = .78) (Table 2). There were 7 AEs reported before ICS deprescribing vs 0 following ICS deprescribing (P < .001). Five patients (7%) reported throat hoarseness, 1 (1%) reported pneumonia, and 1 (1%) reported oral candidiasis. Eighteen patients were reinitiated on ICS (24%). ICS reinitiation was most commonly due to patients reporting worsening symptoms (56%) (Table 3).

Discussion

This study sought to determine the impact of pharmacist-led ICS deprescribing on AEs and exacerbations experienced by patients with COPD. COPD exacerbations were not significantly different before vs after ICS deprescribing. The pharmacist-led ICS deprescribing program did not lead to increased COPD exacerbations. Similar to the SUNSET trial, the results of this study showed exacerbations did not significantly increase upon ICS deprescribing; however, this study differed by specifying pharmacist- led intervention.⁶

There was a decrease in ICS-related AEs following ICS deprescribing. Several patients were reinitiated on an ICS. As expected with deprescribing, some patients were not able to tolerate ICS withdrawal or had clinical indications to resume therapy (ie, an exacerbation). Similar results were found in another study where 8.9% of patients were restarted on ICS and 10.9% were de-escalated to a lower dose but were unable to stop completely.⁷ A 2024 systematic review by Georgiou et al found a wide range of patients resumed ICS therapy following withdrawal (21%-74%). Of note, only 2 of the randomized controlled trials and 3 observational studies included this meta-analysis included data on ICS reinitiation. Georgiou et al concluded there was insufficient evidence to determine the proportion of patients reinitiated on ICS but patients were commonly resumed on ICS therapy due to worsening symptoms, experiencing an exacerbation or decline in FEV₁.⁸ Although the rate of ICS reinitiation was unclear in the Georgiou et al meta-analysis, reasons for re-initiation were similar to what was found in our study.⁸

Strengths and Limitations

The retrospective nature of this study and its small sample size of 76 patients limit its findings. The retrospective nature of the study required researchers to rely on proper chart documentation, which is not always accurate or up to date. Lack of documentation of COPD exacerbations or patients who received care outside the VA following initial deprescribing could have biased study results. This patient population is representative of the veteran population in South Dakota but is not representative of the female or non-White patient population which may be more prevalent at other VA Health Care Systems as well as nonveteran patient populations. Additionally, this study was limited to a review of 52 weeks pre- and post-ICS deprescribing which may have impacted results. Patients may have had a COPD exacerbation or were restarted on ICS therapy beyond 52 weeks. Finally, the retrospective nature and small sample size limited the findings for the primary endpoint which could have been improved with a larger sample size and a randomized controlled design.

The comparison of patients with themselves before and after ICS deprescribing reduced the potential for bias seen in retrospective studies. This method did not require a second control group which would potentially introduce confounding factors.

Conclusions

This study found that in a small population of veterans with COPD, pharmacist-led ICS deprescribing did not lead to an increase in COPD exacerbations and decreased the risk of AEs related to ICS therapy. Some patients were reinitiated on ICS therapy; however, reinitiation was rarely attributable to a COPD exacerbation. This study suggests that pharmacists were able to appropriately identify candidates for ICS deprescribing without increasing their risk of exacerbations. By de-escalating ICS therapy, pharmacists decreased medication burden and potential AEs caused by ICS therapy. These findings support expanding the role of clinical pharmacists in COPD management, particularly in identifying candidates for safe ICS deprescribing.

Chronic obstructive pulmonary disease (COPD) affects about 25% of the veteran population and is the third-leading cause of death globally.^1,2 In patients with COPD, cigarette smoking leads to increased respiratory symptoms, a greater annual rate of decline in forced expiratory volume in 1 second (FEV₁), and an increase in COPD mortality rate vs nonsmokers.³ Veterans are at a higher risk of COPD due to increased prevalence of smoking within this population as well as military activities leading to environmental and occupational exposure.⁴

According to the 2024 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, the primary treatment goals of COPD therapy are to reduce symptoms and future risk of exacerbations.³ Bronchodilators are recommended for initial COPD pharmacotherapy, including long-acting muscarinic antagonists (LAMAs) and/or long-acting Β₂-agonists (LABAs). In some cases, treatment may include inhaled corticosteroids (ICS). Evidence supports ICS therapy in patients with COPD experiencing hospitalizations for exacerbations, ≥ 2 moderate exacerbations per year, blood eosinophil count ≥ 300 cells/μL or concomitant asthma.³

While the 2024 GOLD guidelines caution against the use of ICS outside of certain patient groups, previous GOLD guidelines recommended the use of ICS more broadly.⁵ Due to these changes, many patients may be using ICS therapy unnecessarily. At the Sioux Falls Veterans Affairs Health Care System (SFVAHCS), ICS overuse was identified as a driver of increased medication burden and potential adverse effects (AEs). To help reduce unnecessary ICS use, a data dashboard was created to identify potential candidates for ICS deprescribing. SFVAHCS clinical pharmacy practitioners are licensed pharmacists who work as independent practitioners with a scope of practice that allows them to initiate, modify, or discontinue medication therapy within medication management clinics. Pharmacists contacted dashboard patients to de-escalate ICS therapy when appropriate.

The SUNSET trial directly compared the continuation of triple therapy (tiotropium + salmeterol/fluticasone propionate) vs deprescribing to LABA/LAMA (indacaterol/ glycopyrronium) in patients with COPD.⁶ It evaluated whether LABA/LAMA was noninferior to LABA/LAMA/ICS therapy when comparing COPD exacerbations in patients whose COPD exacerbations were infrequent. Participants were randomized to triple therapy continuation or indacaterol/glycopyrronium and followed for 26 weeks. Patients on indacaterol/glycopyrronium did not have a significant difference in exacerbations than patients utilizing triple therapy.

The Implementation of a Targeted ICS De-Escalation in Patients with COPD in the Primary Care Setting trial evaluated the success of pharmacist-led ICS deprescribing in appropriate patients with COPD.⁷ Pharmacists followed GOLD guidelines to recommend ICS deprescribing and have risk vs benefit discussions with certain patients. Patients were considered for ICS deprescribing if they had a history of recurrent pneumonia or had no exacerbations within the previous year and eosinophils < 300 cells/μL (risk-benefit discussion if no eosinophil count available). This study found that 19.6% of patients were unable to tolerate ICS withdrawal and resumed either a standard or reduced dose of ICS therapy.⁷

Current guidelines and evidence recommend deprescribing ICS for appropriate patients. There is no current literature defining the impact of pharmacists on ICS deprescribing within the US Department of Veterans Affairs (VA) system. This study will allow for a quantifiable measure of pharmacists’ impact on reducing AEs associated with unnecessary ICS use.

Methods

This retrospective, single-center study was conducted at the SFVAHCS. Data were collected through manual chart review of SFVAHCS electronic health records. Veterans aged ≥ 18 years with a COPD diagnosis who underwent ICS deprescribing by a SFVAHCS pharmacist between February 2022 and December 2023 were included. Records were examined for 52 weeks prior to ICS withdrawal (baseline) and 52 weeks following withdrawal. Patients were excluded from the study if they had a history of asthma or ICS was used for < 52 weeks before deprescribing. Baseline characteristics were collected, including age, race, sex, current tobacco use, eosinophil count, COPD maintenance therapy, FEV₁/forced vital capacity (FVC) ratio, and mean postbronchodilator FEV₁ improvement.

The primary endpoint was number of COPD exacerbations at 52 weeks before vs after deprescribing. Secondary endpoints included the number of patients restarted on an ICS within 52 weeks of deprescribing, as well as ICS AEs, including pneumonia, oral candidiasis, and throat hoarseness.

Statistical Analysis

The primary endpoint was analyzed using the Wilcoxon signed rank test and secondary endpoints were analyzed using the McNemar exact test. Results with P < .05 were considered statistically significant for both tests.

Results

Seventy-six patients were included. Patients had a mean age of 75 years and 91% identified as White, which is representative of the SFVAHCS patient population (Table 1). Twenty-nine (38%) patients were current tobacco users and 55 patients (72%) used LAMA/LABA therapy (after ICS deprescribing) with an eosinophil count < 300 cells/μL. There was no significant difference in exacerbations before vs after ICS deprescribing (P = .78) (Table 2). There were 7 AEs reported before ICS deprescribing vs 0 following ICS deprescribing (P < .001). Five patients (7%) reported throat hoarseness, 1 (1%) reported pneumonia, and 1 (1%) reported oral candidiasis. Eighteen patients were reinitiated on ICS (24%). ICS reinitiation was most commonly due to patients reporting worsening symptoms (56%) (Table 3).

Discussion

This study sought to determine the impact of pharmacist-led ICS deprescribing on AEs and exacerbations experienced by patients with COPD. COPD exacerbations were not significantly different before vs after ICS deprescribing. The pharmacist-led ICS deprescribing program did not lead to increased COPD exacerbations. Similar to the SUNSET trial, the results of this study showed exacerbations did not significantly increase upon ICS deprescribing; however, this study differed by specifying pharmacist- led intervention.⁶

There was a decrease in ICS-related AEs following ICS deprescribing. Several patients were reinitiated on an ICS. As expected with deprescribing, some patients were not able to tolerate ICS withdrawal or had clinical indications to resume therapy (ie, an exacerbation). Similar results were found in another study where 8.9% of patients were restarted on ICS and 10.9% were de-escalated to a lower dose but were unable to stop completely.⁷ A 2024 systematic review by Georgiou et al found a wide range of patients resumed ICS therapy following withdrawal (21%-74%). Of note, only 2 of the randomized controlled trials and 3 observational studies included this meta-analysis included data on ICS reinitiation. Georgiou et al concluded there was insufficient evidence to determine the proportion of patients reinitiated on ICS but patients were commonly resumed on ICS therapy due to worsening symptoms, experiencing an exacerbation or decline in FEV₁.⁸ Although the rate of ICS reinitiation was unclear in the Georgiou et al meta-analysis, reasons for re-initiation were similar to what was found in our study.⁸

Strengths and Limitations

The retrospective nature of this study and its small sample size of 76 patients limit its findings. The retrospective nature of the study required researchers to rely on proper chart documentation, which is not always accurate or up to date. Lack of documentation of COPD exacerbations or patients who received care outside the VA following initial deprescribing could have biased study results. This patient population is representative of the veteran population in South Dakota but is not representative of the female or non-White patient population which may be more prevalent at other VA Health Care Systems as well as nonveteran patient populations. Additionally, this study was limited to a review of 52 weeks pre- and post-ICS deprescribing which may have impacted results. Patients may have had a COPD exacerbation or were restarted on ICS therapy beyond 52 weeks. Finally, the retrospective nature and small sample size limited the findings for the primary endpoint which could have been improved with a larger sample size and a randomized controlled design.

The comparison of patients with themselves before and after ICS deprescribing reduced the potential for bias seen in retrospective studies. This method did not require a second control group which would potentially introduce confounding factors.

Conclusions

This study found that in a small population of veterans with COPD, pharmacist-led ICS deprescribing did not lead to an increase in COPD exacerbations and decreased the risk of AEs related to ICS therapy. Some patients were reinitiated on ICS therapy; however, reinitiation was rarely attributable to a COPD exacerbation. This study suggests that pharmacists were able to appropriately identify candidates for ICS deprescribing without increasing their risk of exacerbations. By de-escalating ICS therapy, pharmacists decreased medication burden and potential AEs caused by ICS therapy. These findings support expanding the role of clinical pharmacists in COPD management, particularly in identifying candidates for safe ICS deprescribing.

Chronic obstructive pulmonary disease (COPD) affects about 25% of the veteran population and is the third-leading cause of death globally.^1,2 In patients with COPD, cigarette smoking leads to increased respiratory symptoms, a greater annual rate of decline in forced expiratory volume in 1 second (FEV₁), and an increase in COPD mortality rate vs nonsmokers.³ Veterans are at a higher risk of COPD due to increased prevalence of smoking within this population as well as military activities leading to environmental and occupational exposure.⁴

According to the 2024 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, the primary treatment goals of COPD therapy are to reduce symptoms and future risk of exacerbations.³ Bronchodilators are recommended for initial COPD pharmacotherapy, including long-acting muscarinic antagonists (LAMAs) and/or long-acting Β₂-agonists (LABAs). In some cases, treatment may include inhaled corticosteroids (ICS). Evidence supports ICS therapy in patients with COPD experiencing hospitalizations for exacerbations, ≥ 2 moderate exacerbations per year, blood eosinophil count ≥ 300 cells/μL or concomitant asthma.³

While the 2024 GOLD guidelines caution against the use of ICS outside of certain patient groups, previous GOLD guidelines recommended the use of ICS more broadly.⁵ Due to these changes, many patients may be using ICS therapy unnecessarily. At the Sioux Falls Veterans Affairs Health Care System (SFVAHCS), ICS overuse was identified as a driver of increased medication burden and potential adverse effects (AEs). To help reduce unnecessary ICS use, a data dashboard was created to identify potential candidates for ICS deprescribing. SFVAHCS clinical pharmacy practitioners are licensed pharmacists who work as independent practitioners with a scope of practice that allows them to initiate, modify, or discontinue medication therapy within medication management clinics. Pharmacists contacted dashboard patients to de-escalate ICS therapy when appropriate.

The SUNSET trial directly compared the continuation of triple therapy (tiotropium + salmeterol/fluticasone propionate) vs deprescribing to LABA/LAMA (indacaterol/ glycopyrronium) in patients with COPD.⁶ It evaluated whether LABA/LAMA was noninferior to LABA/LAMA/ICS therapy when comparing COPD exacerbations in patients whose COPD exacerbations were infrequent. Participants were randomized to triple therapy continuation or indacaterol/glycopyrronium and followed for 26 weeks. Patients on indacaterol/glycopyrronium did not have a significant difference in exacerbations than patients utilizing triple therapy.

The Implementation of a Targeted ICS De-Escalation in Patients with COPD in the Primary Care Setting trial evaluated the success of pharmacist-led ICS deprescribing in appropriate patients with COPD.⁷ Pharmacists followed GOLD guidelines to recommend ICS deprescribing and have risk vs benefit discussions with certain patients. Patients were considered for ICS deprescribing if they had a history of recurrent pneumonia or had no exacerbations within the previous year and eosinophils < 300 cells/μL (risk-benefit discussion if no eosinophil count available). This study found that 19.6% of patients were unable to tolerate ICS withdrawal and resumed either a standard or reduced dose of ICS therapy.⁷

Current guidelines and evidence recommend deprescribing ICS for appropriate patients. There is no current literature defining the impact of pharmacists on ICS deprescribing within the US Department of Veterans Affairs (VA) system. This study will allow for a quantifiable measure of pharmacists’ impact on reducing AEs associated with unnecessary ICS use.

Methods

This retrospective, single-center study was conducted at the SFVAHCS. Data were collected through manual chart review of SFVAHCS electronic health records. Veterans aged ≥ 18 years with a COPD diagnosis who underwent ICS deprescribing by a SFVAHCS pharmacist between February 2022 and December 2023 were included. Records were examined for 52 weeks prior to ICS withdrawal (baseline) and 52 weeks following withdrawal. Patients were excluded from the study if they had a history of asthma or ICS was used for < 52 weeks before deprescribing. Baseline characteristics were collected, including age, race, sex, current tobacco use, eosinophil count, COPD maintenance therapy, FEV₁/forced vital capacity (FVC) ratio, and mean postbronchodilator FEV₁ improvement.

The primary endpoint was number of COPD exacerbations at 52 weeks before vs after deprescribing. Secondary endpoints included the number of patients restarted on an ICS within 52 weeks of deprescribing, as well as ICS AEs, including pneumonia, oral candidiasis, and throat hoarseness.

Statistical Analysis

The primary endpoint was analyzed using the Wilcoxon signed rank test and secondary endpoints were analyzed using the McNemar exact test. Results with P < .05 were considered statistically significant for both tests.

Results

Seventy-six patients were included. Patients had a mean age of 75 years and 91% identified as White, which is representative of the SFVAHCS patient population (Table 1). Twenty-nine (38%) patients were current tobacco users and 55 patients (72%) used LAMA/LABA therapy (after ICS deprescribing) with an eosinophil count < 300 cells/μL. There was no significant difference in exacerbations before vs after ICS deprescribing (P = .78) (Table 2). There were 7 AEs reported before ICS deprescribing vs 0 following ICS deprescribing (P < .001). Five patients (7%) reported throat hoarseness, 1 (1%) reported pneumonia, and 1 (1%) reported oral candidiasis. Eighteen patients were reinitiated on ICS (24%). ICS reinitiation was most commonly due to patients reporting worsening symptoms (56%) (Table 3).

Discussion

This study sought to determine the impact of pharmacist-led ICS deprescribing on AEs and exacerbations experienced by patients with COPD. COPD exacerbations were not significantly different before vs after ICS deprescribing. The pharmacist-led ICS deprescribing program did not lead to increased COPD exacerbations. Similar to the SUNSET trial, the results of this study showed exacerbations did not significantly increase upon ICS deprescribing; however, this study differed by specifying pharmacist- led intervention.⁶

There was a decrease in ICS-related AEs following ICS deprescribing. Several patients were reinitiated on an ICS. As expected with deprescribing, some patients were not able to tolerate ICS withdrawal or had clinical indications to resume therapy (ie, an exacerbation). Similar results were found in another study where 8.9% of patients were restarted on ICS and 10.9% were de-escalated to a lower dose but were unable to stop completely.⁷ A 2024 systematic review by Georgiou et al found a wide range of patients resumed ICS therapy following withdrawal (21%-74%). Of note, only 2 of the randomized controlled trials and 3 observational studies included this meta-analysis included data on ICS reinitiation. Georgiou et al concluded there was insufficient evidence to determine the proportion of patients reinitiated on ICS but patients were commonly resumed on ICS therapy due to worsening symptoms, experiencing an exacerbation or decline in FEV₁.⁸ Although the rate of ICS reinitiation was unclear in the Georgiou et al meta-analysis, reasons for re-initiation were similar to what was found in our study.⁸

Strengths and Limitations

The retrospective nature of this study and its small sample size of 76 patients limit its findings. The retrospective nature of the study required researchers to rely on proper chart documentation, which is not always accurate or up to date. Lack of documentation of COPD exacerbations or patients who received care outside the VA following initial deprescribing could have biased study results. This patient population is representative of the veteran population in South Dakota but is not representative of the female or non-White patient population which may be more prevalent at other VA Health Care Systems as well as nonveteran patient populations. Additionally, this study was limited to a review of 52 weeks pre- and post-ICS deprescribing which may have impacted results. Patients may have had a COPD exacerbation or were restarted on ICS therapy beyond 52 weeks. Finally, the retrospective nature and small sample size limited the findings for the primary endpoint which could have been improved with a larger sample size and a randomized controlled design.

The comparison of patients with themselves before and after ICS deprescribing reduced the potential for bias seen in retrospective studies. This method did not require a second control group which would potentially introduce confounding factors.

Conclusions

This study found that in a small population of veterans with COPD, pharmacist-led ICS deprescribing did not lead to an increase in COPD exacerbations and decreased the risk of AEs related to ICS therapy. Some patients were reinitiated on ICS therapy; however, reinitiation was rarely attributable to a COPD exacerbation. This study suggests that pharmacists were able to appropriately identify candidates for ICS deprescribing without increasing their risk of exacerbations. By de-escalating ICS therapy, pharmacists decreased medication burden and potential AEs caused by ICS therapy. These findings support expanding the role of clinical pharmacists in COPD management, particularly in identifying candidates for safe ICS deprescribing.

Disruptions caused by the COVID-19 pandemic led to an estimated 619 missed cases of colorectal cancer (CRC) diagnoses among US veterans, and those whose cases were caught had larger tumors and more malignant bowel obstructions compared with a prepandemic period, a new longitudinal study finds.

The decline in diagnoses during the pandemic (March 2020-October 2023) represented a 5% decrease in anticipated cases compared with the prepandemic period (January 2017-February 2020) reported Veterans Health Administration (VHA) researchers in the Journal of Gastrointestinal Surgery.

Meanwhile, the percentage of cancers > 4 cm increased from 48.9% to 57.3% from the prepandemic to pandemic periods, and the percentage of patients with malignant bowel obstructions at presentation nearly doubled from 2.7% to 5.3%. 

“The COVID-19 pandemic resulted in a significant initial decrease in rates of colon cancer diagnosis, with a slow return to baseline,” Louise Davies, MD, MS, a head-and-neck surgeon at the University of Wisconsin-Madison and senior author of the study told Federal Practitioner. “The length of time it took for things to return to normal surprised us. Patterns of detection did not return to more normal baselines until 2023.”

The Pandemic’s Toll on Colonoscopies

While mortality and diagnosis rates have fallen significantly over the past 3 decades, an estimated 158,850 colorectal cancer cases will be diagnosed in the US in 2026, and 55,230 patients will die. Within the VHA, an estimated 4000 new cases of colorectal cancer are diagnosed annually. 

The pandemic disrupted medical care across the board, and colonoscopies were no exceptions. “There are various estimates that there were anywhere from 2 to 3 million missed exams,” said Timothy Pawlik, MD, PhD, MBA, MPH, a surgical oncologist and professor at The Ohio State University Wexner Medical Center, in an interview. 

“At the height of the pandemic, all nonurgent procedures were put on hold,” explained Pawlik, who was not involved in the new study. “I suspect that a number of procedures were missed because different institutions and GI practices simply weren't providing that service at that time. In addition, I'm sure there was some reticence among patients to seek care even after the procedures were restarted and reoffered, especially at a hospital.”

Inside the VHA Data

The researchers found that 22,256 VHA patients were diagnosed with CRC during the study period (mean age, 71 years; 95.6% male; 72.1% White, 19.3% Black, and 6.4% Hispanic). 

In a subset of 1087 patients, the percentage with an American Society of Anesthesiologists class ≥ 3 rose from 74.4% before the pandemic to 78.9% during it. 

In light of the study findings, “clinicians should encourage their eligible patients to get screened for colon cancer, especially if they delayed screening as a result of the pandemic,” Davies said. 

Why Colonoscopy Delays Matter

Pawlik, the Ohio State University Wexner Medical Center surgical oncologist, said even small delays in colonoscopies can be important. 

“There are data suggesting that even a delay beyond 6 to 12 months can significantly increase the risk of advanced-stage cancer. Longer delays of a year, which were associated with the pandemic, definitely increase the risk of presenting with later stages of disease and potentially have a meaningful impact on your prognosis and survival.”

However, he noted that the study findings are limited because the results don’t clarify when patients were due for colonoscopies. 

Still, in the big picture, the research “emphasizes the importance of timely colonoscopy compliance with national guidelines for screening of colon cancer,” he said. 

Lessons About At-Home Tests

Pawlik added that the research also highlights that in times of limited access such as pandemics, there can be value to pivoting to home-based screening methods.

Study coauthor Douglas Robertson, MD, MPH, national deputy director of the Colorectal Cancer Screening Program with the US Department of Veterans Affairs National Gastroenterology and Hepatology Program, said the pandemic spurred a shift toward fecal immunochemical testing (FIT) via mail. 

The VA is now mailing > 40,000 FIT tests per month to veterans. “This program was an outgrowth of and response to the pandemic and would enhance VA’s readiness to maintain CRC screening efforts should something similar occur in the future,” Robertson said in an interview.

The Department of Veterans Affairs funded the study. Davies, Robertson, and the other study authors have no disclosures. Pawlik is co-editor-in-chief of the Journal of Gastrointestinal Surgery and has no other disclosures. 

Disruptions caused by the COVID-19 pandemic led to an estimated 619 missed cases of colorectal cancer (CRC) diagnoses among US veterans, and those whose cases were caught had larger tumors and more malignant bowel obstructions compared with a prepandemic period, a new longitudinal study finds.

The decline in diagnoses during the pandemic (March 2020-October 2023) represented a 5% decrease in anticipated cases compared with the prepandemic period (January 2017-February 2020) reported Veterans Health Administration (VHA) researchers in the Journal of Gastrointestinal Surgery.

Meanwhile, the percentage of cancers > 4 cm increased from 48.9% to 57.3% from the prepandemic to pandemic periods, and the percentage of patients with malignant bowel obstructions at presentation nearly doubled from 2.7% to 5.3%. 

“The COVID-19 pandemic resulted in a significant initial decrease in rates of colon cancer diagnosis, with a slow return to baseline,” Louise Davies, MD, MS, a head-and-neck surgeon at the University of Wisconsin-Madison and senior author of the study told Federal Practitioner. “The length of time it took for things to return to normal surprised us. Patterns of detection did not return to more normal baselines until 2023.”

The Pandemic’s Toll on Colonoscopies

While mortality and diagnosis rates have fallen significantly over the past 3 decades, an estimated 158,850 colorectal cancer cases will be diagnosed in the US in 2026, and 55,230 patients will die. Within the VHA, an estimated 4000 new cases of colorectal cancer are diagnosed annually. 

The pandemic disrupted medical care across the board, and colonoscopies were no exceptions. “There are various estimates that there were anywhere from 2 to 3 million missed exams,” said Timothy Pawlik, MD, PhD, MBA, MPH, a surgical oncologist and professor at The Ohio State University Wexner Medical Center, in an interview. 

“At the height of the pandemic, all nonurgent procedures were put on hold,” explained Pawlik, who was not involved in the new study. “I suspect that a number of procedures were missed because different institutions and GI practices simply weren't providing that service at that time. In addition, I'm sure there was some reticence among patients to seek care even after the procedures were restarted and reoffered, especially at a hospital.”

Inside the VHA Data

The researchers found that 22,256 VHA patients were diagnosed with CRC during the study period (mean age, 71 years; 95.6% male; 72.1% White, 19.3% Black, and 6.4% Hispanic). 

In a subset of 1087 patients, the percentage with an American Society of Anesthesiologists class ≥ 3 rose from 74.4% before the pandemic to 78.9% during it. 

In light of the study findings, “clinicians should encourage their eligible patients to get screened for colon cancer, especially if they delayed screening as a result of the pandemic,” Davies said. 

Why Colonoscopy Delays Matter

Pawlik, the Ohio State University Wexner Medical Center surgical oncologist, said even small delays in colonoscopies can be important. 

“There are data suggesting that even a delay beyond 6 to 12 months can significantly increase the risk of advanced-stage cancer. Longer delays of a year, which were associated with the pandemic, definitely increase the risk of presenting with later stages of disease and potentially have a meaningful impact on your prognosis and survival.”

However, he noted that the study findings are limited because the results don’t clarify when patients were due for colonoscopies. 

Still, in the big picture, the research “emphasizes the importance of timely colonoscopy compliance with national guidelines for screening of colon cancer,” he said. 

Lessons About At-Home Tests

Pawlik added that the research also highlights that in times of limited access such as pandemics, there can be value to pivoting to home-based screening methods.

Study coauthor Douglas Robertson, MD, MPH, national deputy director of the Colorectal Cancer Screening Program with the US Department of Veterans Affairs National Gastroenterology and Hepatology Program, said the pandemic spurred a shift toward fecal immunochemical testing (FIT) via mail. 

The VA is now mailing > 40,000 FIT tests per month to veterans. “This program was an outgrowth of and response to the pandemic and would enhance VA’s readiness to maintain CRC screening efforts should something similar occur in the future,” Robertson said in an interview.

The Department of Veterans Affairs funded the study. Davies, Robertson, and the other study authors have no disclosures. Pawlik is co-editor-in-chief of the Journal of Gastrointestinal Surgery and has no other disclosures. 

Disruptions caused by the COVID-19 pandemic led to an estimated 619 missed cases of colorectal cancer (CRC) diagnoses among US veterans, and those whose cases were caught had larger tumors and more malignant bowel obstructions compared with a prepandemic period, a new longitudinal study finds.

The decline in diagnoses during the pandemic (March 2020-October 2023) represented a 5% decrease in anticipated cases compared with the prepandemic period (January 2017-February 2020) reported Veterans Health Administration (VHA) researchers in the Journal of Gastrointestinal Surgery.

Meanwhile, the percentage of cancers > 4 cm increased from 48.9% to 57.3% from the prepandemic to pandemic periods, and the percentage of patients with malignant bowel obstructions at presentation nearly doubled from 2.7% to 5.3%. 

“The COVID-19 pandemic resulted in a significant initial decrease in rates of colon cancer diagnosis, with a slow return to baseline,” Louise Davies, MD, MS, a head-and-neck surgeon at the University of Wisconsin-Madison and senior author of the study told Federal Practitioner. “The length of time it took for things to return to normal surprised us. Patterns of detection did not return to more normal baselines until 2023.”

The Pandemic’s Toll on Colonoscopies

While mortality and diagnosis rates have fallen significantly over the past 3 decades, an estimated 158,850 colorectal cancer cases will be diagnosed in the US in 2026, and 55,230 patients will die. Within the VHA, an estimated 4000 new cases of colorectal cancer are diagnosed annually. 

The pandemic disrupted medical care across the board, and colonoscopies were no exceptions. “There are various estimates that there were anywhere from 2 to 3 million missed exams,” said Timothy Pawlik, MD, PhD, MBA, MPH, a surgical oncologist and professor at The Ohio State University Wexner Medical Center, in an interview. 

“At the height of the pandemic, all nonurgent procedures were put on hold,” explained Pawlik, who was not involved in the new study. “I suspect that a number of procedures were missed because different institutions and GI practices simply weren't providing that service at that time. In addition, I'm sure there was some reticence among patients to seek care even after the procedures were restarted and reoffered, especially at a hospital.”

Inside the VHA Data

The researchers found that 22,256 VHA patients were diagnosed with CRC during the study period (mean age, 71 years; 95.6% male; 72.1% White, 19.3% Black, and 6.4% Hispanic). 

In a subset of 1087 patients, the percentage with an American Society of Anesthesiologists class ≥ 3 rose from 74.4% before the pandemic to 78.9% during it. 

In light of the study findings, “clinicians should encourage their eligible patients to get screened for colon cancer, especially if they delayed screening as a result of the pandemic,” Davies said. 

Why Colonoscopy Delays Matter

Pawlik, the Ohio State University Wexner Medical Center surgical oncologist, said even small delays in colonoscopies can be important. 

“There are data suggesting that even a delay beyond 6 to 12 months can significantly increase the risk of advanced-stage cancer. Longer delays of a year, which were associated with the pandemic, definitely increase the risk of presenting with later stages of disease and potentially have a meaningful impact on your prognosis and survival.”

However, he noted that the study findings are limited because the results don’t clarify when patients were due for colonoscopies. 

Still, in the big picture, the research “emphasizes the importance of timely colonoscopy compliance with national guidelines for screening of colon cancer,” he said. 

Lessons About At-Home Tests

Pawlik added that the research also highlights that in times of limited access such as pandemics, there can be value to pivoting to home-based screening methods.

Study coauthor Douglas Robertson, MD, MPH, national deputy director of the Colorectal Cancer Screening Program with the US Department of Veterans Affairs National Gastroenterology and Hepatology Program, said the pandemic spurred a shift toward fecal immunochemical testing (FIT) via mail. 

The VA is now mailing > 40,000 FIT tests per month to veterans. “This program was an outgrowth of and response to the pandemic and would enhance VA’s readiness to maintain CRC screening efforts should something similar occur in the future,” Robertson said in an interview.

The Department of Veterans Affairs funded the study. Davies, Robertson, and the other study authors have no disclosures. Pawlik is co-editor-in-chief of the Journal of Gastrointestinal Surgery and has no other disclosures. 

TOPLINE:

In a population-based study, human papillomavirus (HPV) vaccination in England was associated with a 100% reduction in mortality due to cervical cancer between 2020 and 2024 among women aged 20-24 years who were mostly vaccinated at the age of 12-13 years.

METHODOLOGY:

• Researchers conducted a population-based study using cervical cancer mortality data of women aged 20-24, 25-29, and 30-34 years from the National Disease Registration Service and Office for National Statistics in England from 2000 to 2024.
• The analysis included women from the first eligible birth cohort (born from September 1990 to August 1991) who were targeted by England's school-based HPV vaccination programme introduced in September 2008 for girls aged 12-13 years, with a catch-up programme for girls aged 14-18 years implemented in 2008-2010.
• HPV vaccination coverage by birth cohort was obtained from annual reports of the UK Health Security Agency and used to estimate the proportion of women vaccinated for each age group and calendar year.
• The relative risk reduction (RRR) in mortality among vaccinated women compared with expected rates in the absence of vaccination, assuming no herd immunity, was evaluated.

TAKEAWAY:

• Among women aged 20-24 years between 2020 and 2024 with approximately 88%-91% vaccination coverage, no deaths occurred compared with 23.1 expected deaths on the basis of the observed average rate from 2000 to 2014, corresponding to a reduction in mortality of 100% (95% CI, 84%-100%).
• Among vaccinated women, the RRR in mortality due to cervical cancer was estimated at 100% (P = .0008) in those aged 20-24 years, 100% (P < .0001) in those aged 25-29 years, and 63% (P = .094) in those aged 30-34 years.
• Mortality reductions of 80% (95% CI, 51%-94%) were observed in women aged 20-24 years during 2015-2019 and 69% (95% CI, 55%-79%) were observed in those aged 25-29 years during 2020-2024.
• Up until the end of 2024, the HPV vaccination programme in England was associated with a reduction of approximately 199.6 deaths due to cervical cancer (95% CI, 125.0-274.2) among cohorts offered vaccination.

IN PRACTICE:

The authors concluded that "we found a substantial reduction in cervical cancer mortality in women aged 20-29 years that was associated with high uptake of HPV vaccination." "This observation further supports the benefit of HPV vaccination in reducing not only the incidence of but also the mortality from a cancer that is globally still the second most common cause of cancer death in women younger than 65 years," they added. SOURCE: The study was led by Peter Sasieni, PhD, Centre for Cancer Screening, Prevention and Early Diagnosis, Wolfson Institute of Population Health, Queen Mary University of London, London, England. It was published online on June 17, 2026, in The Lancet.

LIMITATIONS:

The analysis relied on population-level vaccination coverage data instead of individual-level status; the researchers had access to mortality data in 5-year age groups only rather than single-year cohorts, and the study assumed no herd protection among unvaccinated women within birth cohorts.

DISCLOSURES:

The study was funded by the Cancer Research UK. One author reported serving as a lead investigator of a trial examining the HPV vaccine Gardasil 9 that was partially supported by a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme. Additional disclosures are listed in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

TOPLINE:

In a population-based study, human papillomavirus (HPV) vaccination in England was associated with a 100% reduction in mortality due to cervical cancer between 2020 and 2024 among women aged 20-24 years who were mostly vaccinated at the age of 12-13 years.

METHODOLOGY:

• Researchers conducted a population-based study using cervical cancer mortality data of women aged 20-24, 25-29, and 30-34 years from the National Disease Registration Service and Office for National Statistics in England from 2000 to 2024.
• The analysis included women from the first eligible birth cohort (born from September 1990 to August 1991) who were targeted by England's school-based HPV vaccination programme introduced in September 2008 for girls aged 12-13 years, with a catch-up programme for girls aged 14-18 years implemented in 2008-2010.
• HPV vaccination coverage by birth cohort was obtained from annual reports of the UK Health Security Agency and used to estimate the proportion of women vaccinated for each age group and calendar year.
• The relative risk reduction (RRR) in mortality among vaccinated women compared with expected rates in the absence of vaccination, assuming no herd immunity, was evaluated.

TAKEAWAY:

• Among women aged 20-24 years between 2020 and 2024 with approximately 88%-91% vaccination coverage, no deaths occurred compared with 23.1 expected deaths on the basis of the observed average rate from 2000 to 2014, corresponding to a reduction in mortality of 100% (95% CI, 84%-100%).
• Among vaccinated women, the RRR in mortality due to cervical cancer was estimated at 100% (P = .0008) in those aged 20-24 years, 100% (P < .0001) in those aged 25-29 years, and 63% (P = .094) in those aged 30-34 years.
• Mortality reductions of 80% (95% CI, 51%-94%) were observed in women aged 20-24 years during 2015-2019 and 69% (95% CI, 55%-79%) were observed in those aged 25-29 years during 2020-2024.
• Up until the end of 2024, the HPV vaccination programme in England was associated with a reduction of approximately 199.6 deaths due to cervical cancer (95% CI, 125.0-274.2) among cohorts offered vaccination.

IN PRACTICE:

The authors concluded that "we found a substantial reduction in cervical cancer mortality in women aged 20-29 years that was associated with high uptake of HPV vaccination." "This observation further supports the benefit of HPV vaccination in reducing not only the incidence of but also the mortality from a cancer that is globally still the second most common cause of cancer death in women younger than 65 years," they added. SOURCE: The study was led by Peter Sasieni, PhD, Centre for Cancer Screening, Prevention and Early Diagnosis, Wolfson Institute of Population Health, Queen Mary University of London, London, England. It was published online on June 17, 2026, in The Lancet.

LIMITATIONS:

The analysis relied on population-level vaccination coverage data instead of individual-level status; the researchers had access to mortality data in 5-year age groups only rather than single-year cohorts, and the study assumed no herd protection among unvaccinated women within birth cohorts.

DISCLOSURES:

The study was funded by the Cancer Research UK. One author reported serving as a lead investigator of a trial examining the HPV vaccine Gardasil 9 that was partially supported by a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme. Additional disclosures are listed in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

TOPLINE:

In a population-based study, human papillomavirus (HPV) vaccination in England was associated with a 100% reduction in mortality due to cervical cancer between 2020 and 2024 among women aged 20-24 years who were mostly vaccinated at the age of 12-13 years.

METHODOLOGY:

• Researchers conducted a population-based study using cervical cancer mortality data of women aged 20-24, 25-29, and 30-34 years from the National Disease Registration Service and Office for National Statistics in England from 2000 to 2024.
• The analysis included women from the first eligible birth cohort (born from September 1990 to August 1991) who were targeted by England's school-based HPV vaccination programme introduced in September 2008 for girls aged 12-13 years, with a catch-up programme for girls aged 14-18 years implemented in 2008-2010.
• HPV vaccination coverage by birth cohort was obtained from annual reports of the UK Health Security Agency and used to estimate the proportion of women vaccinated for each age group and calendar year.
• The relative risk reduction (RRR) in mortality among vaccinated women compared with expected rates in the absence of vaccination, assuming no herd immunity, was evaluated.

TAKEAWAY:

• Among women aged 20-24 years between 2020 and 2024 with approximately 88%-91% vaccination coverage, no deaths occurred compared with 23.1 expected deaths on the basis of the observed average rate from 2000 to 2014, corresponding to a reduction in mortality of 100% (95% CI, 84%-100%).
• Among vaccinated women, the RRR in mortality due to cervical cancer was estimated at 100% (P = .0008) in those aged 20-24 years, 100% (P < .0001) in those aged 25-29 years, and 63% (P = .094) in those aged 30-34 years.
• Mortality reductions of 80% (95% CI, 51%-94%) were observed in women aged 20-24 years during 2015-2019 and 69% (95% CI, 55%-79%) were observed in those aged 25-29 years during 2020-2024.
• Up until the end of 2024, the HPV vaccination programme in England was associated with a reduction of approximately 199.6 deaths due to cervical cancer (95% CI, 125.0-274.2) among cohorts offered vaccination.

IN PRACTICE:

The authors concluded that "we found a substantial reduction in cervical cancer mortality in women aged 20-29 years that was associated with high uptake of HPV vaccination." "This observation further supports the benefit of HPV vaccination in reducing not only the incidence of but also the mortality from a cancer that is globally still the second most common cause of cancer death in women younger than 65 years," they added. SOURCE: The study was led by Peter Sasieni, PhD, Centre for Cancer Screening, Prevention and Early Diagnosis, Wolfson Institute of Population Health, Queen Mary University of London, London, England. It was published online on June 17, 2026, in The Lancet.

LIMITATIONS:

The analysis relied on population-level vaccination coverage data instead of individual-level status; the researchers had access to mortality data in 5-year age groups only rather than single-year cohorts, and the study assumed no herd protection among unvaccinated women within birth cohorts.

DISCLOSURES:

The study was funded by the Cancer Research UK. One author reported serving as a lead investigator of a trial examining the HPV vaccine Gardasil 9 that was partially supported by a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme. Additional disclosures are listed in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

Rapid-growing nontuberculous mycobacteria (NTM) were strongly associated with death or retransplantation in adult lung transplant patients, based on data from a new study of about 1000 individuals.

NTM are ubiquitous environmental organisms, but the clinical significance of isolating NTM posttransplant remains poorly defined, and previous studies have been mainly small and single center, said lead author Gabrielle Mezochow, MD, a pulmonology and critical care fellow at the University of Pennsylvania in Philadelphia.

“This is important because treatment is particularly challenging in lung transplant recipients, requiring prolonged multidrug regimens that can be toxic and interact with immunosuppression,” Mezochow said. “We conducted this study to better understand how often NTM is isolated after lung transplant, and whether isolation is associated with important outcomes such as chronic lung allograft dysfunction (CLAD) and death or retransplantation in a large multicenter cohort,” she said.

In the study, presented at the annual meeting of the International Society for Heart and Lung Transplantation (ISHLT), Mezochow et al reviewed data from 1044 adult lung transplant recipients in the Lung Transplant Outcomes Group cohort who underwent transplant between 2007 and 2022 at 3 centers.

The researchers evaluated the time from transplantation to graft failure (defined as death or retransplantation) and CLAD (as defined by the ISHLT). They used a proportional hazards model adjusted for age, diagnosis, BMI, primary graft dysfunction, postoperative extracorporeal membrane oxygenation, and transplant type.

A total of 136 patients (13%) had pulmonary growth of NTM within a year of their transplants; the most common types were Mycobacterium avium (88 patients) and Mycobacterium abscessus (16 patients).

Overall, the association between early growth of any NTM and the risk for graft failure did not reach statistical significance (adjusted hazard ratio [HR], 1.27). However, patients who had early growth of rapid-growing NTM (including M abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium immunogenum, Mycobacterium mageritense, and Mycobacterium mucogenicum) had an increased risk for graft failure compared to those with early growth of slow-growing NTM such as M avium (unadjusted HR, 2.36; adjusted HR, 2.49). The associations were consistent when patients with cystic fibrosis were excluded, and no significant association was observed between early NTM growth by slow or rapid types and increased risk for CLAD (adjusted HR, 1.09).

“One of the most interesting findings was that associations differed by NTM species,” Mezochow said. “Rapid-growing NTM were most strongly associated with death or retransplantation, whereas slow-growing NTM appeared to have a stronger association with CLAD,” she said. “We were also intrigued by the stronger associations with negative outcomes observed among recipients with ILD [interstitial lung disease], particularly those undergoing single lung transplantation,” Mezochow noted. “This raises the possibility that characteristics of the native lung or underlying lung disease may influence susceptibility and outcomes,” she said.

“Importantly, our study evaluated NTM isolation rather than NTM pulmonary disease, which is often difficult to define in lung transplant recipients,” said Mezochow. The results suggest that NTM isolation should not be dismissed as a benign microbiologic finding and could serve as an early marker of lung transplant recipients at increased risk for poor outcomes, even before disease can be definitively established, she noted. “Certain subgroups of recipients, including those with specific NTM species or underlying diagnoses, may be at a particularly elevated risk for poor outcomes, while not all patients with NTM isolation are likely to require treatment,” she added.

Limitations and Next Steps

The findings were limited by several factors including the observational design and lack of detailed patient-level medication data including longitudinal immunosuppression, antibiotic exposures, and azithromycin use for bronchiolitis obliterans syndrome prevention, any of which could influence both NTM isolation and downstream outcomes, Mezochow said.

The researchers also were unable to adjudicate NTM pulmonary disease according to current guideline-based definitions because of the lack of longitudinal radiographic and symptom data, she added. “That said, these diagnostic criteria were developed outside the transplant setting and have not been validated in lung transplant recipients, so their applicability here is uncertain,” she added. “Although we focused on the first posttransplant year, when surveillance bronchoscopy is relatively routine, some residual ascertainment bias is still likely,” she noted.

“Future research should focus on identifying which recipients with NTM isolation are most likely to progress to CLAD or death, understanding the biologic mechanisms linking NTM and allograft injury, and determining whether treatment strategies or immunosuppression modifications can improve outcomes,” said Mezochow. “Ultimately, the goal is to develop a framework that helps clinicians distinguish who may benefit from treatment from those who can be safely observed,” she said.

Added Value for Patient Assessment

The current study addresses major questions in lung transplantation, namely, whether isolation of NTM species in the first year after a lung transplant is a marker of airway vulnerability, structural airway defects, patient frailty, or a true contributor to allograft function and failure, said Jacqueline Burnell, MD, an associate professor of clinical medicine at the Lewis Katz School of Medicine at Temple University in Philadelphia, and a specialist in infections in transplant and immunocompromised patients. “This study separated rapidly growing NTM from slow growers to attempt to identify species associated with poor outcomes and provide prognostication,” said Burnell, who was not involved in the study. The association of rapidly growing NTM and poorer outcomes was not surprising, she noted. “Mycobacterium abscessus species, which accounted for the majority of rapidly growing isolates, are thought to be more aggressive and are certainly more challenging to treat,” she said. “The absence of association with CLAD is interesting, as this has been found in other studies looking at NTM infections post-lung transplant,” she added.

The results suggest that rapidly growing NTM should be risk-stratified separately from slow-growing NTM, said Burnell. “Early growth of rapid-growing NTM should prompt careful evaluation and assessment in a multidisciplinary fashion and not be deemed colonization without thorough evaluation,” she said. Routine posttransplant cultures also may have prognostic value in graft failure, she noted.

However, additional research with more granular detail regarding patient characteristics would be useful for risk stratification, said Burnell. “For example, information about pretransplant colonization, type of transplant (single vs double), immunosuppressive regimens, co-infections, and other factors would be useful,” she said. The current study did not address delineation between colonization, transient isolation, and infection, and data on treatment regimens and timing were lacking; therefore, collaborative studies are needed to assess these factors and their relationship to patient outcomes, Burnell noted.

The study was funded by institutional grants from the National Heart, Lung, and Blood Institute. Mezochow and Burnell had no financial conflicts to disclose.

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

Rapid-growing nontuberculous mycobacteria (NTM) were strongly associated with death or retransplantation in adult lung transplant patients, based on data from a new study of about 1000 individuals.

NTM are ubiquitous environmental organisms, but the clinical significance of isolating NTM posttransplant remains poorly defined, and previous studies have been mainly small and single center, said lead author Gabrielle Mezochow, MD, a pulmonology and critical care fellow at the University of Pennsylvania in Philadelphia.

“This is important because treatment is particularly challenging in lung transplant recipients, requiring prolonged multidrug regimens that can be toxic and interact with immunosuppression,” Mezochow said. “We conducted this study to better understand how often NTM is isolated after lung transplant, and whether isolation is associated with important outcomes such as chronic lung allograft dysfunction (CLAD) and death or retransplantation in a large multicenter cohort,” she said.

In the study, presented at the annual meeting of the International Society for Heart and Lung Transplantation (ISHLT), Mezochow et al reviewed data from 1044 adult lung transplant recipients in the Lung Transplant Outcomes Group cohort who underwent transplant between 2007 and 2022 at 3 centers.

The researchers evaluated the time from transplantation to graft failure (defined as death or retransplantation) and CLAD (as defined by the ISHLT). They used a proportional hazards model adjusted for age, diagnosis, BMI, primary graft dysfunction, postoperative extracorporeal membrane oxygenation, and transplant type.

A total of 136 patients (13%) had pulmonary growth of NTM within a year of their transplants; the most common types were Mycobacterium avium (88 patients) and Mycobacterium abscessus (16 patients).

Overall, the association between early growth of any NTM and the risk for graft failure did not reach statistical significance (adjusted hazard ratio [HR], 1.27). However, patients who had early growth of rapid-growing NTM (including M abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium immunogenum, Mycobacterium mageritense, and Mycobacterium mucogenicum) had an increased risk for graft failure compared to those with early growth of slow-growing NTM such as M avium (unadjusted HR, 2.36; adjusted HR, 2.49). The associations were consistent when patients with cystic fibrosis were excluded, and no significant association was observed between early NTM growth by slow or rapid types and increased risk for CLAD (adjusted HR, 1.09).

“One of the most interesting findings was that associations differed by NTM species,” Mezochow said. “Rapid-growing NTM were most strongly associated with death or retransplantation, whereas slow-growing NTM appeared to have a stronger association with CLAD,” she said. “We were also intrigued by the stronger associations with negative outcomes observed among recipients with ILD [interstitial lung disease], particularly those undergoing single lung transplantation,” Mezochow noted. “This raises the possibility that characteristics of the native lung or underlying lung disease may influence susceptibility and outcomes,” she said.

“Importantly, our study evaluated NTM isolation rather than NTM pulmonary disease, which is often difficult to define in lung transplant recipients,” said Mezochow. The results suggest that NTM isolation should not be dismissed as a benign microbiologic finding and could serve as an early marker of lung transplant recipients at increased risk for poor outcomes, even before disease can be definitively established, she noted. “Certain subgroups of recipients, including those with specific NTM species or underlying diagnoses, may be at a particularly elevated risk for poor outcomes, while not all patients with NTM isolation are likely to require treatment,” she added.

Limitations and Next Steps

The findings were limited by several factors including the observational design and lack of detailed patient-level medication data including longitudinal immunosuppression, antibiotic exposures, and azithromycin use for bronchiolitis obliterans syndrome prevention, any of which could influence both NTM isolation and downstream outcomes, Mezochow said.

The researchers also were unable to adjudicate NTM pulmonary disease according to current guideline-based definitions because of the lack of longitudinal radiographic and symptom data, she added. “That said, these diagnostic criteria were developed outside the transplant setting and have not been validated in lung transplant recipients, so their applicability here is uncertain,” she added. “Although we focused on the first posttransplant year, when surveillance bronchoscopy is relatively routine, some residual ascertainment bias is still likely,” she noted.

“Future research should focus on identifying which recipients with NTM isolation are most likely to progress to CLAD or death, understanding the biologic mechanisms linking NTM and allograft injury, and determining whether treatment strategies or immunosuppression modifications can improve outcomes,” said Mezochow. “Ultimately, the goal is to develop a framework that helps clinicians distinguish who may benefit from treatment from those who can be safely observed,” she said.

Added Value for Patient Assessment

The current study addresses major questions in lung transplantation, namely, whether isolation of NTM species in the first year after a lung transplant is a marker of airway vulnerability, structural airway defects, patient frailty, or a true contributor to allograft function and failure, said Jacqueline Burnell, MD, an associate professor of clinical medicine at the Lewis Katz School of Medicine at Temple University in Philadelphia, and a specialist in infections in transplant and immunocompromised patients. “This study separated rapidly growing NTM from slow growers to attempt to identify species associated with poor outcomes and provide prognostication,” said Burnell, who was not involved in the study. The association of rapidly growing NTM and poorer outcomes was not surprising, she noted. “Mycobacterium abscessus species, which accounted for the majority of rapidly growing isolates, are thought to be more aggressive and are certainly more challenging to treat,” she said. “The absence of association with CLAD is interesting, as this has been found in other studies looking at NTM infections post-lung transplant,” she added.

The results suggest that rapidly growing NTM should be risk-stratified separately from slow-growing NTM, said Burnell. “Early growth of rapid-growing NTM should prompt careful evaluation and assessment in a multidisciplinary fashion and not be deemed colonization without thorough evaluation,” she said. Routine posttransplant cultures also may have prognostic value in graft failure, she noted.

However, additional research with more granular detail regarding patient characteristics would be useful for risk stratification, said Burnell. “For example, information about pretransplant colonization, type of transplant (single vs double), immunosuppressive regimens, co-infections, and other factors would be useful,” she said. The current study did not address delineation between colonization, transient isolation, and infection, and data on treatment regimens and timing were lacking; therefore, collaborative studies are needed to assess these factors and their relationship to patient outcomes, Burnell noted.

The study was funded by institutional grants from the National Heart, Lung, and Blood Institute. Mezochow and Burnell had no financial conflicts to disclose.

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

Rapid-growing nontuberculous mycobacteria (NTM) were strongly associated with death or retransplantation in adult lung transplant patients, based on data from a new study of about 1000 individuals.

NTM are ubiquitous environmental organisms, but the clinical significance of isolating NTM posttransplant remains poorly defined, and previous studies have been mainly small and single center, said lead author Gabrielle Mezochow, MD, a pulmonology and critical care fellow at the University of Pennsylvania in Philadelphia.

“This is important because treatment is particularly challenging in lung transplant recipients, requiring prolonged multidrug regimens that can be toxic and interact with immunosuppression,” Mezochow said. “We conducted this study to better understand how often NTM is isolated after lung transplant, and whether isolation is associated with important outcomes such as chronic lung allograft dysfunction (CLAD) and death or retransplantation in a large multicenter cohort,” she said.

In the study, presented at the annual meeting of the International Society for Heart and Lung Transplantation (ISHLT), Mezochow et al reviewed data from 1044 adult lung transplant recipients in the Lung Transplant Outcomes Group cohort who underwent transplant between 2007 and 2022 at 3 centers.

The researchers evaluated the time from transplantation to graft failure (defined as death or retransplantation) and CLAD (as defined by the ISHLT). They used a proportional hazards model adjusted for age, diagnosis, BMI, primary graft dysfunction, postoperative extracorporeal membrane oxygenation, and transplant type.

A total of 136 patients (13%) had pulmonary growth of NTM within a year of their transplants; the most common types were Mycobacterium avium (88 patients) and Mycobacterium abscessus (16 patients).

Overall, the association between early growth of any NTM and the risk for graft failure did not reach statistical significance (adjusted hazard ratio [HR], 1.27). However, patients who had early growth of rapid-growing NTM (including M abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium immunogenum, Mycobacterium mageritense, and Mycobacterium mucogenicum) had an increased risk for graft failure compared to those with early growth of slow-growing NTM such as M avium (unadjusted HR, 2.36; adjusted HR, 2.49). The associations were consistent when patients with cystic fibrosis were excluded, and no significant association was observed between early NTM growth by slow or rapid types and increased risk for CLAD (adjusted HR, 1.09).

“One of the most interesting findings was that associations differed by NTM species,” Mezochow said. “Rapid-growing NTM were most strongly associated with death or retransplantation, whereas slow-growing NTM appeared to have a stronger association with CLAD,” she said. “We were also intrigued by the stronger associations with negative outcomes observed among recipients with ILD [interstitial lung disease], particularly those undergoing single lung transplantation,” Mezochow noted. “This raises the possibility that characteristics of the native lung or underlying lung disease may influence susceptibility and outcomes,” she said.

“Importantly, our study evaluated NTM isolation rather than NTM pulmonary disease, which is often difficult to define in lung transplant recipients,” said Mezochow. The results suggest that NTM isolation should not be dismissed as a benign microbiologic finding and could serve as an early marker of lung transplant recipients at increased risk for poor outcomes, even before disease can be definitively established, she noted. “Certain subgroups of recipients, including those with specific NTM species or underlying diagnoses, may be at a particularly elevated risk for poor outcomes, while not all patients with NTM isolation are likely to require treatment,” she added.

Limitations and Next Steps

The findings were limited by several factors including the observational design and lack of detailed patient-level medication data including longitudinal immunosuppression, antibiotic exposures, and azithromycin use for bronchiolitis obliterans syndrome prevention, any of which could influence both NTM isolation and downstream outcomes, Mezochow said.

The researchers also were unable to adjudicate NTM pulmonary disease according to current guideline-based definitions because of the lack of longitudinal radiographic and symptom data, she added. “That said, these diagnostic criteria were developed outside the transplant setting and have not been validated in lung transplant recipients, so their applicability here is uncertain,” she added. “Although we focused on the first posttransplant year, when surveillance bronchoscopy is relatively routine, some residual ascertainment bias is still likely,” she noted.

“Future research should focus on identifying which recipients with NTM isolation are most likely to progress to CLAD or death, understanding the biologic mechanisms linking NTM and allograft injury, and determining whether treatment strategies or immunosuppression modifications can improve outcomes,” said Mezochow. “Ultimately, the goal is to develop a framework that helps clinicians distinguish who may benefit from treatment from those who can be safely observed,” she said.

Added Value for Patient Assessment

The current study addresses major questions in lung transplantation, namely, whether isolation of NTM species in the first year after a lung transplant is a marker of airway vulnerability, structural airway defects, patient frailty, or a true contributor to allograft function and failure, said Jacqueline Burnell, MD, an associate professor of clinical medicine at the Lewis Katz School of Medicine at Temple University in Philadelphia, and a specialist in infections in transplant and immunocompromised patients. “This study separated rapidly growing NTM from slow growers to attempt to identify species associated with poor outcomes and provide prognostication,” said Burnell, who was not involved in the study. The association of rapidly growing NTM and poorer outcomes was not surprising, she noted. “Mycobacterium abscessus species, which accounted for the majority of rapidly growing isolates, are thought to be more aggressive and are certainly more challenging to treat,” she said. “The absence of association with CLAD is interesting, as this has been found in other studies looking at NTM infections post-lung transplant,” she added.

The results suggest that rapidly growing NTM should be risk-stratified separately from slow-growing NTM, said Burnell. “Early growth of rapid-growing NTM should prompt careful evaluation and assessment in a multidisciplinary fashion and not be deemed colonization without thorough evaluation,” she said. Routine posttransplant cultures also may have prognostic value in graft failure, she noted.

However, additional research with more granular detail regarding patient characteristics would be useful for risk stratification, said Burnell. “For example, information about pretransplant colonization, type of transplant (single vs double), immunosuppressive regimens, co-infections, and other factors would be useful,” she said. The current study did not address delineation between colonization, transient isolation, and infection, and data on treatment regimens and timing were lacking; therefore, collaborative studies are needed to assess these factors and their relationship to patient outcomes, Burnell noted.

The study was funded by institutional grants from the National Heart, Lung, and Blood Institute. Mezochow and Burnell had no financial conflicts to disclose.

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

June 24 (Reuters) - The US military has resumed requiring flu vaccines for some service members in an exception to Defense Secretary Pete Hegseth’s guidance declaring the shots voluntary 2 months ago.

The decision follows a flu outbreak among recruits at Joint Base San Antonio-Lackland in Texas and sharp criticism of the policy from public health experts. More than 220 ‌recruits have been diagnosed with influenza and 4 hospitalized in the outbreak, according to media reports.

Hegseth said in April that the annual flu vaccine would become optional for all US military personnel under the Pentagon’s new vaccine policy. It ‌had previously been mandated and considered critical to troop preparedness.

The Under Secretary for War ‌Personnel and Readiness approved exception requests ‌for the Army, Navy, Air Force, National Security Agency, and Defense Health Agency, according to a statement from chief Pentagon spokesperson Sean Parnell on ‌Wednesday.

“The decisions were based upon thorough risk assessments and are designed to maximize operational readiness, lethality, ‌and force generation, while safeguarding at-risk populations,” Parnell said.

Each department is responsible for implementation, the spokesperson added.

The World Health Organization recommends the flu shot for those aged ≥ 6 months.

Trump administration Health Secretary Robert ‌F. ‌Kennedy Jr., a longtime antivaccine activist, has enacted policies that have decreased the use ‌of inoculations in the US, including dropping its 2025 flu vaccine campaign. Kennedy’s Make America Healthy Again movement has sought to weaken school enrollment mandates around the country.

Flu vaccines from Sanofi, CSL Seqirus, GSK and AstraZeneca are approved ‌in the United States.

(Reporting by Idrees Ali, Mariam Sunny and Mrinalika Roy; Editing by Caroline Humer and Bill Berkrot)

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

June 24 (Reuters) - The US military has resumed requiring flu vaccines for some service members in an exception to Defense Secretary Pete Hegseth’s guidance declaring the shots voluntary 2 months ago.

The decision follows a flu outbreak among recruits at Joint Base San Antonio-Lackland in Texas and sharp criticism of the policy from public health experts. More than 220 ‌recruits have been diagnosed with influenza and 4 hospitalized in the outbreak, according to media reports.

Hegseth said in April that the annual flu vaccine would become optional for all US military personnel under the Pentagon’s new vaccine policy. It ‌had previously been mandated and considered critical to troop preparedness.

The Under Secretary for War ‌Personnel and Readiness approved exception requests ‌for the Army, Navy, Air Force, National Security Agency, and Defense Health Agency, according to a statement from chief Pentagon spokesperson Sean Parnell on ‌Wednesday.

“The decisions were based upon thorough risk assessments and are designed to maximize operational readiness, lethality, ‌and force generation, while safeguarding at-risk populations,” Parnell said.

Each department is responsible for implementation, the spokesperson added.

The World Health Organization recommends the flu shot for those aged ≥ 6 months.

Trump administration Health Secretary Robert ‌F. ‌Kennedy Jr., a longtime antivaccine activist, has enacted policies that have decreased the use ‌of inoculations in the US, including dropping its 2025 flu vaccine campaign. Kennedy’s Make America Healthy Again movement has sought to weaken school enrollment mandates around the country.

Flu vaccines from Sanofi, CSL Seqirus, GSK and AstraZeneca are approved ‌in the United States.

(Reporting by Idrees Ali, Mariam Sunny and Mrinalika Roy; Editing by Caroline Humer and Bill Berkrot)

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

June 24 (Reuters) - The US military has resumed requiring flu vaccines for some service members in an exception to Defense Secretary Pete Hegseth’s guidance declaring the shots voluntary 2 months ago.

The decision follows a flu outbreak among recruits at Joint Base San Antonio-Lackland in Texas and sharp criticism of the policy from public health experts. More than 220 ‌recruits have been diagnosed with influenza and 4 hospitalized in the outbreak, according to media reports.

Hegseth said in April that the annual flu vaccine would become optional for all US military personnel under the Pentagon’s new vaccine policy. It ‌had previously been mandated and considered critical to troop preparedness.

The Under Secretary for War ‌Personnel and Readiness approved exception requests ‌for the Army, Navy, Air Force, National Security Agency, and Defense Health Agency, according to a statement from chief Pentagon spokesperson Sean Parnell on ‌Wednesday.

“The decisions were based upon thorough risk assessments and are designed to maximize operational readiness, lethality, ‌and force generation, while safeguarding at-risk populations,” Parnell said.

Each department is responsible for implementation, the spokesperson added.

The World Health Organization recommends the flu shot for those aged ≥ 6 months.

Trump administration Health Secretary Robert ‌F. ‌Kennedy Jr., a longtime antivaccine activist, has enacted policies that have decreased the use ‌of inoculations in the US, including dropping its 2025 flu vaccine campaign. Kennedy’s Make America Healthy Again movement has sought to weaken school enrollment mandates around the country.

Flu vaccines from Sanofi, CSL Seqirus, GSK and AstraZeneca are approved ‌in the United States.

(Reporting by Idrees Ali, Mariam Sunny and Mrinalika Roy; Editing by Caroline Humer and Bill Berkrot)

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

A retrospective cohort study links clomiphene citrate (CC) to significantly lower mortality rates when compared with testosterone replacement therapy (TRT) in male veterans with hypogonadism or infertility. CC is not approved by the US Food and Drug Administration (FDA) for hypogonadism but is often used off label. Patients taking clomiphene also had significantly lower risk of diseases of the circulatory system, brain, and bones. 

The study tracked matched cohorts of 2518 patients taking CC or TRT for a mean 3.5 years. All-cause mortality was lower in the CC group (1.83%) than the TRT group (10.13%, P < .001), reported researchers at the Kansas City Veterans Affairs Medical Center and University of Missouri-Kansas City School of Medicine, et al in Andrology.

The researchers also reported that outcomes were better in the CC group than the TRT group for new-onset hypertension (6.04% vs 10.48%, P < .001), cerebrovascular accident (0.52% vs 1.43%, P < .001), coronary artery disease (1.51% vs 2.26%, P < .048), polycythemia (1.07% vs 2.22%, P < .001), and osteoporosis (1.15% vs 2.07%, P = .009), respectively. 

“It seems like clomiphene is a good medication to be used long term, but we still need more investigation into this,” endocrinologist Mariana Garcia-Touza, MD said in an interview with Federal Practitioner. 

TRT is a common therapy for male hypogonadism, although the study notes it is linked to thickened blood, breast growth, infertility, fluid retention, obstructive sleep apnea, and cardiovascular and prostate problems. Guidelines recommend against its use in patients with prostate cancer, at high cardiovascular risk, and those trying to have children.

CC is a selective estrogen receptor modulator and used off-label to treat male hypogonadism because it can boost the production of testosterone. The study notes how many Veterans health Administration patients have low testosterone, with previous research reporting the rate among veterans aged ≥ 60 years at 34%. 

Garcia-Touza was especially interested in any effect clomiphene has on bones: “We’ve been hearing that it probably affects the bone and can cause osteoporosis, but no one has looked into it.”

The study tracked veterans from December 1990 to September 2024; follow-ups lasted up to 34 years. Patient mean ages were 46.5 and 47.5 years for the HRT and CC groups, respectively. Hypogonadism was the treatment indication for 98.4% and 64.5% and infertility was the indication for 1.6% and 35.5% for the HRT and CC groups, respectively. About 70% of both groups were White. 

There were no statistically significant gaps between the groups regarding hip fractures, pulmonary embolism, thrombosis, and vertebral fractures. Garcia-Touza said the all-cause mortality gap the study reported was surprising, although the study did not control for factors that may have differed between the groups.

“This needs to be more carefully examined to see if this is a real finding or if there is some bias in the study that is causing it,” she said.

Moving forward, Garcia-Touza said she hopes to launch a prospective study of TRT vs CC.

Parviz K. Kavoussi, MD, a reproductive urologist at the University of Texas at Austin who was not involved in the study, said in an interview the study’s findings highlight the importance of monitoring patients on TRT for an increase in hematocrit. 

“Not all testosterone replacement therapies are created equal from this standpoint,” he said, noting that risk depends on the delivery method. “There are multiple modalities — topical gels, patches, nasal gels, intramuscular injections, subcutaneous pellets, subcutaneous autoinjector pens, and oral testosterone pills. Each of these has a defined percentage risk of secondary erythrocytosis, with some being significantly higher than others.”

As for other potential risks from TRT such as a possible higher mortality rate, Kavoussi noted that a landmark 2023 trial of middle-aged and older men convinced the FDA to no longer require testosterone products to include a black-box warning about cardiovascular disease. 

Regarding the question of whether clomiphene works as well as testosterone, Kavoussi noted his group’s research has found clomiphene can normalize testosterone levels biochemically. However, “where clomiphene typically falls short in data and in clinical practice is the level of symptomatic improvement in testosterone deficiency symptoms that patients can achieve in comparison to exogenous testosterone replacement.” 

No funding was reported, and the authors – including Garcia-Touza – had no disclosures. Kavoussi discloses relationships with Halozyme and Verity.

A retrospective cohort study links clomiphene citrate (CC) to significantly lower mortality rates when compared with testosterone replacement therapy (TRT) in male veterans with hypogonadism or infertility. CC is not approved by the US Food and Drug Administration (FDA) for hypogonadism but is often used off label. Patients taking clomiphene also had significantly lower risk of diseases of the circulatory system, brain, and bones. 

The study tracked matched cohorts of 2518 patients taking CC or TRT for a mean 3.5 years. All-cause mortality was lower in the CC group (1.83%) than the TRT group (10.13%, P < .001), reported researchers at the Kansas City Veterans Affairs Medical Center and University of Missouri-Kansas City School of Medicine, et al in Andrology.

The researchers also reported that outcomes were better in the CC group than the TRT group for new-onset hypertension (6.04% vs 10.48%, P < .001), cerebrovascular accident (0.52% vs 1.43%, P < .001), coronary artery disease (1.51% vs 2.26%, P < .048), polycythemia (1.07% vs 2.22%, P < .001), and osteoporosis (1.15% vs 2.07%, P = .009), respectively. 

“It seems like clomiphene is a good medication to be used long term, but we still need more investigation into this,” endocrinologist Mariana Garcia-Touza, MD said in an interview with Federal Practitioner. 

TRT is a common therapy for male hypogonadism, although the study notes it is linked to thickened blood, breast growth, infertility, fluid retention, obstructive sleep apnea, and cardiovascular and prostate problems. Guidelines recommend against its use in patients with prostate cancer, at high cardiovascular risk, and those trying to have children.

CC is a selective estrogen receptor modulator and used off-label to treat male hypogonadism because it can boost the production of testosterone. The study notes how many Veterans health Administration patients have low testosterone, with previous research reporting the rate among veterans aged ≥ 60 years at 34%. 

Garcia-Touza was especially interested in any effect clomiphene has on bones: “We’ve been hearing that it probably affects the bone and can cause osteoporosis, but no one has looked into it.”

The study tracked veterans from December 1990 to September 2024; follow-ups lasted up to 34 years. Patient mean ages were 46.5 and 47.5 years for the HRT and CC groups, respectively. Hypogonadism was the treatment indication for 98.4% and 64.5% and infertility was the indication for 1.6% and 35.5% for the HRT and CC groups, respectively. About 70% of both groups were White. 

There were no statistically significant gaps between the groups regarding hip fractures, pulmonary embolism, thrombosis, and vertebral fractures. Garcia-Touza said the all-cause mortality gap the study reported was surprising, although the study did not control for factors that may have differed between the groups.

“This needs to be more carefully examined to see if this is a real finding or if there is some bias in the study that is causing it,” she said.

Moving forward, Garcia-Touza said she hopes to launch a prospective study of TRT vs CC.

Parviz K. Kavoussi, MD, a reproductive urologist at the University of Texas at Austin who was not involved in the study, said in an interview the study’s findings highlight the importance of monitoring patients on TRT for an increase in hematocrit. 

“Not all testosterone replacement therapies are created equal from this standpoint,” he said, noting that risk depends on the delivery method. “There are multiple modalities — topical gels, patches, nasal gels, intramuscular injections, subcutaneous pellets, subcutaneous autoinjector pens, and oral testosterone pills. Each of these has a defined percentage risk of secondary erythrocytosis, with some being significantly higher than others.”

As for other potential risks from TRT such as a possible higher mortality rate, Kavoussi noted that a landmark 2023 trial of middle-aged and older men convinced the FDA to no longer require testosterone products to include a black-box warning about cardiovascular disease. 

Regarding the question of whether clomiphene works as well as testosterone, Kavoussi noted his group’s research has found clomiphene can normalize testosterone levels biochemically. However, “where clomiphene typically falls short in data and in clinical practice is the level of symptomatic improvement in testosterone deficiency symptoms that patients can achieve in comparison to exogenous testosterone replacement.” 

No funding was reported, and the authors – including Garcia-Touza – had no disclosures. Kavoussi discloses relationships with Halozyme and Verity.

A retrospective cohort study links clomiphene citrate (CC) to significantly lower mortality rates when compared with testosterone replacement therapy (TRT) in male veterans with hypogonadism or infertility. CC is not approved by the US Food and Drug Administration (FDA) for hypogonadism but is often used off label. Patients taking clomiphene also had significantly lower risk of diseases of the circulatory system, brain, and bones. 

The study tracked matched cohorts of 2518 patients taking CC or TRT for a mean 3.5 years. All-cause mortality was lower in the CC group (1.83%) than the TRT group (10.13%, P < .001), reported researchers at the Kansas City Veterans Affairs Medical Center and University of Missouri-Kansas City School of Medicine, et al in Andrology.

The researchers also reported that outcomes were better in the CC group than the TRT group for new-onset hypertension (6.04% vs 10.48%, P < .001), cerebrovascular accident (0.52% vs 1.43%, P < .001), coronary artery disease (1.51% vs 2.26%, P < .048), polycythemia (1.07% vs 2.22%, P < .001), and osteoporosis (1.15% vs 2.07%, P = .009), respectively. 

“It seems like clomiphene is a good medication to be used long term, but we still need more investigation into this,” endocrinologist Mariana Garcia-Touza, MD said in an interview with Federal Practitioner. 

TRT is a common therapy for male hypogonadism, although the study notes it is linked to thickened blood, breast growth, infertility, fluid retention, obstructive sleep apnea, and cardiovascular and prostate problems. Guidelines recommend against its use in patients with prostate cancer, at high cardiovascular risk, and those trying to have children.

CC is a selective estrogen receptor modulator and used off-label to treat male hypogonadism because it can boost the production of testosterone. The study notes how many Veterans health Administration patients have low testosterone, with previous research reporting the rate among veterans aged ≥ 60 years at 34%. 

Garcia-Touza was especially interested in any effect clomiphene has on bones: “We’ve been hearing that it probably affects the bone and can cause osteoporosis, but no one has looked into it.”

The study tracked veterans from December 1990 to September 2024; follow-ups lasted up to 34 years. Patient mean ages were 46.5 and 47.5 years for the HRT and CC groups, respectively. Hypogonadism was the treatment indication for 98.4% and 64.5% and infertility was the indication for 1.6% and 35.5% for the HRT and CC groups, respectively. About 70% of both groups were White. 

There were no statistically significant gaps between the groups regarding hip fractures, pulmonary embolism, thrombosis, and vertebral fractures. Garcia-Touza said the all-cause mortality gap the study reported was surprising, although the study did not control for factors that may have differed between the groups.

“This needs to be more carefully examined to see if this is a real finding or if there is some bias in the study that is causing it,” she said.

Moving forward, Garcia-Touza said she hopes to launch a prospective study of TRT vs CC.

Parviz K. Kavoussi, MD, a reproductive urologist at the University of Texas at Austin who was not involved in the study, said in an interview the study’s findings highlight the importance of monitoring patients on TRT for an increase in hematocrit. 

“Not all testosterone replacement therapies are created equal from this standpoint,” he said, noting that risk depends on the delivery method. “There are multiple modalities — topical gels, patches, nasal gels, intramuscular injections, subcutaneous pellets, subcutaneous autoinjector pens, and oral testosterone pills. Each of these has a defined percentage risk of secondary erythrocytosis, with some being significantly higher than others.”

As for other potential risks from TRT such as a possible higher mortality rate, Kavoussi noted that a landmark 2023 trial of middle-aged and older men convinced the FDA to no longer require testosterone products to include a black-box warning about cardiovascular disease. 

Regarding the question of whether clomiphene works as well as testosterone, Kavoussi noted his group’s research has found clomiphene can normalize testosterone levels biochemically. However, “where clomiphene typically falls short in data and in clinical practice is the level of symptomatic improvement in testosterone deficiency symptoms that patients can achieve in comparison to exogenous testosterone replacement.” 

No funding was reported, and the authors – including Garcia-Touza – had no disclosures. Kavoussi discloses relationships with Halozyme and Verity.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the misfolding of the TTR protein, which results in aggregation of amyloid fibrils that deposit in the myocardium and causes restrictive cardiomyopathy. Though it remains underdiagnosed, ATTR-CM is increasingly being recognized as a cause of heart failure in geriatric patients.¹ There are 2 categories of ATTRCM: wild-type ATTR-CM (wtATTR-CM), in which there is no mutation in the TTR gene, and hereditary ATTR-CM (hATTR-CM), in which a mutation is present in the TTR gene. Research has shown that wtATTR-CM accounted for as many as 30% of cases of heart failure (HF) with preserved ejection fraction (HFpEF) in patients aged > 75 years.² A significant percentage of the veteran patient population consists of older males. Given their age, these patients are at greater risk for ATTR diagnosis.³

Identifying red flags for patients within this population may allow clinicians to make earlier diagnoses and improve outcomes. A high index of suspicion is needed to diagnose ATTR because many early signs and symptoms are extracardiac, which leads to delayed diagnoses and worse outcomes. This article describes 8 cases of ATTR-CM within the US Department of Veterans Affairs (VA) New York Harbor Healthcare System-Brooklyn (VANYHHSB).

Methods

This retrospective case series was reviewed and approved by the VANYHHSB Institutional Review Board where it was conducted. Patients diagnosed with ATTR between 2017 and 2024 were identified using International Classification of Diseases, Tenth Revision codes. Eleven patients were identified; 3 were excluded due to insufficient medical records. The remaining 8 patient records were retrospectively reviewed and included.

Case 1

A 67-year-old male with a history of carpal tunnel syndrome (CTS) presented following a syncopal episode. Initial electrocardiogram (ECG) showed sinus rhythm, first-degree atrioventricular block, and a bifascicular block. Transthoracic echocardiogram (TTE) showed moderate asymmetric left ventricular (LV) hypertrophy (LVH) and biatrial enlargement with an ejection fraction (EF) > 55%. The patient was discharged with a loop recorder and an outpatient follow-up appointment scheduled. One month later, he presented with worsening dyspnea on exertion with clinical signs of hypervolemia. A repeat TTE showed global LV wall thickening, moderately reduced LV systolic function (EF 40%), and moderate pulmonary hypertension. Given these findings, the patient underwent cardiac magnetic resonance imaging (CMR), which suggested an infiltrative cardiomyopathy. Amyloid light-chain (AL) amyloidosis evaluation, technetium-99m (^99mTC) pyrophosphate imaging, and a fat pad biopsy were unrevealing. An endomyocardial biopsy was performed with electron microscopy, which confirmed amyloidosis. Genetic testing was negative, and the patient began taking tafamidis. There were no later admissions for decompensated HF; however, the patient developed atrial fibrillation (AF) and an interval TTE demonstrated no improvement in his EF. He died at age 73 years.

Case 2

A 78-year-old male with a history of CTS presented with lightheadedness. Initial ECG showed rate-controlled AF and TTE revealed a moderately thickened LV wall with normal LV size, mild left atrial enlargement, and an EF of 65%. The patient was discharged with a scheduled outpatient CMR appointment; however, he defaulted from follow-up. Two years later, he presented with recurrent syncopal episodes and physical examination was consistent with hypervolemia. Repeat TTE revealed moderate LVH, biatrial enlargement, and an EF of 55%. An inpatient CMR was suggestive of cardiac amyloidosis, and a pyrophosphate scan was diagnostic for ATTR. The patient started taking tafamidis, but continued to have recurrent admissions for HF exacerbation. He died at age 81 years.

Case 3

A 71-year-old male with a history of CTS presented with exertional dyspnea. The initial ECG showed sinus rhythm with left atrial enlargement and left axis deviation. Subsequent TTE revealed severe LVH, mildly reduced LV cavity size, moderate to severe biatrial enlargement, and an EF of 25% to 30%. Outpatient ^99mTC pyrophosphate imaging suggested cardiac amyloidosis, and laboratory testing showed no evidence of monoclonal proteins. The patient was started on tafamidis for ATTR. At 2-year follow-up, he had new AF and to date has had no further hospitalizations for acute decompensated HF.

Case 4

A 92-year-old male with a history of AF and bilateral CTS presented with lightheadedness. An ECG revealed AF with a slowed ventricular response. Subsequent Holter monitoring demonstrated pauses exceeding 3 seconds, and a permanent pacemaker was recommended. During his preoperative evaluation, TTE revealed severe concentric LVH with a speckled appearance of the myocardium, mild-tomoderate biatrial enlargement, and an EF of 50% to 55%. 99mTC pyrophosphate imaging was positive for amyloidosis and the patient started taking tafamidis. Recurrent hospital admissions for decompensated HF complicated his progression. The patient died at age 95 years.

Case 5

A 72-year-old male with a history of bilateral CTS and cervical spinal stenosis presented with dyspnea on exertion. An ECG revealed a normal sinus rhythm. A TTE found severely reduced systolic function with an EF ≤ 25%, mild concentric LVH, grade 3 diastolic dysfunction, mild-tomoderate biatrial enlargement, and moderate pulmonary hypertension (Figure 1). He was started on guideline-directed medical therapy (GDMT) for HF, which included sacubitril/valsartan, metoprolol succinate, and empagliflozin. The patient’s dyspnea improved, and a workup for nonischemic cardiomyopathy was initiated. 99mTC pyrophosphate imaging 1 year after his initial presentation was positive, leading to ATTR-CM diagnosis. The patient started taking tafamidis and he has since had a stable progression and continued to demonstrate good exercise tolerance with no hospitalizations. His most recent TTE indicated an EF of 40% to 45%.

Case 6

A 76-year-old male with a history of paroxysmal AF status after multiple ablations, bilateral CTS, and severe cervical spinal stenosis presented with dyspnea on exertion. The patient’s ECG showed normal sinus rhythm and left axis deviation with concern for left anterior hemiblock. A TTE revealed moderate LVH with a speckled appearance of the myocardium and grade 3 diastolic dysfunction with preserved EF. Before completing the workup for underlying cardiomyopathy, the patient underwent an interventional radiology procedure for an angiomyolipoma, and his postoperative course was complicated by pulmonary edema, requiring admission to the coronary care unit for diuresis. A repeat TTE revealed a reduced EF of 35%, and he was discharged on GDMT. No monoclonal protein was seen in the serum or urine. The patient’s progression was complicated by recurrent admissions for acute decompensated HF and supraventricular tachycardia despite being on amiodarone, which led to a delay in obtaining 99mTC pyrophosphate imaging. Due to hypotension, the patient was unable to tolerate GDMT. He eventually underwent 99mTC pyrophosphate imaging that confirmed ATTR-CM and was started on tafamidis. One year following initial presentation, the patient’s EF progressively declined to 20% to 25%, and he died shortly after discharge to subacute rehabilitation.

Case 7

A 95-year-old male with a history of longstanding persistent AF and bilateral CTS presented with dyspnea on exertion, bendopnea, and worsening bilateral pedal edema for a week. An ECG showed AF with a controlled ventricular response and low-voltage QRS waves (Figure 2). A TTE showed biatrial enlargement, LVH, and preserved EF > 55%. He started taking furosemide and was discharged with a diagnosis of HFpEF. The patient missed cardiology follow-up and presented 1 year later with decompensated HF. An amyloidosis workup was recommended, but due to intermittent periods of being lost to follow-up, the patient did not pursue this workup until 3 years after his initial presentation when 99mTC pyrophosphate imaging confirmed ATTR-CM. The patient declined tafamidis and continued to be followed by the cardiology team. His HF is managed with furosemide as needed due to intolerance to GDMT.

Case 8

A 74-year-old male with history of bilateral CTS presented with right-sided chest pain associated with shortness of breath, diaphoresis, dizziness, and worsening abdominal pain. He was found to have inferior wall myocardial infarction on ECG with later percutaneous coronary intervention to the left circumflex. His hospital course was complicated by decompensated HF (EF 45% to 50%) and AF with rapid ventricular response. He was treated and discharged with follow-up visits scheduled in the cardiology clinic. Multiple attempts were made to place him on GDMT; however, the patient was unable to tolerate these medications due to recurrent admissions for syncope. During a cardiology clinic visit 3 years after his initial presentation, an amyloidosis workup was initiated. 99mTC pyrophosphate imaging was positive for ATTR-CM, and he started taking tafamidis. Before this diagnosis, ECG indicated low-voltage QRS complexes. His progression has since been complicated by admissions for decompensated HF, recurrent episodes of AF requiring atrioventricular node ablation, and biventricular implantable cardioverter-defibrillator implantation after failed attempts at electrical cardioversion. He continued to follow up in the HF clinic.

Discussion

ATTR-CM is an underdiagnosed cause of cardiomyopathy, particularly in older adults. TTR is a transport protein produced in the liver, and misfolding can occur due to age-related instability of the wild-type protein (wtATTR) or pathologic variants in the TTR (hATTR). The misfolding leads to restrictive physiology, HF (often with preserved EF) arrhythmias, and conduction system disease.¹ It is likely that the predominantly older male veteran population would be predisposed to wtATTR cardiomyopathy given that misfolding in the condition is believed to be age-related.

Current criteria for ATTR diagnosis require a combination of clinical suspicion, imaging, laboratory testing, and, in some cases, tissue biopsy confirmation and genetic testing.^1,4,5 The diagnostic algorithm is as follows:

Clinical suspicion. Consider ATTR in patients with unexplained HFpEF, LV wall thickness ≥ 12 to 14 mm, discordance between ECG voltage and wall thickness, or associated extracardiac manifestations such as CTS, lumbar spinal stenosis, or peripheral/ autonomic neuropathy.

Exclusion of AL amyloidosis. Bone scintigraphy alone cannot distinguish between AL amyloidosis and ATTR, so patients with suspected amyloid cardiomyopathy should undergo serum and urine immunofixation electrophoresis and serum free light chain assay to rule out a monoclonal gammopathy as seen in AL amyloidosis.

Cardiac scintigraphy. Once AL amyloidosis is excluded, a positive 99mTC-labeled boneavid tracer image (such as a pyrophosphate scan) with grade 2 or grade 3 myocardial uptake is diagnostic of ATTR.

Tissue biopsy. If there is monoclonal gammopathy or equivocal imaging, tissue biopsy (eg, endomyocardial) with Congo red staining and amyloid typing by mass spectrometry or immunohistochemistry is necessary.

Genetic testing. Once ATTR is confirmed, genetic testing distinguishes hATTR from wtATTR, which impacts management and determines the need to screen family members.

Currently, there are 3 therapies approved by the US Food and Drug Administration (FDA) to treat ATTR-CM: tafamidis, acoramidis, and vutrisiran.^6-8 Tafamidis and acoramidis stabilize the TTR tetramer, preventing amyloid formation. Vutrisiran uses RNA interference to silence the gene that produces TTR. Tafamidis has been found to improve cardiovascular outcomes in ATTR-CM. In the ATTR-ACT trial, it reduced all-cause mortality and cardiovascular hospitalizations in patients with ATTR-CM and New York Heart Association class I-III symptoms.⁶ There are other disease-modifying therapies, such the TTR gene silencers inotersen and patisiran; however, these are only FDA-approved for hATTR polyneuropathy and not for ATTRCM; ongoing trials are evaluating their cardiac efficacy.

The mean age of ATTR-CM diagnosis in the patients described in this case series was 79 years, which is older than the mean age of 74 years reported in prior research.⁴ All patients were male, and the most common presenting symptom was dyspnea on exertion. Table 1 outlines baseline characteristics and associated comorbidities of patients in this case series. The patients presented with many red-flag signs of ATTR-CM (Figure 3). Among them included syncope (4 of 8 patients), spinal stenosis (2 of 8 patients), arrhythmia (7 of 8 patients), heart failure (7 of 8 patients), and bilateral CTS (all patients).

Bilateral CTS was diagnosed in all patients before their diagnosis of ATTR-CM. Patient 7 had a diagnosis of CTS 9 years before his ATTR-CM diagnosis, underscoring a subtle, yet important extracardiac sign that may increase clinical suspicion for ATTR-CM. Previous research found that the probability of having CTS is highest 5 to 9 years prior to the development of cardiomyopathy. Its presence is also a prognostic marker in ATTR, independent of cardiac involvement.⁹ The median interval between CTS diagnosis and cardiomyopathy diagnosis was 5 years in this series.

Although screening criteria for ATTR have been proposed, none have been incorporated into formal guidelines.^10,11 We propose that a baseline ECG and screening TTE be obtained in any patient aged > 65 years with cardiac risk equivalents such as hypertension and diabetes, presenting with ≥ 1 extracardiac red-flag signs, such as bilateral CTS and spinal stenosis. This will likely facilitate an earlier diagnosis of ATTR-CM, leading to earlier treatment initiation and better patient outcomes. This initiative can be started in the primary care setting and facilitates early cardiology referral. This recommendation is based on literature supporting clinical patterns and observations the authors have made in clinical practice.

Obstructive sleep apnea (OSA) was a comorbidity present in 50% of the patients described in this case series. The literature describing this association is sparse; however, a prospective observational study reported that disorders of sleep inclusive of OSA are frequent in patients with cardiac amyloidosis.¹² A theory behind this association is that amyloid deposits in the upper airway tissues lead to airway narrowing. ¹³ More research is needed to further assess the relationship between OSA and cardiac amyloidosis, particularly with respect to the timing of OSA prior to the development of cardiomyopathy as it may be a potential early sign for clinicians to acknowledge.

An important observation from this case series is the variability in the timing of tafamidis initiation relative to symptom onset and confirmed diagnosis of ATTR-CM (Table 2). Although tafamidis has been found to slow disease progression, several patients in this series began treatment at advanced stages or years after the onset of cardiac symptoms, potentially limiting its clinical benefit.

For example, patient 1 was diagnosed with ATTR 2 years before tafamidis became available on the market and was initially treated with diflunisal. Patients who started tafamidis earlier in the disease course (eg, patients 3 and 5) appeared to have better long-term outcomes, including an absence of heart failure hospitalizations after initiation. In contrast, patients with delayed treatment initiation (eg, patients 2, 6, and 8) experienced ongoing decompensations or early mortality. Patient 7 declined tafamidis, underscoring challenges in medication uptake among older adults. Randomized controlled trials are warranted to compare the effectiveness of tafamidis with other recently FDA-approved therapies, such as acoramidis and vutrisiran, particularly in terms of cardiovascular outcomes.

AF was the most common arrhythmia observed in these patients and may occur years before the development of HF symptoms in the setting of ATTR-CM. Due to inherent conduction system disease, AF in this population may have a controlled or slow ventricular response, as observed in patient 4. Patients with atrial fibrillation and cardiac amyloidosis should receive anticoagulation regardless of CHA2DS2- VASc score due to their high risk of intracardiac thrombus formation.⁴

Limitations

This case series lacked genetic testing following a confirmed ATTR-CM diagnosis. Although much of the treatment is the same regardless of the presence of a TTR mutation, knowing the specific subtype of ATTR-CM has implications for prognosis and for screening family members.

Conclusions

Following analysis of 8 patients diagnosed with ATTR, this case series could serve as a blueprint for research into ATTR in veterans. In clinical practice, following military service, veterans may not be routinely seen by an outpatient physician and may present with sequelae of advanced stages of ATTR. Early identification of red-flag symptoms can lead to a higher clinical suspicion, prompting early diagnostic evaluation and treatment initiation and ultimately mitigating adverse outcomes. Future research that includes genetic testing for those with confirmed ATTR-CM may prove useful as a foundation for detailed and informed discussions with patients and their families regarding prognosis and, if indicated, screening for family members.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the misfolding of the TTR protein, which results in aggregation of amyloid fibrils that deposit in the myocardium and causes restrictive cardiomyopathy. Though it remains underdiagnosed, ATTR-CM is increasingly being recognized as a cause of heart failure in geriatric patients.¹ There are 2 categories of ATTRCM: wild-type ATTR-CM (wtATTR-CM), in which there is no mutation in the TTR gene, and hereditary ATTR-CM (hATTR-CM), in which a mutation is present in the TTR gene. Research has shown that wtATTR-CM accounted for as many as 30% of cases of heart failure (HF) with preserved ejection fraction (HFpEF) in patients aged > 75 years.² A significant percentage of the veteran patient population consists of older males. Given their age, these patients are at greater risk for ATTR diagnosis.³

Identifying red flags for patients within this population may allow clinicians to make earlier diagnoses and improve outcomes. A high index of suspicion is needed to diagnose ATTR because many early signs and symptoms are extracardiac, which leads to delayed diagnoses and worse outcomes. This article describes 8 cases of ATTR-CM within the US Department of Veterans Affairs (VA) New York Harbor Healthcare System-Brooklyn (VANYHHSB).

Methods

This retrospective case series was reviewed and approved by the VANYHHSB Institutional Review Board where it was conducted. Patients diagnosed with ATTR between 2017 and 2024 were identified using International Classification of Diseases, Tenth Revision codes. Eleven patients were identified; 3 were excluded due to insufficient medical records. The remaining 8 patient records were retrospectively reviewed and included.

Case 1

A 67-year-old male with a history of carpal tunnel syndrome (CTS) presented following a syncopal episode. Initial electrocardiogram (ECG) showed sinus rhythm, first-degree atrioventricular block, and a bifascicular block. Transthoracic echocardiogram (TTE) showed moderate asymmetric left ventricular (LV) hypertrophy (LVH) and biatrial enlargement with an ejection fraction (EF) > 55%. The patient was discharged with a loop recorder and an outpatient follow-up appointment scheduled. One month later, he presented with worsening dyspnea on exertion with clinical signs of hypervolemia. A repeat TTE showed global LV wall thickening, moderately reduced LV systolic function (EF 40%), and moderate pulmonary hypertension. Given these findings, the patient underwent cardiac magnetic resonance imaging (CMR), which suggested an infiltrative cardiomyopathy. Amyloid light-chain (AL) amyloidosis evaluation, technetium-99m (^99mTC) pyrophosphate imaging, and a fat pad biopsy were unrevealing. An endomyocardial biopsy was performed with electron microscopy, which confirmed amyloidosis. Genetic testing was negative, and the patient began taking tafamidis. There were no later admissions for decompensated HF; however, the patient developed atrial fibrillation (AF) and an interval TTE demonstrated no improvement in his EF. He died at age 73 years.

Case 2

A 78-year-old male with a history of CTS presented with lightheadedness. Initial ECG showed rate-controlled AF and TTE revealed a moderately thickened LV wall with normal LV size, mild left atrial enlargement, and an EF of 65%. The patient was discharged with a scheduled outpatient CMR appointment; however, he defaulted from follow-up. Two years later, he presented with recurrent syncopal episodes and physical examination was consistent with hypervolemia. Repeat TTE revealed moderate LVH, biatrial enlargement, and an EF of 55%. An inpatient CMR was suggestive of cardiac amyloidosis, and a pyrophosphate scan was diagnostic for ATTR. The patient started taking tafamidis, but continued to have recurrent admissions for HF exacerbation. He died at age 81 years.

Case 3

A 71-year-old male with a history of CTS presented with exertional dyspnea. The initial ECG showed sinus rhythm with left atrial enlargement and left axis deviation. Subsequent TTE revealed severe LVH, mildly reduced LV cavity size, moderate to severe biatrial enlargement, and an EF of 25% to 30%. Outpatient ^99mTC pyrophosphate imaging suggested cardiac amyloidosis, and laboratory testing showed no evidence of monoclonal proteins. The patient was started on tafamidis for ATTR. At 2-year follow-up, he had new AF and to date has had no further hospitalizations for acute decompensated HF.

Case 4

A 92-year-old male with a history of AF and bilateral CTS presented with lightheadedness. An ECG revealed AF with a slowed ventricular response. Subsequent Holter monitoring demonstrated pauses exceeding 3 seconds, and a permanent pacemaker was recommended. During his preoperative evaluation, TTE revealed severe concentric LVH with a speckled appearance of the myocardium, mild-tomoderate biatrial enlargement, and an EF of 50% to 55%. 99mTC pyrophosphate imaging was positive for amyloidosis and the patient started taking tafamidis. Recurrent hospital admissions for decompensated HF complicated his progression. The patient died at age 95 years.

Case 5

A 72-year-old male with a history of bilateral CTS and cervical spinal stenosis presented with dyspnea on exertion. An ECG revealed a normal sinus rhythm. A TTE found severely reduced systolic function with an EF ≤ 25%, mild concentric LVH, grade 3 diastolic dysfunction, mild-tomoderate biatrial enlargement, and moderate pulmonary hypertension (Figure 1). He was started on guideline-directed medical therapy (GDMT) for HF, which included sacubitril/valsartan, metoprolol succinate, and empagliflozin. The patient’s dyspnea improved, and a workup for nonischemic cardiomyopathy was initiated. 99mTC pyrophosphate imaging 1 year after his initial presentation was positive, leading to ATTR-CM diagnosis. The patient started taking tafamidis and he has since had a stable progression and continued to demonstrate good exercise tolerance with no hospitalizations. His most recent TTE indicated an EF of 40% to 45%.

Case 6

A 76-year-old male with a history of paroxysmal AF status after multiple ablations, bilateral CTS, and severe cervical spinal stenosis presented with dyspnea on exertion. The patient’s ECG showed normal sinus rhythm and left axis deviation with concern for left anterior hemiblock. A TTE revealed moderate LVH with a speckled appearance of the myocardium and grade 3 diastolic dysfunction with preserved EF. Before completing the workup for underlying cardiomyopathy, the patient underwent an interventional radiology procedure for an angiomyolipoma, and his postoperative course was complicated by pulmonary edema, requiring admission to the coronary care unit for diuresis. A repeat TTE revealed a reduced EF of 35%, and he was discharged on GDMT. No monoclonal protein was seen in the serum or urine. The patient’s progression was complicated by recurrent admissions for acute decompensated HF and supraventricular tachycardia despite being on amiodarone, which led to a delay in obtaining 99mTC pyrophosphate imaging. Due to hypotension, the patient was unable to tolerate GDMT. He eventually underwent 99mTC pyrophosphate imaging that confirmed ATTR-CM and was started on tafamidis. One year following initial presentation, the patient’s EF progressively declined to 20% to 25%, and he died shortly after discharge to subacute rehabilitation.

Case 7

A 95-year-old male with a history of longstanding persistent AF and bilateral CTS presented with dyspnea on exertion, bendopnea, and worsening bilateral pedal edema for a week. An ECG showed AF with a controlled ventricular response and low-voltage QRS waves (Figure 2). A TTE showed biatrial enlargement, LVH, and preserved EF > 55%. He started taking furosemide and was discharged with a diagnosis of HFpEF. The patient missed cardiology follow-up and presented 1 year later with decompensated HF. An amyloidosis workup was recommended, but due to intermittent periods of being lost to follow-up, the patient did not pursue this workup until 3 years after his initial presentation when 99mTC pyrophosphate imaging confirmed ATTR-CM. The patient declined tafamidis and continued to be followed by the cardiology team. His HF is managed with furosemide as needed due to intolerance to GDMT.

Case 8

A 74-year-old male with history of bilateral CTS presented with right-sided chest pain associated with shortness of breath, diaphoresis, dizziness, and worsening abdominal pain. He was found to have inferior wall myocardial infarction on ECG with later percutaneous coronary intervention to the left circumflex. His hospital course was complicated by decompensated HF (EF 45% to 50%) and AF with rapid ventricular response. He was treated and discharged with follow-up visits scheduled in the cardiology clinic. Multiple attempts were made to place him on GDMT; however, the patient was unable to tolerate these medications due to recurrent admissions for syncope. During a cardiology clinic visit 3 years after his initial presentation, an amyloidosis workup was initiated. 99mTC pyrophosphate imaging was positive for ATTR-CM, and he started taking tafamidis. Before this diagnosis, ECG indicated low-voltage QRS complexes. His progression has since been complicated by admissions for decompensated HF, recurrent episodes of AF requiring atrioventricular node ablation, and biventricular implantable cardioverter-defibrillator implantation after failed attempts at electrical cardioversion. He continued to follow up in the HF clinic.

Discussion

ATTR-CM is an underdiagnosed cause of cardiomyopathy, particularly in older adults. TTR is a transport protein produced in the liver, and misfolding can occur due to age-related instability of the wild-type protein (wtATTR) or pathologic variants in the TTR (hATTR). The misfolding leads to restrictive physiology, HF (often with preserved EF) arrhythmias, and conduction system disease.¹ It is likely that the predominantly older male veteran population would be predisposed to wtATTR cardiomyopathy given that misfolding in the condition is believed to be age-related.

Current criteria for ATTR diagnosis require a combination of clinical suspicion, imaging, laboratory testing, and, in some cases, tissue biopsy confirmation and genetic testing.^1,4,5 The diagnostic algorithm is as follows:

Clinical suspicion. Consider ATTR in patients with unexplained HFpEF, LV wall thickness ≥ 12 to 14 mm, discordance between ECG voltage and wall thickness, or associated extracardiac manifestations such as CTS, lumbar spinal stenosis, or peripheral/ autonomic neuropathy.

Exclusion of AL amyloidosis. Bone scintigraphy alone cannot distinguish between AL amyloidosis and ATTR, so patients with suspected amyloid cardiomyopathy should undergo serum and urine immunofixation electrophoresis and serum free light chain assay to rule out a monoclonal gammopathy as seen in AL amyloidosis.

Cardiac scintigraphy. Once AL amyloidosis is excluded, a positive 99mTC-labeled boneavid tracer image (such as a pyrophosphate scan) with grade 2 or grade 3 myocardial uptake is diagnostic of ATTR.

Tissue biopsy. If there is monoclonal gammopathy or equivocal imaging, tissue biopsy (eg, endomyocardial) with Congo red staining and amyloid typing by mass spectrometry or immunohistochemistry is necessary.

Genetic testing. Once ATTR is confirmed, genetic testing distinguishes hATTR from wtATTR, which impacts management and determines the need to screen family members.

Currently, there are 3 therapies approved by the US Food and Drug Administration (FDA) to treat ATTR-CM: tafamidis, acoramidis, and vutrisiran.^6-8 Tafamidis and acoramidis stabilize the TTR tetramer, preventing amyloid formation. Vutrisiran uses RNA interference to silence the gene that produces TTR. Tafamidis has been found to improve cardiovascular outcomes in ATTR-CM. In the ATTR-ACT trial, it reduced all-cause mortality and cardiovascular hospitalizations in patients with ATTR-CM and New York Heart Association class I-III symptoms.⁶ There are other disease-modifying therapies, such the TTR gene silencers inotersen and patisiran; however, these are only FDA-approved for hATTR polyneuropathy and not for ATTRCM; ongoing trials are evaluating their cardiac efficacy.

The mean age of ATTR-CM diagnosis in the patients described in this case series was 79 years, which is older than the mean age of 74 years reported in prior research.⁴ All patients were male, and the most common presenting symptom was dyspnea on exertion. Table 1 outlines baseline characteristics and associated comorbidities of patients in this case series. The patients presented with many red-flag signs of ATTR-CM (Figure 3). Among them included syncope (4 of 8 patients), spinal stenosis (2 of 8 patients), arrhythmia (7 of 8 patients), heart failure (7 of 8 patients), and bilateral CTS (all patients).

Bilateral CTS was diagnosed in all patients before their diagnosis of ATTR-CM. Patient 7 had a diagnosis of CTS 9 years before his ATTR-CM diagnosis, underscoring a subtle, yet important extracardiac sign that may increase clinical suspicion for ATTR-CM. Previous research found that the probability of having CTS is highest 5 to 9 years prior to the development of cardiomyopathy. Its presence is also a prognostic marker in ATTR, independent of cardiac involvement.⁹ The median interval between CTS diagnosis and cardiomyopathy diagnosis was 5 years in this series.

Although screening criteria for ATTR have been proposed, none have been incorporated into formal guidelines.^10,11 We propose that a baseline ECG and screening TTE be obtained in any patient aged > 65 years with cardiac risk equivalents such as hypertension and diabetes, presenting with ≥ 1 extracardiac red-flag signs, such as bilateral CTS and spinal stenosis. This will likely facilitate an earlier diagnosis of ATTR-CM, leading to earlier treatment initiation and better patient outcomes. This initiative can be started in the primary care setting and facilitates early cardiology referral. This recommendation is based on literature supporting clinical patterns and observations the authors have made in clinical practice.

Obstructive sleep apnea (OSA) was a comorbidity present in 50% of the patients described in this case series. The literature describing this association is sparse; however, a prospective observational study reported that disorders of sleep inclusive of OSA are frequent in patients with cardiac amyloidosis.¹² A theory behind this association is that amyloid deposits in the upper airway tissues lead to airway narrowing. ¹³ More research is needed to further assess the relationship between OSA and cardiac amyloidosis, particularly with respect to the timing of OSA prior to the development of cardiomyopathy as it may be a potential early sign for clinicians to acknowledge.

An important observation from this case series is the variability in the timing of tafamidis initiation relative to symptom onset and confirmed diagnosis of ATTR-CM (Table 2). Although tafamidis has been found to slow disease progression, several patients in this series began treatment at advanced stages or years after the onset of cardiac symptoms, potentially limiting its clinical benefit.

For example, patient 1 was diagnosed with ATTR 2 years before tafamidis became available on the market and was initially treated with diflunisal. Patients who started tafamidis earlier in the disease course (eg, patients 3 and 5) appeared to have better long-term outcomes, including an absence of heart failure hospitalizations after initiation. In contrast, patients with delayed treatment initiation (eg, patients 2, 6, and 8) experienced ongoing decompensations or early mortality. Patient 7 declined tafamidis, underscoring challenges in medication uptake among older adults. Randomized controlled trials are warranted to compare the effectiveness of tafamidis with other recently FDA-approved therapies, such as acoramidis and vutrisiran, particularly in terms of cardiovascular outcomes.

AF was the most common arrhythmia observed in these patients and may occur years before the development of HF symptoms in the setting of ATTR-CM. Due to inherent conduction system disease, AF in this population may have a controlled or slow ventricular response, as observed in patient 4. Patients with atrial fibrillation and cardiac amyloidosis should receive anticoagulation regardless of CHA2DS2- VASc score due to their high risk of intracardiac thrombus formation.⁴

Limitations

This case series lacked genetic testing following a confirmed ATTR-CM diagnosis. Although much of the treatment is the same regardless of the presence of a TTR mutation, knowing the specific subtype of ATTR-CM has implications for prognosis and for screening family members.

Conclusions

Following analysis of 8 patients diagnosed with ATTR, this case series could serve as a blueprint for research into ATTR in veterans. In clinical practice, following military service, veterans may not be routinely seen by an outpatient physician and may present with sequelae of advanced stages of ATTR. Early identification of red-flag symptoms can lead to a higher clinical suspicion, prompting early diagnostic evaluation and treatment initiation and ultimately mitigating adverse outcomes. Future research that includes genetic testing for those with confirmed ATTR-CM may prove useful as a foundation for detailed and informed discussions with patients and their families regarding prognosis and, if indicated, screening for family members.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the misfolding of the TTR protein, which results in aggregation of amyloid fibrils that deposit in the myocardium and causes restrictive cardiomyopathy. Though it remains underdiagnosed, ATTR-CM is increasingly being recognized as a cause of heart failure in geriatric patients.¹ There are 2 categories of ATTRCM: wild-type ATTR-CM (wtATTR-CM), in which there is no mutation in the TTR gene, and hereditary ATTR-CM (hATTR-CM), in which a mutation is present in the TTR gene. Research has shown that wtATTR-CM accounted for as many as 30% of cases of heart failure (HF) with preserved ejection fraction (HFpEF) in patients aged > 75 years.² A significant percentage of the veteran patient population consists of older males. Given their age, these patients are at greater risk for ATTR diagnosis.³

Identifying red flags for patients within this population may allow clinicians to make earlier diagnoses and improve outcomes. A high index of suspicion is needed to diagnose ATTR because many early signs and symptoms are extracardiac, which leads to delayed diagnoses and worse outcomes. This article describes 8 cases of ATTR-CM within the US Department of Veterans Affairs (VA) New York Harbor Healthcare System-Brooklyn (VANYHHSB).

Methods

This retrospective case series was reviewed and approved by the VANYHHSB Institutional Review Board where it was conducted. Patients diagnosed with ATTR between 2017 and 2024 were identified using International Classification of Diseases, Tenth Revision codes. Eleven patients were identified; 3 were excluded due to insufficient medical records. The remaining 8 patient records were retrospectively reviewed and included.

Case 1

A 67-year-old male with a history of carpal tunnel syndrome (CTS) presented following a syncopal episode. Initial electrocardiogram (ECG) showed sinus rhythm, first-degree atrioventricular block, and a bifascicular block. Transthoracic echocardiogram (TTE) showed moderate asymmetric left ventricular (LV) hypertrophy (LVH) and biatrial enlargement with an ejection fraction (EF) > 55%. The patient was discharged with a loop recorder and an outpatient follow-up appointment scheduled. One month later, he presented with worsening dyspnea on exertion with clinical signs of hypervolemia. A repeat TTE showed global LV wall thickening, moderately reduced LV systolic function (EF 40%), and moderate pulmonary hypertension. Given these findings, the patient underwent cardiac magnetic resonance imaging (CMR), which suggested an infiltrative cardiomyopathy. Amyloid light-chain (AL) amyloidosis evaluation, technetium-99m (^99mTC) pyrophosphate imaging, and a fat pad biopsy were unrevealing. An endomyocardial biopsy was performed with electron microscopy, which confirmed amyloidosis. Genetic testing was negative, and the patient began taking tafamidis. There were no later admissions for decompensated HF; however, the patient developed atrial fibrillation (AF) and an interval TTE demonstrated no improvement in his EF. He died at age 73 years.

Case 2

A 78-year-old male with a history of CTS presented with lightheadedness. Initial ECG showed rate-controlled AF and TTE revealed a moderately thickened LV wall with normal LV size, mild left atrial enlargement, and an EF of 65%. The patient was discharged with a scheduled outpatient CMR appointment; however, he defaulted from follow-up. Two years later, he presented with recurrent syncopal episodes and physical examination was consistent with hypervolemia. Repeat TTE revealed moderate LVH, biatrial enlargement, and an EF of 55%. An inpatient CMR was suggestive of cardiac amyloidosis, and a pyrophosphate scan was diagnostic for ATTR. The patient started taking tafamidis, but continued to have recurrent admissions for HF exacerbation. He died at age 81 years.

Case 3

A 71-year-old male with a history of CTS presented with exertional dyspnea. The initial ECG showed sinus rhythm with left atrial enlargement and left axis deviation. Subsequent TTE revealed severe LVH, mildly reduced LV cavity size, moderate to severe biatrial enlargement, and an EF of 25% to 30%. Outpatient ^99mTC pyrophosphate imaging suggested cardiac amyloidosis, and laboratory testing showed no evidence of monoclonal proteins. The patient was started on tafamidis for ATTR. At 2-year follow-up, he had new AF and to date has had no further hospitalizations for acute decompensated HF.

Case 4

A 92-year-old male with a history of AF and bilateral CTS presented with lightheadedness. An ECG revealed AF with a slowed ventricular response. Subsequent Holter monitoring demonstrated pauses exceeding 3 seconds, and a permanent pacemaker was recommended. During his preoperative evaluation, TTE revealed severe concentric LVH with a speckled appearance of the myocardium, mild-tomoderate biatrial enlargement, and an EF of 50% to 55%. 99mTC pyrophosphate imaging was positive for amyloidosis and the patient started taking tafamidis. Recurrent hospital admissions for decompensated HF complicated his progression. The patient died at age 95 years.

Case 5

A 72-year-old male with a history of bilateral CTS and cervical spinal stenosis presented with dyspnea on exertion. An ECG revealed a normal sinus rhythm. A TTE found severely reduced systolic function with an EF ≤ 25%, mild concentric LVH, grade 3 diastolic dysfunction, mild-tomoderate biatrial enlargement, and moderate pulmonary hypertension (Figure 1). He was started on guideline-directed medical therapy (GDMT) for HF, which included sacubitril/valsartan, metoprolol succinate, and empagliflozin. The patient’s dyspnea improved, and a workup for nonischemic cardiomyopathy was initiated. 99mTC pyrophosphate imaging 1 year after his initial presentation was positive, leading to ATTR-CM diagnosis. The patient started taking tafamidis and he has since had a stable progression and continued to demonstrate good exercise tolerance with no hospitalizations. His most recent TTE indicated an EF of 40% to 45%.

Case 6

A 76-year-old male with a history of paroxysmal AF status after multiple ablations, bilateral CTS, and severe cervical spinal stenosis presented with dyspnea on exertion. The patient’s ECG showed normal sinus rhythm and left axis deviation with concern for left anterior hemiblock. A TTE revealed moderate LVH with a speckled appearance of the myocardium and grade 3 diastolic dysfunction with preserved EF. Before completing the workup for underlying cardiomyopathy, the patient underwent an interventional radiology procedure for an angiomyolipoma, and his postoperative course was complicated by pulmonary edema, requiring admission to the coronary care unit for diuresis. A repeat TTE revealed a reduced EF of 35%, and he was discharged on GDMT. No monoclonal protein was seen in the serum or urine. The patient’s progression was complicated by recurrent admissions for acute decompensated HF and supraventricular tachycardia despite being on amiodarone, which led to a delay in obtaining 99mTC pyrophosphate imaging. Due to hypotension, the patient was unable to tolerate GDMT. He eventually underwent 99mTC pyrophosphate imaging that confirmed ATTR-CM and was started on tafamidis. One year following initial presentation, the patient’s EF progressively declined to 20% to 25%, and he died shortly after discharge to subacute rehabilitation.

Case 7

A 95-year-old male with a history of longstanding persistent AF and bilateral CTS presented with dyspnea on exertion, bendopnea, and worsening bilateral pedal edema for a week. An ECG showed AF with a controlled ventricular response and low-voltage QRS waves (Figure 2). A TTE showed biatrial enlargement, LVH, and preserved EF > 55%. He started taking furosemide and was discharged with a diagnosis of HFpEF. The patient missed cardiology follow-up and presented 1 year later with decompensated HF. An amyloidosis workup was recommended, but due to intermittent periods of being lost to follow-up, the patient did not pursue this workup until 3 years after his initial presentation when 99mTC pyrophosphate imaging confirmed ATTR-CM. The patient declined tafamidis and continued to be followed by the cardiology team. His HF is managed with furosemide as needed due to intolerance to GDMT.

Case 8

A 74-year-old male with history of bilateral CTS presented with right-sided chest pain associated with shortness of breath, diaphoresis, dizziness, and worsening abdominal pain. He was found to have inferior wall myocardial infarction on ECG with later percutaneous coronary intervention to the left circumflex. His hospital course was complicated by decompensated HF (EF 45% to 50%) and AF with rapid ventricular response. He was treated and discharged with follow-up visits scheduled in the cardiology clinic. Multiple attempts were made to place him on GDMT; however, the patient was unable to tolerate these medications due to recurrent admissions for syncope. During a cardiology clinic visit 3 years after his initial presentation, an amyloidosis workup was initiated. 99mTC pyrophosphate imaging was positive for ATTR-CM, and he started taking tafamidis. Before this diagnosis, ECG indicated low-voltage QRS complexes. His progression has since been complicated by admissions for decompensated HF, recurrent episodes of AF requiring atrioventricular node ablation, and biventricular implantable cardioverter-defibrillator implantation after failed attempts at electrical cardioversion. He continued to follow up in the HF clinic.

Discussion

ATTR-CM is an underdiagnosed cause of cardiomyopathy, particularly in older adults. TTR is a transport protein produced in the liver, and misfolding can occur due to age-related instability of the wild-type protein (wtATTR) or pathologic variants in the TTR (hATTR). The misfolding leads to restrictive physiology, HF (often with preserved EF) arrhythmias, and conduction system disease.¹ It is likely that the predominantly older male veteran population would be predisposed to wtATTR cardiomyopathy given that misfolding in the condition is believed to be age-related.

Current criteria for ATTR diagnosis require a combination of clinical suspicion, imaging, laboratory testing, and, in some cases, tissue biopsy confirmation and genetic testing.^1,4,5 The diagnostic algorithm is as follows:

Clinical suspicion. Consider ATTR in patients with unexplained HFpEF, LV wall thickness ≥ 12 to 14 mm, discordance between ECG voltage and wall thickness, or associated extracardiac manifestations such as CTS, lumbar spinal stenosis, or peripheral/ autonomic neuropathy.

Exclusion of AL amyloidosis. Bone scintigraphy alone cannot distinguish between AL amyloidosis and ATTR, so patients with suspected amyloid cardiomyopathy should undergo serum and urine immunofixation electrophoresis and serum free light chain assay to rule out a monoclonal gammopathy as seen in AL amyloidosis.

Cardiac scintigraphy. Once AL amyloidosis is excluded, a positive 99mTC-labeled boneavid tracer image (such as a pyrophosphate scan) with grade 2 or grade 3 myocardial uptake is diagnostic of ATTR.

Tissue biopsy. If there is monoclonal gammopathy or equivocal imaging, tissue biopsy (eg, endomyocardial) with Congo red staining and amyloid typing by mass spectrometry or immunohistochemistry is necessary.

Genetic testing. Once ATTR is confirmed, genetic testing distinguishes hATTR from wtATTR, which impacts management and determines the need to screen family members.

Currently, there are 3 therapies approved by the US Food and Drug Administration (FDA) to treat ATTR-CM: tafamidis, acoramidis, and vutrisiran.^6-8 Tafamidis and acoramidis stabilize the TTR tetramer, preventing amyloid formation. Vutrisiran uses RNA interference to silence the gene that produces TTR. Tafamidis has been found to improve cardiovascular outcomes in ATTR-CM. In the ATTR-ACT trial, it reduced all-cause mortality and cardiovascular hospitalizations in patients with ATTR-CM and New York Heart Association class I-III symptoms.⁶ There are other disease-modifying therapies, such the TTR gene silencers inotersen and patisiran; however, these are only FDA-approved for hATTR polyneuropathy and not for ATTRCM; ongoing trials are evaluating their cardiac efficacy.

The mean age of ATTR-CM diagnosis in the patients described in this case series was 79 years, which is older than the mean age of 74 years reported in prior research.⁴ All patients were male, and the most common presenting symptom was dyspnea on exertion. Table 1 outlines baseline characteristics and associated comorbidities of patients in this case series. The patients presented with many red-flag signs of ATTR-CM (Figure 3). Among them included syncope (4 of 8 patients), spinal stenosis (2 of 8 patients), arrhythmia (7 of 8 patients), heart failure (7 of 8 patients), and bilateral CTS (all patients).

Bilateral CTS was diagnosed in all patients before their diagnosis of ATTR-CM. Patient 7 had a diagnosis of CTS 9 years before his ATTR-CM diagnosis, underscoring a subtle, yet important extracardiac sign that may increase clinical suspicion for ATTR-CM. Previous research found that the probability of having CTS is highest 5 to 9 years prior to the development of cardiomyopathy. Its presence is also a prognostic marker in ATTR, independent of cardiac involvement.⁹ The median interval between CTS diagnosis and cardiomyopathy diagnosis was 5 years in this series.

Although screening criteria for ATTR have been proposed, none have been incorporated into formal guidelines.^10,11 We propose that a baseline ECG and screening TTE be obtained in any patient aged > 65 years with cardiac risk equivalents such as hypertension and diabetes, presenting with ≥ 1 extracardiac red-flag signs, such as bilateral CTS and spinal stenosis. This will likely facilitate an earlier diagnosis of ATTR-CM, leading to earlier treatment initiation and better patient outcomes. This initiative can be started in the primary care setting and facilitates early cardiology referral. This recommendation is based on literature supporting clinical patterns and observations the authors have made in clinical practice.

Obstructive sleep apnea (OSA) was a comorbidity present in 50% of the patients described in this case series. The literature describing this association is sparse; however, a prospective observational study reported that disorders of sleep inclusive of OSA are frequent in patients with cardiac amyloidosis.¹² A theory behind this association is that amyloid deposits in the upper airway tissues lead to airway narrowing. ¹³ More research is needed to further assess the relationship between OSA and cardiac amyloidosis, particularly with respect to the timing of OSA prior to the development of cardiomyopathy as it may be a potential early sign for clinicians to acknowledge.

An important observation from this case series is the variability in the timing of tafamidis initiation relative to symptom onset and confirmed diagnosis of ATTR-CM (Table 2). Although tafamidis has been found to slow disease progression, several patients in this series began treatment at advanced stages or years after the onset of cardiac symptoms, potentially limiting its clinical benefit.

For example, patient 1 was diagnosed with ATTR 2 years before tafamidis became available on the market and was initially treated with diflunisal. Patients who started tafamidis earlier in the disease course (eg, patients 3 and 5) appeared to have better long-term outcomes, including an absence of heart failure hospitalizations after initiation. In contrast, patients with delayed treatment initiation (eg, patients 2, 6, and 8) experienced ongoing decompensations or early mortality. Patient 7 declined tafamidis, underscoring challenges in medication uptake among older adults. Randomized controlled trials are warranted to compare the effectiveness of tafamidis with other recently FDA-approved therapies, such as acoramidis and vutrisiran, particularly in terms of cardiovascular outcomes.

AF was the most common arrhythmia observed in these patients and may occur years before the development of HF symptoms in the setting of ATTR-CM. Due to inherent conduction system disease, AF in this population may have a controlled or slow ventricular response, as observed in patient 4. Patients with atrial fibrillation and cardiac amyloidosis should receive anticoagulation regardless of CHA2DS2- VASc score due to their high risk of intracardiac thrombus formation.⁴

Limitations

This case series lacked genetic testing following a confirmed ATTR-CM diagnosis. Although much of the treatment is the same regardless of the presence of a TTR mutation, knowing the specific subtype of ATTR-CM has implications for prognosis and for screening family members.

Conclusions

Following analysis of 8 patients diagnosed with ATTR, this case series could serve as a blueprint for research into ATTR in veterans. In clinical practice, following military service, veterans may not be routinely seen by an outpatient physician and may present with sequelae of advanced stages of ATTR. Early identification of red-flag symptoms can lead to a higher clinical suspicion, prompting early diagnostic evaluation and treatment initiation and ultimately mitigating adverse outcomes. Future research that includes genetic testing for those with confirmed ATTR-CM may prove useful as a foundation for detailed and informed discussions with patients and their families regarding prognosis and, if indicated, screening for family members.