Federal Practitioner

Patients treated for chronic obstructive pulmonary disease (COPD) or pneumonia experienced worse outcomes when treated at hospitals acquired by private equity firms, based on data from a new study presented at the American Thoracic Society (ATS) 2026 International Conference.

“Previous studies have linked private equity acquisition of hospitals to worse patient experiences and higher rates of hospital-acquired adverse events, such as falls, although findings for specific medical conditions have been more variable,” according to lead author Stephen Mein, MD, a pulmonologist at Beth Israel Deaconess Medical Center in Boston.

“We wanted to understand whether private equity acquisitions impacted outcomes for patients hospitalized with COPD and pneumonia because these conditions are among the most common reasons for hospitalization and they are widely included in measures of hospital care quality,” he said.

Mein and colleagues reviewed data from Medicare fee-for-service claims data from 41 private equity hospitals and 192 matched control hospitals between 2010 and 2019, including 146,904 COPD visits and 194,993 pneumonia visits.

The study population was Medicare beneficiaries aged 65 years or older who had at least one hospital encounter (defined as observation stay or inpatient admission) for asthma, COPD, or pneumonia. The clinical outcomes were in-hospital mortality, 30-day mortality, and 30-day hospital revisit rates. The researchers compared changes in outcomes across 3 years before and after acquisition in a linear regression analysis. Models adjusted for patient age, sex, race and ethnicity, clinical risk score, and dual eligibility status.

Overall, no changes in patient age, sex, clinical risk scores or dual-eligibility status across all conditions at private equity hospitals were noted compared with control hospitals. However, 30-day hospital revisits among patients with asthma increased significantly at private equity hospitals compared to control hospitals (difference-in-differences, + 8.3 percentage points; 95% CI, 4.0-12.7). No significant changes were noted for in-hospital mortality or 30-day mortality.

Similarly, 30-day hospital revisits were significantly higher for patients with COPD at private equity hospitals than at control hospitals (+ 0.9 percentage points; 95% CI, 0.1-1.6). Patients with pneumonia had an increased in-hospital mortality at private equity hospitals compared with control hospitals (+ 0.7 percentage points; 95% CI, 0.2-1.2), with no differences in 30-day mortality or revisits.

The findings that patients treated for COPD at private equity-acquired hospitals more often returned to the hospital within 30 days after hospital discharge and that patients with pneumonia were more likely to die during their hospital stay were surprising, Mein noted. “The 1-percentage-point increase in deaths among patients with pneumonia is especially concerning as the baseline in-hospital mortality rate for this condition was only 3%-4%,” he said.

“Our findings add to growing concerns around the potential negative effects of private equity ownership in healthcare and highlight the need for stronger oversight of these acquisitions to help protect our patients, and the results have implications for many patients as private equity acquisitions of US hospitals are becoming more common,” Mein said.

The findings were limited by the focus on older adults with Medicare insurance, and may not be generalizable to other patient populations, said Mein. “In addition, we were unable to account for differences in private equity firm practices or identify potential heterogeneity in outcomes across hospitals acquired by different private equity firms,” he said. More research is needed to understand the factors contributing to worse outcomes at private equity-acquired hospitals in the current study and other published work, Mein added.

Vigilance is Needed to Optimize Outcomes

“Given the rapid increase in acquisitions of US hospitals by private equity firms, it is important to evaluate how these acquisitions affect patient health outcomes,” said Arianne K. Baldomero, MD, MS, a pulmonologist, critical care physician, and assistant professor of medicine at the University of Minnesota, Minneapolis.

“The worse outcomes observed among patients hospitalized in privately acquired hospitals were not entirely unexpected,” said Baldomero, who was not involved in the study. “Although not explicitly stated in the abstract, these acquisitions may involve cost-containment strategies, such as potential reductions in staffing. particularly nursing and support staff, changes in supply chain management, or the scaling back of less profitable services, which likely contribute to worse patient outcomes,” she said.

More research is needed to identify the potential etiologies driving these differences in outcomes, which would help inform strategies for improvement, said Baldomero. However, the results of the new study suggest that clinicians managing patients discharged from acquired hospitals should be vigilant about discharge planning, transitions, and follow-up to mitigate poor health outcomes, she said.

The study received no outside funding. The researchers and Baldomero had no financial conflicts to disclose.

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

Patients treated for chronic obstructive pulmonary disease (COPD) or pneumonia experienced worse outcomes when treated at hospitals acquired by private equity firms, based on data from a new study presented at the American Thoracic Society (ATS) 2026 International Conference.

“Previous studies have linked private equity acquisition of hospitals to worse patient experiences and higher rates of hospital-acquired adverse events, such as falls, although findings for specific medical conditions have been more variable,” according to lead author Stephen Mein, MD, a pulmonologist at Beth Israel Deaconess Medical Center in Boston.

“We wanted to understand whether private equity acquisitions impacted outcomes for patients hospitalized with COPD and pneumonia because these conditions are among the most common reasons for hospitalization and they are widely included in measures of hospital care quality,” he said.

Mein and colleagues reviewed data from Medicare fee-for-service claims data from 41 private equity hospitals and 192 matched control hospitals between 2010 and 2019, including 146,904 COPD visits and 194,993 pneumonia visits.

The study population was Medicare beneficiaries aged 65 years or older who had at least one hospital encounter (defined as observation stay or inpatient admission) for asthma, COPD, or pneumonia. The clinical outcomes were in-hospital mortality, 30-day mortality, and 30-day hospital revisit rates. The researchers compared changes in outcomes across 3 years before and after acquisition in a linear regression analysis. Models adjusted for patient age, sex, race and ethnicity, clinical risk score, and dual eligibility status.

Overall, no changes in patient age, sex, clinical risk scores or dual-eligibility status across all conditions at private equity hospitals were noted compared with control hospitals. However, 30-day hospital revisits among patients with asthma increased significantly at private equity hospitals compared to control hospitals (difference-in-differences, + 8.3 percentage points; 95% CI, 4.0-12.7). No significant changes were noted for in-hospital mortality or 30-day mortality.

Similarly, 30-day hospital revisits were significantly higher for patients with COPD at private equity hospitals than at control hospitals (+ 0.9 percentage points; 95% CI, 0.1-1.6). Patients with pneumonia had an increased in-hospital mortality at private equity hospitals compared with control hospitals (+ 0.7 percentage points; 95% CI, 0.2-1.2), with no differences in 30-day mortality or revisits.

The findings that patients treated for COPD at private equity-acquired hospitals more often returned to the hospital within 30 days after hospital discharge and that patients with pneumonia were more likely to die during their hospital stay were surprising, Mein noted. “The 1-percentage-point increase in deaths among patients with pneumonia is especially concerning as the baseline in-hospital mortality rate for this condition was only 3%-4%,” he said.

“Our findings add to growing concerns around the potential negative effects of private equity ownership in healthcare and highlight the need for stronger oversight of these acquisitions to help protect our patients, and the results have implications for many patients as private equity acquisitions of US hospitals are becoming more common,” Mein said.

The findings were limited by the focus on older adults with Medicare insurance, and may not be generalizable to other patient populations, said Mein. “In addition, we were unable to account for differences in private equity firm practices or identify potential heterogeneity in outcomes across hospitals acquired by different private equity firms,” he said. More research is needed to understand the factors contributing to worse outcomes at private equity-acquired hospitals in the current study and other published work, Mein added.

Vigilance is Needed to Optimize Outcomes

“Given the rapid increase in acquisitions of US hospitals by private equity firms, it is important to evaluate how these acquisitions affect patient health outcomes,” said Arianne K. Baldomero, MD, MS, a pulmonologist, critical care physician, and assistant professor of medicine at the University of Minnesota, Minneapolis.

“The worse outcomes observed among patients hospitalized in privately acquired hospitals were not entirely unexpected,” said Baldomero, who was not involved in the study. “Although not explicitly stated in the abstract, these acquisitions may involve cost-containment strategies, such as potential reductions in staffing. particularly nursing and support staff, changes in supply chain management, or the scaling back of less profitable services, which likely contribute to worse patient outcomes,” she said.

More research is needed to identify the potential etiologies driving these differences in outcomes, which would help inform strategies for improvement, said Baldomero. However, the results of the new study suggest that clinicians managing patients discharged from acquired hospitals should be vigilant about discharge planning, transitions, and follow-up to mitigate poor health outcomes, she said.

The study received no outside funding. The researchers and Baldomero had no financial conflicts to disclose.

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

Patients treated for chronic obstructive pulmonary disease (COPD) or pneumonia experienced worse outcomes when treated at hospitals acquired by private equity firms, based on data from a new study presented at the American Thoracic Society (ATS) 2026 International Conference.

“Previous studies have linked private equity acquisition of hospitals to worse patient experiences and higher rates of hospital-acquired adverse events, such as falls, although findings for specific medical conditions have been more variable,” according to lead author Stephen Mein, MD, a pulmonologist at Beth Israel Deaconess Medical Center in Boston.

“We wanted to understand whether private equity acquisitions impacted outcomes for patients hospitalized with COPD and pneumonia because these conditions are among the most common reasons for hospitalization and they are widely included in measures of hospital care quality,” he said.

Mein and colleagues reviewed data from Medicare fee-for-service claims data from 41 private equity hospitals and 192 matched control hospitals between 2010 and 2019, including 146,904 COPD visits and 194,993 pneumonia visits.

The study population was Medicare beneficiaries aged 65 years or older who had at least one hospital encounter (defined as observation stay or inpatient admission) for asthma, COPD, or pneumonia. The clinical outcomes were in-hospital mortality, 30-day mortality, and 30-day hospital revisit rates. The researchers compared changes in outcomes across 3 years before and after acquisition in a linear regression analysis. Models adjusted for patient age, sex, race and ethnicity, clinical risk score, and dual eligibility status.

Overall, no changes in patient age, sex, clinical risk scores or dual-eligibility status across all conditions at private equity hospitals were noted compared with control hospitals. However, 30-day hospital revisits among patients with asthma increased significantly at private equity hospitals compared to control hospitals (difference-in-differences, + 8.3 percentage points; 95% CI, 4.0-12.7). No significant changes were noted for in-hospital mortality or 30-day mortality.

Similarly, 30-day hospital revisits were significantly higher for patients with COPD at private equity hospitals than at control hospitals (+ 0.9 percentage points; 95% CI, 0.1-1.6). Patients with pneumonia had an increased in-hospital mortality at private equity hospitals compared with control hospitals (+ 0.7 percentage points; 95% CI, 0.2-1.2), with no differences in 30-day mortality or revisits.

The findings that patients treated for COPD at private equity-acquired hospitals more often returned to the hospital within 30 days after hospital discharge and that patients with pneumonia were more likely to die during their hospital stay were surprising, Mein noted. “The 1-percentage-point increase in deaths among patients with pneumonia is especially concerning as the baseline in-hospital mortality rate for this condition was only 3%-4%,” he said.

“Our findings add to growing concerns around the potential negative effects of private equity ownership in healthcare and highlight the need for stronger oversight of these acquisitions to help protect our patients, and the results have implications for many patients as private equity acquisitions of US hospitals are becoming more common,” Mein said.

The findings were limited by the focus on older adults with Medicare insurance, and may not be generalizable to other patient populations, said Mein. “In addition, we were unable to account for differences in private equity firm practices or identify potential heterogeneity in outcomes across hospitals acquired by different private equity firms,” he said. More research is needed to understand the factors contributing to worse outcomes at private equity-acquired hospitals in the current study and other published work, Mein added.

Vigilance is Needed to Optimize Outcomes

“Given the rapid increase in acquisitions of US hospitals by private equity firms, it is important to evaluate how these acquisitions affect patient health outcomes,” said Arianne K. Baldomero, MD, MS, a pulmonologist, critical care physician, and assistant professor of medicine at the University of Minnesota, Minneapolis.

“The worse outcomes observed among patients hospitalized in privately acquired hospitals were not entirely unexpected,” said Baldomero, who was not involved in the study. “Although not explicitly stated in the abstract, these acquisitions may involve cost-containment strategies, such as potential reductions in staffing. particularly nursing and support staff, changes in supply chain management, or the scaling back of less profitable services, which likely contribute to worse patient outcomes,” she said.

More research is needed to identify the potential etiologies driving these differences in outcomes, which would help inform strategies for improvement, said Baldomero. However, the results of the new study suggest that clinicians managing patients discharged from acquired hospitals should be vigilant about discharge planning, transitions, and follow-up to mitigate poor health outcomes, she said.

The study received no outside funding. The researchers and Baldomero had no financial conflicts to disclose.

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

Artificial intelligence (AI) scribes produced lower-quality documentation of clinical notes than human clinicians, and especially struggled in settings with background noise or clinicians wearing masks, a new Veterans Health Administration (VHA) study finds.

In 5 simulated clinical cases, notes written by various AI programs scored lower than reports produced by humans on the modified Physician Documentation Quality Instrument (PDQI-9), a measurement of note quality scale, reported Ashok Reddy, MD, MSc, of the University of Washington and Veterans Affairs Puget Sound Health Care System, Seattle, et al in the April issue of Annals of Internal Medicine.

AI scribes scored lower compared with humans across all domains, including accuracy, thoroughness, and usefulness. There was an especially large gap in scores on the 50-point PDQI-9 in an acute low back pain case (human, 43.8 points; AI, 20.3 points; difference, 23.5 points).

“For clinicians, AI scribes should be regarded as tools for generating draft documentation that requires review and editing, rather than as a substitute for clinician-authored notes,” the authors wrote. “Although ambient AI scribes hold promise for reducing clinician burden, rigorous and ongoing evaluation of their quality is essential to ensure that these tools enhance rather than compromise the quality of clinical care.”

AI Scribe Use is Widespread

Taylor N. Anderson, MD, a clinical informatics fellow at Oregon Health & Science University, Portland, is familiar with the study findings and noted that the use of AI scribes in medicine has grown rapidly. All major health organizations are either using it or facing “enormous pressure” from clinicians to do so, she told Federal Practitioner. 

Previous research has linked the use of AI scribes for clinical notes to less electronic health record usage and documentation time for clinicians, leading to more time for patient visits. Still, the quality of clinical notes written by AI is “quite variable across vendors,” Anderson said.

Anderson led a 2025 study that examined 5 AI scribe platforms and found an average of 3.0 errors per case with “potential for moderate-to-severe harm.”

For the new study on the simulated cases, part of a VHA-sponsored “technology sprint” via Challenge.gov, researchers developed audio descriptions of 5 clinical cases reflecting common patient encounters in primary care: acute low back pain, chest pain, a new diagnosis of diabetes, a pharmacy consultation, and a follow-up with a nurse case manager for heart failure. 

Two cases included non-English accents, 1 included background noise, and 1 featured speech through a medical mask. All the “patients” were played by what the authors described as “trained standardized patient actors.”

For each case, 3 humans and 11 AI scribe programs produced clinical notes. The clinical notes were then evaluated by 6 raters.

Researchers found that AI scribe-generated notes scored worse than human-generated notes across all 10 domains of the modified PDQI-9 (accuracy, thoroughness, usefulness, organization, comprehensiveness, succinctness, synthesization, internal consistency, and freedom from hallucination and bias).

There were especially large gaps between the AI and human notes in the domains of thoroughness, organization, and usefulness. Even wider gaps were observed for the encounters with noise and mask usage.

“These findings highlight that although ambient AI scribes can generate complete notes, the overall quality remains broadly below that of human-authored documentation,” the authors wrote. 

No Comparison Between AI Scribes

The researchers noted that “given contractual limitations, we cannot interpret the results for specific vendors.” They also noted that the study did not use professional scribes, who may produce even higher-quality results, and the humans were not producing notes in a real-world clinical environment.

Anderson, the clinical informatics fellow, pointed out that the study does not examine the common scenario in which a clinician edits notes produced by an AI scribe. In fact, she said, there is no current research on this, failing to examine “the postediting note that would actually go into the chart.”

In an accompanying commentary, collaborative scientist Aaron Tierney, PhD, and Kristine Lee, MD, an associate executive director, both with the Permanente Medical Group, California, called for future research to focus on “real-world performance, promote the development of documentation policies that prioritize patient care over billing requirements, and systematically incorporate patient perspectives into assessments of quality.”

Why AI Misses the Mark

In an interview with Federal Practitioner, AI researcher Maxim Topaz, PhD, RN, MA, an associate professor of Nursing and Data Science at Columbia University School of Nursing, New York City, who is familiar with the study but did not participate in it, praised the research. 

He pointed out that AI has trouble accurately representing clinical encounters because they “tend to fill gaps with plausible-sounding language, which can mask omissions and make errors harder to catch.” Also, “ambient scribes can only document what is verbalized aloud. Physical exam findings the clinician notices but does not narrate, nonverbal cues, and patient-initiated concerns that drift past in conversation are systematically underrepresented.”

Moving forward, Topaz advised clinicians to “treat AI-generated notes as a first draft, not a finished product. Read them carefully, especially for omissions, which the current evidence suggests are by far the most common error type and which are harder to spot than fabrications because the surrounding note still reads coherently.”

Two study authors disclosed employment by the US Department of Veterans Affairs. Other authors had no disclosures. The commentary authors have no disclosures. Anderson has no disclosures. Topaz discloses relationships with the National Institutes of Health and other federal sources.

Artificial intelligence (AI) scribes produced lower-quality documentation of clinical notes than human clinicians, and especially struggled in settings with background noise or clinicians wearing masks, a new Veterans Health Administration (VHA) study finds.

In 5 simulated clinical cases, notes written by various AI programs scored lower than reports produced by humans on the modified Physician Documentation Quality Instrument (PDQI-9), a measurement of note quality scale, reported Ashok Reddy, MD, MSc, of the University of Washington and Veterans Affairs Puget Sound Health Care System, Seattle, et al in the April issue of Annals of Internal Medicine.

AI scribes scored lower compared with humans across all domains, including accuracy, thoroughness, and usefulness. There was an especially large gap in scores on the 50-point PDQI-9 in an acute low back pain case (human, 43.8 points; AI, 20.3 points; difference, 23.5 points).

“For clinicians, AI scribes should be regarded as tools for generating draft documentation that requires review and editing, rather than as a substitute for clinician-authored notes,” the authors wrote. “Although ambient AI scribes hold promise for reducing clinician burden, rigorous and ongoing evaluation of their quality is essential to ensure that these tools enhance rather than compromise the quality of clinical care.”

AI Scribe Use is Widespread

Taylor N. Anderson, MD, a clinical informatics fellow at Oregon Health & Science University, Portland, is familiar with the study findings and noted that the use of AI scribes in medicine has grown rapidly. All major health organizations are either using it or facing “enormous pressure” from clinicians to do so, she told Federal Practitioner. 

Previous research has linked the use of AI scribes for clinical notes to less electronic health record usage and documentation time for clinicians, leading to more time for patient visits. Still, the quality of clinical notes written by AI is “quite variable across vendors,” Anderson said.

Anderson led a 2025 study that examined 5 AI scribe platforms and found an average of 3.0 errors per case with “potential for moderate-to-severe harm.”

For the new study on the simulated cases, part of a VHA-sponsored “technology sprint” via Challenge.gov, researchers developed audio descriptions of 5 clinical cases reflecting common patient encounters in primary care: acute low back pain, chest pain, a new diagnosis of diabetes, a pharmacy consultation, and a follow-up with a nurse case manager for heart failure. 

Two cases included non-English accents, 1 included background noise, and 1 featured speech through a medical mask. All the “patients” were played by what the authors described as “trained standardized patient actors.”

For each case, 3 humans and 11 AI scribe programs produced clinical notes. The clinical notes were then evaluated by 6 raters.

Researchers found that AI scribe-generated notes scored worse than human-generated notes across all 10 domains of the modified PDQI-9 (accuracy, thoroughness, usefulness, organization, comprehensiveness, succinctness, synthesization, internal consistency, and freedom from hallucination and bias).

There were especially large gaps between the AI and human notes in the domains of thoroughness, organization, and usefulness. Even wider gaps were observed for the encounters with noise and mask usage.

“These findings highlight that although ambient AI scribes can generate complete notes, the overall quality remains broadly below that of human-authored documentation,” the authors wrote. 

No Comparison Between AI Scribes

The researchers noted that “given contractual limitations, we cannot interpret the results for specific vendors.” They also noted that the study did not use professional scribes, who may produce even higher-quality results, and the humans were not producing notes in a real-world clinical environment.

Anderson, the clinical informatics fellow, pointed out that the study does not examine the common scenario in which a clinician edits notes produced by an AI scribe. In fact, she said, there is no current research on this, failing to examine “the postediting note that would actually go into the chart.”

In an accompanying commentary, collaborative scientist Aaron Tierney, PhD, and Kristine Lee, MD, an associate executive director, both with the Permanente Medical Group, California, called for future research to focus on “real-world performance, promote the development of documentation policies that prioritize patient care over billing requirements, and systematically incorporate patient perspectives into assessments of quality.”

Why AI Misses the Mark

In an interview with Federal Practitioner, AI researcher Maxim Topaz, PhD, RN, MA, an associate professor of Nursing and Data Science at Columbia University School of Nursing, New York City, who is familiar with the study but did not participate in it, praised the research. 

He pointed out that AI has trouble accurately representing clinical encounters because they “tend to fill gaps with plausible-sounding language, which can mask omissions and make errors harder to catch.” Also, “ambient scribes can only document what is verbalized aloud. Physical exam findings the clinician notices but does not narrate, nonverbal cues, and patient-initiated concerns that drift past in conversation are systematically underrepresented.”

Moving forward, Topaz advised clinicians to “treat AI-generated notes as a first draft, not a finished product. Read them carefully, especially for omissions, which the current evidence suggests are by far the most common error type and which are harder to spot than fabrications because the surrounding note still reads coherently.”

Two study authors disclosed employment by the US Department of Veterans Affairs. Other authors had no disclosures. The commentary authors have no disclosures. Anderson has no disclosures. Topaz discloses relationships with the National Institutes of Health and other federal sources.

Artificial intelligence (AI) scribes produced lower-quality documentation of clinical notes than human clinicians, and especially struggled in settings with background noise or clinicians wearing masks, a new Veterans Health Administration (VHA) study finds.

In 5 simulated clinical cases, notes written by various AI programs scored lower than reports produced by humans on the modified Physician Documentation Quality Instrument (PDQI-9), a measurement of note quality scale, reported Ashok Reddy, MD, MSc, of the University of Washington and Veterans Affairs Puget Sound Health Care System, Seattle, et al in the April issue of Annals of Internal Medicine.

AI scribes scored lower compared with humans across all domains, including accuracy, thoroughness, and usefulness. There was an especially large gap in scores on the 50-point PDQI-9 in an acute low back pain case (human, 43.8 points; AI, 20.3 points; difference, 23.5 points).

“For clinicians, AI scribes should be regarded as tools for generating draft documentation that requires review and editing, rather than as a substitute for clinician-authored notes,” the authors wrote. “Although ambient AI scribes hold promise for reducing clinician burden, rigorous and ongoing evaluation of their quality is essential to ensure that these tools enhance rather than compromise the quality of clinical care.”

AI Scribe Use is Widespread

Taylor N. Anderson, MD, a clinical informatics fellow at Oregon Health & Science University, Portland, is familiar with the study findings and noted that the use of AI scribes in medicine has grown rapidly. All major health organizations are either using it or facing “enormous pressure” from clinicians to do so, she told Federal Practitioner. 

Previous research has linked the use of AI scribes for clinical notes to less electronic health record usage and documentation time for clinicians, leading to more time for patient visits. Still, the quality of clinical notes written by AI is “quite variable across vendors,” Anderson said.

Anderson led a 2025 study that examined 5 AI scribe platforms and found an average of 3.0 errors per case with “potential for moderate-to-severe harm.”

For the new study on the simulated cases, part of a VHA-sponsored “technology sprint” via Challenge.gov, researchers developed audio descriptions of 5 clinical cases reflecting common patient encounters in primary care: acute low back pain, chest pain, a new diagnosis of diabetes, a pharmacy consultation, and a follow-up with a nurse case manager for heart failure. 

Two cases included non-English accents, 1 included background noise, and 1 featured speech through a medical mask. All the “patients” were played by what the authors described as “trained standardized patient actors.”

For each case, 3 humans and 11 AI scribe programs produced clinical notes. The clinical notes were then evaluated by 6 raters.

Researchers found that AI scribe-generated notes scored worse than human-generated notes across all 10 domains of the modified PDQI-9 (accuracy, thoroughness, usefulness, organization, comprehensiveness, succinctness, synthesization, internal consistency, and freedom from hallucination and bias).

There were especially large gaps between the AI and human notes in the domains of thoroughness, organization, and usefulness. Even wider gaps were observed for the encounters with noise and mask usage.

“These findings highlight that although ambient AI scribes can generate complete notes, the overall quality remains broadly below that of human-authored documentation,” the authors wrote. 

No Comparison Between AI Scribes

The researchers noted that “given contractual limitations, we cannot interpret the results for specific vendors.” They also noted that the study did not use professional scribes, who may produce even higher-quality results, and the humans were not producing notes in a real-world clinical environment.

Anderson, the clinical informatics fellow, pointed out that the study does not examine the common scenario in which a clinician edits notes produced by an AI scribe. In fact, she said, there is no current research on this, failing to examine “the postediting note that would actually go into the chart.”

In an accompanying commentary, collaborative scientist Aaron Tierney, PhD, and Kristine Lee, MD, an associate executive director, both with the Permanente Medical Group, California, called for future research to focus on “real-world performance, promote the development of documentation policies that prioritize patient care over billing requirements, and systematically incorporate patient perspectives into assessments of quality.”

Why AI Misses the Mark

In an interview with Federal Practitioner, AI researcher Maxim Topaz, PhD, RN, MA, an associate professor of Nursing and Data Science at Columbia University School of Nursing, New York City, who is familiar with the study but did not participate in it, praised the research. 

He pointed out that AI has trouble accurately representing clinical encounters because they “tend to fill gaps with plausible-sounding language, which can mask omissions and make errors harder to catch.” Also, “ambient scribes can only document what is verbalized aloud. Physical exam findings the clinician notices but does not narrate, nonverbal cues, and patient-initiated concerns that drift past in conversation are systematically underrepresented.”

Moving forward, Topaz advised clinicians to “treat AI-generated notes as a first draft, not a finished product. Read them carefully, especially for omissions, which the current evidence suggests are by far the most common error type and which are harder to spot than fabrications because the surrounding note still reads coherently.”

Two study authors disclosed employment by the US Department of Veterans Affairs. Other authors had no disclosures. The commentary authors have no disclosures. Anderson has no disclosures. Topaz discloses relationships with the National Institutes of Health and other federal sources.

TOPLINE: Among veterans and demographically matched nonveterans from 2002 to 2019, higher state household firearm ownership was associated with higher rates of deaths by suicide, while greater state firearm law restrictiveness was associated with lower rates of deaths by suicide. In 2017 to 2019 models, these associations were seen for both veterans and matched nonveterans and driven primarily by firearm deaths by suicide rates.

METHODOLOGY:

• US state-level data across 6 consecutive 3-year periods from 2002-2019, stratified suicide rates by veteran status (veteran vs matched nonveterans) and method (firearm vs nonfirearm). 

• Data sources included US Department of Veterans Affairs (VA) Office of Mental Health and Suicide Prevention counts matched to the National Death Index, plus Centers for Disease Control suicide counts and population estimates by sex and age. 

• Participants included veterans with state- and period-specific death suicide counts and population denominators from the VetPop model, and a matched nonveteran comparison created by comparing state deaths by suicide data to veterans’ age and gender distributions. 

• Exposure measures included annual state household firearm ownership rate estimates carried forward to 2017-2019, and a 7-item state firearm policy restrictiveness index derived from the RAND Corporation state firearm law database.

TAKEAWAY:

• Average death by suicide rates from 2002-2019 were 28.2 per 100,000 for veterans and 27.5 per 100,000 for matched nonveterans, with most deaths involving a firearm. 

• Across states, the maximum average death by suicide rate was about 3 times the minimum over the study period, and veteran and matched nonveteran state patterns aligned closely. 

• Higher household firearm ownership was associated with higher firearm death by suicide rates for veterans and matched nonveterans from 2017-2019.

• Greater firearm law restrictiveness, equivalent to 3 additional restrictive laws, was associated with fewer firearm deaths by suicide for veterans and matched nonveterans from 2017-2019.

IN PRACTICE: “The results suggest that changes to state firearm laws and policies should be investigated as a possibly cost-effective primary prevention strategy for reducing suicide rates among veterans and nonveterans,” the authors wrote.

SOURCE:The study was led by Andrew R. Morral, PhD, RAND Corporation in Arlington, Virginia, and Terry L. Schell, PhD, and Adam Scherling, RAND Corporation in Santa Monica, California and published online in Injury Prevention.

LIMITATIONS: The estimates are correlational and should not be interpreted as causal effect estimates, as most interstate variation in gun ownership and firearm laws predates the beginning of the available VA death by suicide data, limiting the analytical approach to identify causal effects. VA does not share microdata on veteran suicide, requiring construction of a matched comparison sample of nonveterans by estimating veteran decedent removal from general population suicide totals within cells of a 5-way table based on publicly released 3-way tables, introducing imprecision. Veteran suicide counts are known to undercount suicides among veterans who separated from the military prior to 1974, likely resulting in a slight underestimate of veteran suicide rates for the oldest cohort of veterans, particularly in earlier study periods. Restricting analysis to identify modeled effects solely through limited changes in state firearm ownership and policies during the study period yields imprecise effect estimates.

DISCLOSURES: This work received support from a grant provided by The RAND Epstein Family Veterans Policy Research Institute, established through a contribution from Daniel J. Epstein via the Epstein Family Foundation. Neither the Institute, the Foundation, nor Mr. Epstein participated in the design, conduct, analysis, or drafting of this report. The authors disclosed no relevant conflicts of interest.

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

TOPLINE: Among veterans and demographically matched nonveterans from 2002 to 2019, higher state household firearm ownership was associated with higher rates of deaths by suicide, while greater state firearm law restrictiveness was associated with lower rates of deaths by suicide. In 2017 to 2019 models, these associations were seen for both veterans and matched nonveterans and driven primarily by firearm deaths by suicide rates.

METHODOLOGY:

• US state-level data across 6 consecutive 3-year periods from 2002-2019, stratified suicide rates by veteran status (veteran vs matched nonveterans) and method (firearm vs nonfirearm). 

• Data sources included US Department of Veterans Affairs (VA) Office of Mental Health and Suicide Prevention counts matched to the National Death Index, plus Centers for Disease Control suicide counts and population estimates by sex and age. 

• Participants included veterans with state- and period-specific death suicide counts and population denominators from the VetPop model, and a matched nonveteran comparison created by comparing state deaths by suicide data to veterans’ age and gender distributions. 

• Exposure measures included annual state household firearm ownership rate estimates carried forward to 2017-2019, and a 7-item state firearm policy restrictiveness index derived from the RAND Corporation state firearm law database.

TAKEAWAY:

• Average death by suicide rates from 2002-2019 were 28.2 per 100,000 for veterans and 27.5 per 100,000 for matched nonveterans, with most deaths involving a firearm. 

• Across states, the maximum average death by suicide rate was about 3 times the minimum over the study period, and veteran and matched nonveteran state patterns aligned closely. 

• Higher household firearm ownership was associated with higher firearm death by suicide rates for veterans and matched nonveterans from 2017-2019.

• Greater firearm law restrictiveness, equivalent to 3 additional restrictive laws, was associated with fewer firearm deaths by suicide for veterans and matched nonveterans from 2017-2019.

IN PRACTICE: “The results suggest that changes to state firearm laws and policies should be investigated as a possibly cost-effective primary prevention strategy for reducing suicide rates among veterans and nonveterans,” the authors wrote.

SOURCE:The study was led by Andrew R. Morral, PhD, RAND Corporation in Arlington, Virginia, and Terry L. Schell, PhD, and Adam Scherling, RAND Corporation in Santa Monica, California and published online in Injury Prevention.

LIMITATIONS: The estimates are correlational and should not be interpreted as causal effect estimates, as most interstate variation in gun ownership and firearm laws predates the beginning of the available VA death by suicide data, limiting the analytical approach to identify causal effects. VA does not share microdata on veteran suicide, requiring construction of a matched comparison sample of nonveterans by estimating veteran decedent removal from general population suicide totals within cells of a 5-way table based on publicly released 3-way tables, introducing imprecision. Veteran suicide counts are known to undercount suicides among veterans who separated from the military prior to 1974, likely resulting in a slight underestimate of veteran suicide rates for the oldest cohort of veterans, particularly in earlier study periods. Restricting analysis to identify modeled effects solely through limited changes in state firearm ownership and policies during the study period yields imprecise effect estimates.

DISCLOSURES: This work received support from a grant provided by The RAND Epstein Family Veterans Policy Research Institute, established through a contribution from Daniel J. Epstein via the Epstein Family Foundation. Neither the Institute, the Foundation, nor Mr. Epstein participated in the design, conduct, analysis, or drafting of this report. The authors disclosed no relevant conflicts of interest.

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

TOPLINE: Among veterans and demographically matched nonveterans from 2002 to 2019, higher state household firearm ownership was associated with higher rates of deaths by suicide, while greater state firearm law restrictiveness was associated with lower rates of deaths by suicide. In 2017 to 2019 models, these associations were seen for both veterans and matched nonveterans and driven primarily by firearm deaths by suicide rates.

METHODOLOGY:

• US state-level data across 6 consecutive 3-year periods from 2002-2019, stratified suicide rates by veteran status (veteran vs matched nonveterans) and method (firearm vs nonfirearm). 

• Data sources included US Department of Veterans Affairs (VA) Office of Mental Health and Suicide Prevention counts matched to the National Death Index, plus Centers for Disease Control suicide counts and population estimates by sex and age. 

• Participants included veterans with state- and period-specific death suicide counts and population denominators from the VetPop model, and a matched nonveteran comparison created by comparing state deaths by suicide data to veterans’ age and gender distributions. 

• Exposure measures included annual state household firearm ownership rate estimates carried forward to 2017-2019, and a 7-item state firearm policy restrictiveness index derived from the RAND Corporation state firearm law database.

TAKEAWAY:

• Average death by suicide rates from 2002-2019 were 28.2 per 100,000 for veterans and 27.5 per 100,000 for matched nonveterans, with most deaths involving a firearm. 

• Across states, the maximum average death by suicide rate was about 3 times the minimum over the study period, and veteran and matched nonveteran state patterns aligned closely. 

• Higher household firearm ownership was associated with higher firearm death by suicide rates for veterans and matched nonveterans from 2017-2019.

• Greater firearm law restrictiveness, equivalent to 3 additional restrictive laws, was associated with fewer firearm deaths by suicide for veterans and matched nonveterans from 2017-2019.

IN PRACTICE: “The results suggest that changes to state firearm laws and policies should be investigated as a possibly cost-effective primary prevention strategy for reducing suicide rates among veterans and nonveterans,” the authors wrote.

SOURCE:The study was led by Andrew R. Morral, PhD, RAND Corporation in Arlington, Virginia, and Terry L. Schell, PhD, and Adam Scherling, RAND Corporation in Santa Monica, California and published online in Injury Prevention.

LIMITATIONS: The estimates are correlational and should not be interpreted as causal effect estimates, as most interstate variation in gun ownership and firearm laws predates the beginning of the available VA death by suicide data, limiting the analytical approach to identify causal effects. VA does not share microdata on veteran suicide, requiring construction of a matched comparison sample of nonveterans by estimating veteran decedent removal from general population suicide totals within cells of a 5-way table based on publicly released 3-way tables, introducing imprecision. Veteran suicide counts are known to undercount suicides among veterans who separated from the military prior to 1974, likely resulting in a slight underestimate of veteran suicide rates for the oldest cohort of veterans, particularly in earlier study periods. Restricting analysis to identify modeled effects solely through limited changes in state firearm ownership and policies during the study period yields imprecise effect estimates.

DISCLOSURES: This work received support from a grant provided by The RAND Epstein Family Veterans Policy Research Institute, established through a contribution from Daniel J. Epstein via the Epstein Family Foundation. Neither the Institute, the Foundation, nor Mr. Epstein participated in the design, conduct, analysis, or drafting of this report. The authors disclosed no relevant conflicts of interest.

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

Drone warfare and repeated attacks on medical infrastructure are reshaping battlefield medicine in Ukraine, driving the development of underground military hospitals designed to stabilize and treat wounded soldiers close to active combat zones, rather than relying on rapid evacuation.

Since the start of Russia’s full-scale invasion of Ukraine, the World Health Organization has documented nearly 3000 attacks on healthcare facilities and violations of the Geneva Conventions that protect medical personnel and healthcare infrastructure during armed conflict.

In response, Ukraine has developed underground military hospitals designed to withstand bombardment and maintain the continuity of medical care. By combining infrastructure inherited from the Cold War with rapidly constructed new facilities, the country has managed to preserve healthcare capacity and support military operations close to the frontlines.

Underground Hospital

In September 2024, the Ukrainian Ministry of Defense, in partnership with the Metinvest Group, opened Ukraine’s first underground military stabilization hospital near the front lines. The project was developed under Metinvest’s military support initiative, known as the Steel Front, which supplies protective infrastructure and equipment for frontline operations.

In addition to producing steel bunkers for these facilities, the company manufactures military support equipment, including mine clearing plows, drone protection screens, systems designed to intercept loitering munitions, armor plates, and vehicle reinforcements for frontline operations.

The underground hospital consists of six steel bunkers, each measuring 7.6 m in length and 2.5 m in diameter, with a total area of 500 m². The structures function as multifunctional units designed to maintain operational capability in high-threat environments. The facility includes ventilation, water supply, drainage, and electrical systems. During construction and installation, security measures aimed to reduce detectability and lower the risk for attack. The hospital also incorporates electronic warfare systems intended to strengthen operational protection.

The total investment reached 20 million Ukrainian hryvnias, approximately 385,000 euros. Of these, 7 million hryvnias funded medical equipment, while 13 million supported metal structures, construction materials, and infrastructure.

The hospital is equipped with oxygen concentrators, ventilators, cardiac monitors, defibrillators, surgical equipment, lighting systems, sterilizers, patient warming systems, and medical furniture. The complex includes two operating rooms, two resuscitation stations, a work area, and a staff rest area. Depending on the staffing and operational configuration, the hospital can stabilize wounded individuals and perform up to four simultaneous procedures. The design follows North Atlantic Treaty Organization standards for second-level field hospitals, designated Role/Echelon 2.

In a statement released by the Metinvest Group after the facility opened in 2024, Roman Kuzev, acting commander of the “East” medical task force, said: “This underground hospital is the best stabilization center available. This will allow us to provide medical care to over 100 patients a day, saving hundreds of lives for our heroes. I hope the number of such facilities will grow.”

Kuzev’s expectations materialized in 2025, when the Metinvest Group completed the construction of a second underground military hospital in one of the most active frontline sectors. The new facility provides greater protection and camouflage, and incorporates structural modifications based on lessons learned from the first hospital. It is buried more than 6 m underground and reinforced with additional protective layers.

The hospital includes four functional units housing surgical and stabilization areas, a delivery room, and a break area for healthcare personnel. The facility covers 350 m² and required an investment exceeding 21 million Ukrainian hryvnias.

The center can simultaneously support up to three surgical procedures of varying complexities. Military authorities supplied equipment, including high-flow infusion pumps, x-ray systems, oxygen concentrators, defibrillators, and additional devices. Medical services are provided by teams of up to 20 professionals, including orthopedic surgeons, general surgeons, anesthesiologists, surgical nurses, and nursing assistants.

 

Historic Origin

World War I marked a turning point in modern warfare by introducing technologies that increased battlefield violence to unprecedented levels. The widespread use of machine guns, poisonous gas, tanks, and trench warfare has turned the battlefield into an extremely deadly environment.

At the same time, the conflict drove advances in military medicine that continue to influence practice today, including blood transfusions, psychological support for soldiers experiencing so called “shell shock,” and the development of field hospitals and mobile medical units.

One of the earliest documented underground hospitals was established in Arras, France, where a network of preexisting tunnels known as boves was expanded by New Zealand engineers to provide Allied forces with a tactical advantage. The tunnels were designed to shelter troops in preparation for the 1917 Arras Offensive, allowing them to assemble safely without being detected by German forces.

The underground hospital in Arras, which opened in 1916, includes waiting rooms, operating rooms, rest areas, spaces accommodating up to 700 stretchers, and a morgue. It also features internal electrical and plumbing systems, making it one of the most advanced medical facilities of its time.

 

Shift in Care

The expanding use of drones on the battlefield has increased the risks linked to casualty evacuation, particularly aeromedical evacuation, reducing the effectiveness of traditional military care models. In response, Ukraine has adopted an approach centered on extended field care and the development of a decentralized medical system, supported by close collaboration with the private sector to rapidly secure resources and infrastructure.

These strategies represent a shift in military medicine toward prolonged onsite stabilization rather than rapid evacuation. The combined use of underground facilities and repurposed infrastructure has helped maintain medical capacity under high threat conditions, improving survival among wounded individuals, and strengthening healthcare system resilience during conflict, according to US Army reports.

In addition to serving as a model for this shift in military medicine, the underground hospital project received the Partnership for Sustainability Award 2025 in Ukraine from the United Nations Global Compact in the “Rebuilding Ukraine” category. The award, presented by the United Nations network that promotes corporate sustainability and Sustainable Development Goals, recognizes private sector initiatives that support postwar reconstruction and strengthen social and institutional resilience.

The project was recognized for its contribution to saving lives and strengthening medical capacity in areas affected by active hostility.

This article was translated from El Médico Interactivo on Univadis, part of the Medscape Professional Network.

A version of this article appeared on Medscape.com.

Drone warfare and repeated attacks on medical infrastructure are reshaping battlefield medicine in Ukraine, driving the development of underground military hospitals designed to stabilize and treat wounded soldiers close to active combat zones, rather than relying on rapid evacuation.

Since the start of Russia’s full-scale invasion of Ukraine, the World Health Organization has documented nearly 3000 attacks on healthcare facilities and violations of the Geneva Conventions that protect medical personnel and healthcare infrastructure during armed conflict.

In response, Ukraine has developed underground military hospitals designed to withstand bombardment and maintain the continuity of medical care. By combining infrastructure inherited from the Cold War with rapidly constructed new facilities, the country has managed to preserve healthcare capacity and support military operations close to the frontlines.

Underground Hospital

In September 2024, the Ukrainian Ministry of Defense, in partnership with the Metinvest Group, opened Ukraine’s first underground military stabilization hospital near the front lines. The project was developed under Metinvest’s military support initiative, known as the Steel Front, which supplies protective infrastructure and equipment for frontline operations.

In addition to producing steel bunkers for these facilities, the company manufactures military support equipment, including mine clearing plows, drone protection screens, systems designed to intercept loitering munitions, armor plates, and vehicle reinforcements for frontline operations.

The underground hospital consists of six steel bunkers, each measuring 7.6 m in length and 2.5 m in diameter, with a total area of 500 m². The structures function as multifunctional units designed to maintain operational capability in high-threat environments. The facility includes ventilation, water supply, drainage, and electrical systems. During construction and installation, security measures aimed to reduce detectability and lower the risk for attack. The hospital also incorporates electronic warfare systems intended to strengthen operational protection.

The total investment reached 20 million Ukrainian hryvnias, approximately 385,000 euros. Of these, 7 million hryvnias funded medical equipment, while 13 million supported metal structures, construction materials, and infrastructure.

The hospital is equipped with oxygen concentrators, ventilators, cardiac monitors, defibrillators, surgical equipment, lighting systems, sterilizers, patient warming systems, and medical furniture. The complex includes two operating rooms, two resuscitation stations, a work area, and a staff rest area. Depending on the staffing and operational configuration, the hospital can stabilize wounded individuals and perform up to four simultaneous procedures. The design follows North Atlantic Treaty Organization standards for second-level field hospitals, designated Role/Echelon 2.

In a statement released by the Metinvest Group after the facility opened in 2024, Roman Kuzev, acting commander of the “East” medical task force, said: “This underground hospital is the best stabilization center available. This will allow us to provide medical care to over 100 patients a day, saving hundreds of lives for our heroes. I hope the number of such facilities will grow.”

Kuzev’s expectations materialized in 2025, when the Metinvest Group completed the construction of a second underground military hospital in one of the most active frontline sectors. The new facility provides greater protection and camouflage, and incorporates structural modifications based on lessons learned from the first hospital. It is buried more than 6 m underground and reinforced with additional protective layers.

The hospital includes four functional units housing surgical and stabilization areas, a delivery room, and a break area for healthcare personnel. The facility covers 350 m² and required an investment exceeding 21 million Ukrainian hryvnias.

The center can simultaneously support up to three surgical procedures of varying complexities. Military authorities supplied equipment, including high-flow infusion pumps, x-ray systems, oxygen concentrators, defibrillators, and additional devices. Medical services are provided by teams of up to 20 professionals, including orthopedic surgeons, general surgeons, anesthesiologists, surgical nurses, and nursing assistants.

 

Historic Origin

World War I marked a turning point in modern warfare by introducing technologies that increased battlefield violence to unprecedented levels. The widespread use of machine guns, poisonous gas, tanks, and trench warfare has turned the battlefield into an extremely deadly environment.

At the same time, the conflict drove advances in military medicine that continue to influence practice today, including blood transfusions, psychological support for soldiers experiencing so called “shell shock,” and the development of field hospitals and mobile medical units.

One of the earliest documented underground hospitals was established in Arras, France, where a network of preexisting tunnels known as boves was expanded by New Zealand engineers to provide Allied forces with a tactical advantage. The tunnels were designed to shelter troops in preparation for the 1917 Arras Offensive, allowing them to assemble safely without being detected by German forces.

The underground hospital in Arras, which opened in 1916, includes waiting rooms, operating rooms, rest areas, spaces accommodating up to 700 stretchers, and a morgue. It also features internal electrical and plumbing systems, making it one of the most advanced medical facilities of its time.

 

Shift in Care

The expanding use of drones on the battlefield has increased the risks linked to casualty evacuation, particularly aeromedical evacuation, reducing the effectiveness of traditional military care models. In response, Ukraine has adopted an approach centered on extended field care and the development of a decentralized medical system, supported by close collaboration with the private sector to rapidly secure resources and infrastructure.

These strategies represent a shift in military medicine toward prolonged onsite stabilization rather than rapid evacuation. The combined use of underground facilities and repurposed infrastructure has helped maintain medical capacity under high threat conditions, improving survival among wounded individuals, and strengthening healthcare system resilience during conflict, according to US Army reports.

In addition to serving as a model for this shift in military medicine, the underground hospital project received the Partnership for Sustainability Award 2025 in Ukraine from the United Nations Global Compact in the “Rebuilding Ukraine” category. The award, presented by the United Nations network that promotes corporate sustainability and Sustainable Development Goals, recognizes private sector initiatives that support postwar reconstruction and strengthen social and institutional resilience.

The project was recognized for its contribution to saving lives and strengthening medical capacity in areas affected by active hostility.

This article was translated from El Médico Interactivo on Univadis, part of the Medscape Professional Network.

A version of this article appeared on Medscape.com.

Drone warfare and repeated attacks on medical infrastructure are reshaping battlefield medicine in Ukraine, driving the development of underground military hospitals designed to stabilize and treat wounded soldiers close to active combat zones, rather than relying on rapid evacuation.

Since the start of Russia’s full-scale invasion of Ukraine, the World Health Organization has documented nearly 3000 attacks on healthcare facilities and violations of the Geneva Conventions that protect medical personnel and healthcare infrastructure during armed conflict.

In response, Ukraine has developed underground military hospitals designed to withstand bombardment and maintain the continuity of medical care. By combining infrastructure inherited from the Cold War with rapidly constructed new facilities, the country has managed to preserve healthcare capacity and support military operations close to the frontlines.

Underground Hospital

In September 2024, the Ukrainian Ministry of Defense, in partnership with the Metinvest Group, opened Ukraine’s first underground military stabilization hospital near the front lines. The project was developed under Metinvest’s military support initiative, known as the Steel Front, which supplies protective infrastructure and equipment for frontline operations.

In addition to producing steel bunkers for these facilities, the company manufactures military support equipment, including mine clearing plows, drone protection screens, systems designed to intercept loitering munitions, armor plates, and vehicle reinforcements for frontline operations.

The underground hospital consists of six steel bunkers, each measuring 7.6 m in length and 2.5 m in diameter, with a total area of 500 m². The structures function as multifunctional units designed to maintain operational capability in high-threat environments. The facility includes ventilation, water supply, drainage, and electrical systems. During construction and installation, security measures aimed to reduce detectability and lower the risk for attack. The hospital also incorporates electronic warfare systems intended to strengthen operational protection.

The total investment reached 20 million Ukrainian hryvnias, approximately 385,000 euros. Of these, 7 million hryvnias funded medical equipment, while 13 million supported metal structures, construction materials, and infrastructure.

The hospital is equipped with oxygen concentrators, ventilators, cardiac monitors, defibrillators, surgical equipment, lighting systems, sterilizers, patient warming systems, and medical furniture. The complex includes two operating rooms, two resuscitation stations, a work area, and a staff rest area. Depending on the staffing and operational configuration, the hospital can stabilize wounded individuals and perform up to four simultaneous procedures. The design follows North Atlantic Treaty Organization standards for second-level field hospitals, designated Role/Echelon 2.

In a statement released by the Metinvest Group after the facility opened in 2024, Roman Kuzev, acting commander of the “East” medical task force, said: “This underground hospital is the best stabilization center available. This will allow us to provide medical care to over 100 patients a day, saving hundreds of lives for our heroes. I hope the number of such facilities will grow.”

Kuzev’s expectations materialized in 2025, when the Metinvest Group completed the construction of a second underground military hospital in one of the most active frontline sectors. The new facility provides greater protection and camouflage, and incorporates structural modifications based on lessons learned from the first hospital. It is buried more than 6 m underground and reinforced with additional protective layers.

The hospital includes four functional units housing surgical and stabilization areas, a delivery room, and a break area for healthcare personnel. The facility covers 350 m² and required an investment exceeding 21 million Ukrainian hryvnias.

The center can simultaneously support up to three surgical procedures of varying complexities. Military authorities supplied equipment, including high-flow infusion pumps, x-ray systems, oxygen concentrators, defibrillators, and additional devices. Medical services are provided by teams of up to 20 professionals, including orthopedic surgeons, general surgeons, anesthesiologists, surgical nurses, and nursing assistants.

 

Historic Origin

World War I marked a turning point in modern warfare by introducing technologies that increased battlefield violence to unprecedented levels. The widespread use of machine guns, poisonous gas, tanks, and trench warfare has turned the battlefield into an extremely deadly environment.

At the same time, the conflict drove advances in military medicine that continue to influence practice today, including blood transfusions, psychological support for soldiers experiencing so called “shell shock,” and the development of field hospitals and mobile medical units.

One of the earliest documented underground hospitals was established in Arras, France, where a network of preexisting tunnels known as boves was expanded by New Zealand engineers to provide Allied forces with a tactical advantage. The tunnels were designed to shelter troops in preparation for the 1917 Arras Offensive, allowing them to assemble safely without being detected by German forces.

The underground hospital in Arras, which opened in 1916, includes waiting rooms, operating rooms, rest areas, spaces accommodating up to 700 stretchers, and a morgue. It also features internal electrical and plumbing systems, making it one of the most advanced medical facilities of its time.

 

Shift in Care

The expanding use of drones on the battlefield has increased the risks linked to casualty evacuation, particularly aeromedical evacuation, reducing the effectiveness of traditional military care models. In response, Ukraine has adopted an approach centered on extended field care and the development of a decentralized medical system, supported by close collaboration with the private sector to rapidly secure resources and infrastructure.

These strategies represent a shift in military medicine toward prolonged onsite stabilization rather than rapid evacuation. The combined use of underground facilities and repurposed infrastructure has helped maintain medical capacity under high threat conditions, improving survival among wounded individuals, and strengthening healthcare system resilience during conflict, according to US Army reports.

In addition to serving as a model for this shift in military medicine, the underground hospital project received the Partnership for Sustainability Award 2025 in Ukraine from the United Nations Global Compact in the “Rebuilding Ukraine” category. The award, presented by the United Nations network that promotes corporate sustainability and Sustainable Development Goals, recognizes private sector initiatives that support postwar reconstruction and strengthen social and institutional resilience.

The project was recognized for its contribution to saving lives and strengthening medical capacity in areas affected by active hostility.

This article was translated from El Médico Interactivo on Univadis, part of the Medscape Professional Network.

A version of this article appeared on Medscape.com.

Approximately about 1 in 4 eligible Americans are up to date on their lung cancer screening, according to a recent study in JAMA Internal Medicine, prompting a need for clinicians to simplify referrals and scheduling of annual appointments.

Despite a 32% increase in lung cancer screening between 2022 and 2024, rates overall remain low at nearly 25%, and especially among patients between ages 50 and 54 years (11.32%; P < .05).

Determining eligibility entails calculating the total years a patient smoked cigarettes, whereas other screenings are based solely on age, such as breast cancer and colon cancer.

Some clinicians “will get into trying to do an actual pack year calculation, or where they smoked half a pack for this many years, and then they quit for this many years, and then, you know, they’re trying to do this massive calculation. And the reality is, we’re just trying to get a patient who’s at high risk for lung cancer” in for screening, said Timothy Mullett, MD, a thoracic surgeon and medical director of the Markey Cancer Center Network Development, University of Kentucky in Lexington, Kentucky, who helped the study authors.

As the second most common form of the disease, lung cancer is the leading cause of such mortality in the US. But low rates of screening mean opportunities for early detection are missed.

In an analysis of national survey data including 26,104 patients (45.6% women and 54.4% men) eligible for lung cancer screening between ages 50 and 79 years, rates increased from 18.49% to 24.49% (P < .05) over a 2-year period starting in 2022. 

Approximately one quarter of men and women were up to date on their screening (P < .05). Nearly one third of patients aged 65 years or older were up to date, whereas those between ages 50 and 54 years (11.32%), 55 and 59 years (19.45%), and 60 and 64 years (23.99%) showed lower rates.

Patients were most likely to be up to date on their screenings in the Northeast region of the country, with Massachusetts showing the highest prevalence rate (38.36%). The rate was lowest in South Dakota (13.43%).

No significant changes in rates were observed for Asian, Black, or Hispanic adults. Adults who were American Indian or Alaska native showed the largest improvement, from 18.74% in 2022 to 30.8% in 2024 (P < .05).

The US Preventive Services Task Force recommends annual screening starting at age 50 for individuals who are current smokers or previous smokers who have a history of consuming at least a pack a day for two decades. Previous smokers must have quit within the previous 15 years to qualify.

Making these calculations can be tricky, Mullett said. Patients’ tobacco use can change over time and a screening tool may not account for those changes. He encourages clinicians to take time to ask patients for more detail about their history. For instance, someone who smokes a half a pack a day now may not immediately qualify for screening, but deeper probing might reveal that they previously smoked two packs a day.

Tamatha Hughes, RN, a nurse navigator for the Missouri Baptist Lung Cancer Screening Program, Missouri Baptist Medical Center in St. Louis, said she often calms fears and corrects misinformation when scheduling patients for their first screening. Some patients think the screening involves an MRI or that radiation from the CT scan is dangerous.

“We go through explaining it as simple as possible,” she said.

If she has a referral for a patient who does not move forward with scheduling, she said she will try them again a few weeks later. Annual screenings are scheduled at a patient’s first appointment, and she said her clinic has an 80% rate for returning patients.

Getting the first scan is the biggest hurdle. Many patients feel stigma or associate lung cancer with a hopeless diagnosis, which can reduce rates, Mullet said.

“There’s a sense of fatalism, because all they’ve ever experienced with lung cancer has been someone who’s died from lung cancer, their grandmother, their grandfather, died of lung cancer. And historically, lung cancer has been found in late stages over 80% of the time,” he said. But screening has drastically improved rates of survival.

“We keep trying to tell patients that this is not your grandfather’s lung cancer,” Mullett said. “This is not what you saw in your family growing up, and we can find it early and we can treat it, and we even if we find it late, we have better treatments now.”

The study was funded by grants from the National Cancer Institute, the William Stamps Farish Endowed Chair in Cancer Research, and the CDC. Mullett and Hughes reported having no relevant financial disclosures.

Kelsey Mesmer, PhD, is a freelance journalist and journalism professor at Saint Louis University in St. Louis.

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

Approximately about 1 in 4 eligible Americans are up to date on their lung cancer screening, according to a recent study in JAMA Internal Medicine, prompting a need for clinicians to simplify referrals and scheduling of annual appointments.

Despite a 32% increase in lung cancer screening between 2022 and 2024, rates overall remain low at nearly 25%, and especially among patients between ages 50 and 54 years (11.32%; P < .05).

Determining eligibility entails calculating the total years a patient smoked cigarettes, whereas other screenings are based solely on age, such as breast cancer and colon cancer.

Some clinicians “will get into trying to do an actual pack year calculation, or where they smoked half a pack for this many years, and then they quit for this many years, and then, you know, they’re trying to do this massive calculation. And the reality is, we’re just trying to get a patient who’s at high risk for lung cancer” in for screening, said Timothy Mullett, MD, a thoracic surgeon and medical director of the Markey Cancer Center Network Development, University of Kentucky in Lexington, Kentucky, who helped the study authors.

As the second most common form of the disease, lung cancer is the leading cause of such mortality in the US. But low rates of screening mean opportunities for early detection are missed.

In an analysis of national survey data including 26,104 patients (45.6% women and 54.4% men) eligible for lung cancer screening between ages 50 and 79 years, rates increased from 18.49% to 24.49% (P < .05) over a 2-year period starting in 2022. 

Approximately one quarter of men and women were up to date on their screening (P < .05). Nearly one third of patients aged 65 years or older were up to date, whereas those between ages 50 and 54 years (11.32%), 55 and 59 years (19.45%), and 60 and 64 years (23.99%) showed lower rates.

Patients were most likely to be up to date on their screenings in the Northeast region of the country, with Massachusetts showing the highest prevalence rate (38.36%). The rate was lowest in South Dakota (13.43%).

No significant changes in rates were observed for Asian, Black, or Hispanic adults. Adults who were American Indian or Alaska native showed the largest improvement, from 18.74% in 2022 to 30.8% in 2024 (P < .05).

The US Preventive Services Task Force recommends annual screening starting at age 50 for individuals who are current smokers or previous smokers who have a history of consuming at least a pack a day for two decades. Previous smokers must have quit within the previous 15 years to qualify.

Making these calculations can be tricky, Mullett said. Patients’ tobacco use can change over time and a screening tool may not account for those changes. He encourages clinicians to take time to ask patients for more detail about their history. For instance, someone who smokes a half a pack a day now may not immediately qualify for screening, but deeper probing might reveal that they previously smoked two packs a day.

Tamatha Hughes, RN, a nurse navigator for the Missouri Baptist Lung Cancer Screening Program, Missouri Baptist Medical Center in St. Louis, said she often calms fears and corrects misinformation when scheduling patients for their first screening. Some patients think the screening involves an MRI or that radiation from the CT scan is dangerous.

“We go through explaining it as simple as possible,” she said.

If she has a referral for a patient who does not move forward with scheduling, she said she will try them again a few weeks later. Annual screenings are scheduled at a patient’s first appointment, and she said her clinic has an 80% rate for returning patients.

Getting the first scan is the biggest hurdle. Many patients feel stigma or associate lung cancer with a hopeless diagnosis, which can reduce rates, Mullet said.

“There’s a sense of fatalism, because all they’ve ever experienced with lung cancer has been someone who’s died from lung cancer, their grandmother, their grandfather, died of lung cancer. And historically, lung cancer has been found in late stages over 80% of the time,” he said. But screening has drastically improved rates of survival.

“We keep trying to tell patients that this is not your grandfather’s lung cancer,” Mullett said. “This is not what you saw in your family growing up, and we can find it early and we can treat it, and we even if we find it late, we have better treatments now.”

The study was funded by grants from the National Cancer Institute, the William Stamps Farish Endowed Chair in Cancer Research, and the CDC. Mullett and Hughes reported having no relevant financial disclosures.

Kelsey Mesmer, PhD, is a freelance journalist and journalism professor at Saint Louis University in St. Louis.

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

Approximately about 1 in 4 eligible Americans are up to date on their lung cancer screening, according to a recent study in JAMA Internal Medicine, prompting a need for clinicians to simplify referrals and scheduling of annual appointments.

Despite a 32% increase in lung cancer screening between 2022 and 2024, rates overall remain low at nearly 25%, and especially among patients between ages 50 and 54 years (11.32%; P < .05).

Determining eligibility entails calculating the total years a patient smoked cigarettes, whereas other screenings are based solely on age, such as breast cancer and colon cancer.

Some clinicians “will get into trying to do an actual pack year calculation, or where they smoked half a pack for this many years, and then they quit for this many years, and then, you know, they’re trying to do this massive calculation. And the reality is, we’re just trying to get a patient who’s at high risk for lung cancer” in for screening, said Timothy Mullett, MD, a thoracic surgeon and medical director of the Markey Cancer Center Network Development, University of Kentucky in Lexington, Kentucky, who helped the study authors.

As the second most common form of the disease, lung cancer is the leading cause of such mortality in the US. But low rates of screening mean opportunities for early detection are missed.

In an analysis of national survey data including 26,104 patients (45.6% women and 54.4% men) eligible for lung cancer screening between ages 50 and 79 years, rates increased from 18.49% to 24.49% (P < .05) over a 2-year period starting in 2022. 

Approximately one quarter of men and women were up to date on their screening (P < .05). Nearly one third of patients aged 65 years or older were up to date, whereas those between ages 50 and 54 years (11.32%), 55 and 59 years (19.45%), and 60 and 64 years (23.99%) showed lower rates.

Patients were most likely to be up to date on their screenings in the Northeast region of the country, with Massachusetts showing the highest prevalence rate (38.36%). The rate was lowest in South Dakota (13.43%).

No significant changes in rates were observed for Asian, Black, or Hispanic adults. Adults who were American Indian or Alaska native showed the largest improvement, from 18.74% in 2022 to 30.8% in 2024 (P < .05).

The US Preventive Services Task Force recommends annual screening starting at age 50 for individuals who are current smokers or previous smokers who have a history of consuming at least a pack a day for two decades. Previous smokers must have quit within the previous 15 years to qualify.

Making these calculations can be tricky, Mullett said. Patients’ tobacco use can change over time and a screening tool may not account for those changes. He encourages clinicians to take time to ask patients for more detail about their history. For instance, someone who smokes a half a pack a day now may not immediately qualify for screening, but deeper probing might reveal that they previously smoked two packs a day.

Tamatha Hughes, RN, a nurse navigator for the Missouri Baptist Lung Cancer Screening Program, Missouri Baptist Medical Center in St. Louis, said she often calms fears and corrects misinformation when scheduling patients for their first screening. Some patients think the screening involves an MRI or that radiation from the CT scan is dangerous.

“We go through explaining it as simple as possible,” she said.

If she has a referral for a patient who does not move forward with scheduling, she said she will try them again a few weeks later. Annual screenings are scheduled at a patient’s first appointment, and she said her clinic has an 80% rate for returning patients.

Getting the first scan is the biggest hurdle. Many patients feel stigma or associate lung cancer with a hopeless diagnosis, which can reduce rates, Mullet said.

“There’s a sense of fatalism, because all they’ve ever experienced with lung cancer has been someone who’s died from lung cancer, their grandmother, their grandfather, died of lung cancer. And historically, lung cancer has been found in late stages over 80% of the time,” he said. But screening has drastically improved rates of survival.

“We keep trying to tell patients that this is not your grandfather’s lung cancer,” Mullett said. “This is not what you saw in your family growing up, and we can find it early and we can treat it, and we even if we find it late, we have better treatments now.”

The study was funded by grants from the National Cancer Institute, the William Stamps Farish Endowed Chair in Cancer Research, and the CDC. Mullett and Hughes reported having no relevant financial disclosures.

Kelsey Mesmer, PhD, is a freelance journalist and journalism professor at Saint Louis University in St. Louis.

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

Chest CT is being ordered too often for incidental pulmonary nodules found on neck imaging, according to a study at one US health system.

It’s not uncommon for neck CT or MRI to show nodules in the lung apices, but there’s been no data on how often those incidental findings turn out to be lung cancer.

For the new study, researchers analyzed data of 22,173 patients who underwent neck, brachial plexus, or parathyroid imaging at the Massachusetts General Brigham in Boston.

Of those patients, 273 (1.2%) had requests for supplemental chest CTs due to incidental lung findings. Ultimately, only one new lung cancer was detected — an indolent adenocarcinoma — yielding a 2-year incidence rate of 0.40%.

The results suggest that recommendations for chest CT “should likely be substantially decreased,” the researchers conclude in the Journal of the American College of Radiology — though they also acknowledge a need for studies of larger datasets.

As for what drives such CT requests, study co-author Mark Hammer, MD, a thoracic radiologist at Brigham and Women’s Hospital, Harvard Medical School in Boston, offered one possibility: Neuroradiologists, who typically interpret neck imaging, might be less familiar with lung nodule follow-up guidelines.

At his institution, Hammer told Medscape Medical News, thoracic radiologists generally follow the Fleischner Society guidelines on management of incidentally detected pulmonary nodules.

“The reality is that neuroradiologists are often unfamiliar with those guidelines and may recommend follow-up for nodules that do not require it,” he said.

The Fleischner guidelines don’t recommend imaging nodules smaller than 6 mm given the very low cancer risk. For nodules of 6-8 mm, they recommend follow-up chest CTs at 3-12 months to see if the nodule has grown or changed. For larger or otherwise suspicious lesions, they advise prompt evaluation.

But while guidelines exist, follow-up decisions after neck imaging are largely at the discretion of the provider, said Dave Yousem, MD, MBA, a neuroradiologist at Johns Hopkins University in Baltimore.

According to Yousem, some physicians might be comfortable with the possibility of missing a low-risk indolent cancer to spare many patients from unnecessary CTs. But there’s also concern that overlooking even one tumor could trigger litigation, he said.

Hammer’s team found that of all patients with chest CT recommendations, only 171 (62.6%) underwent scanning — a rate consistent with previous reports of incidentaloma follow-up.

Hammer said, thoracic radiologists might have been applying the Fleischner guidelines, but some patients might simply have been lost to follow-up, among other possibilities.

He and his colleagues said recommendations for additional imaging should be evidence-based and judicious to ensure “appropriate follow-up and early detection of lung cancer.”

Potential solutions, they added, include incidentaloma tracking systems, improved communication between providers, and AI-assisted image interpretation.

The study was funded by the Association of University Radiologists and the Agency for Healthcare Research and Quality. Hammer and Yousem had no relevant disclosures.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. He is also an MIT Knight Science Journalism fellow. Email: [email protected].

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

Chest CT is being ordered too often for incidental pulmonary nodules found on neck imaging, according to a study at one US health system.

It’s not uncommon for neck CT or MRI to show nodules in the lung apices, but there’s been no data on how often those incidental findings turn out to be lung cancer.

For the new study, researchers analyzed data of 22,173 patients who underwent neck, brachial plexus, or parathyroid imaging at the Massachusetts General Brigham in Boston.

Of those patients, 273 (1.2%) had requests for supplemental chest CTs due to incidental lung findings. Ultimately, only one new lung cancer was detected — an indolent adenocarcinoma — yielding a 2-year incidence rate of 0.40%.

The results suggest that recommendations for chest CT “should likely be substantially decreased,” the researchers conclude in the Journal of the American College of Radiology — though they also acknowledge a need for studies of larger datasets.

As for what drives such CT requests, study co-author Mark Hammer, MD, a thoracic radiologist at Brigham and Women’s Hospital, Harvard Medical School in Boston, offered one possibility: Neuroradiologists, who typically interpret neck imaging, might be less familiar with lung nodule follow-up guidelines.

At his institution, Hammer told Medscape Medical News, thoracic radiologists generally follow the Fleischner Society guidelines on management of incidentally detected pulmonary nodules.

“The reality is that neuroradiologists are often unfamiliar with those guidelines and may recommend follow-up for nodules that do not require it,” he said.

The Fleischner guidelines don’t recommend imaging nodules smaller than 6 mm given the very low cancer risk. For nodules of 6-8 mm, they recommend follow-up chest CTs at 3-12 months to see if the nodule has grown or changed. For larger or otherwise suspicious lesions, they advise prompt evaluation.

But while guidelines exist, follow-up decisions after neck imaging are largely at the discretion of the provider, said Dave Yousem, MD, MBA, a neuroradiologist at Johns Hopkins University in Baltimore.

According to Yousem, some physicians might be comfortable with the possibility of missing a low-risk indolent cancer to spare many patients from unnecessary CTs. But there’s also concern that overlooking even one tumor could trigger litigation, he said.

Hammer’s team found that of all patients with chest CT recommendations, only 171 (62.6%) underwent scanning — a rate consistent with previous reports of incidentaloma follow-up.

Hammer said, thoracic radiologists might have been applying the Fleischner guidelines, but some patients might simply have been lost to follow-up, among other possibilities.

He and his colleagues said recommendations for additional imaging should be evidence-based and judicious to ensure “appropriate follow-up and early detection of lung cancer.”

Potential solutions, they added, include incidentaloma tracking systems, improved communication between providers, and AI-assisted image interpretation.

The study was funded by the Association of University Radiologists and the Agency for Healthcare Research and Quality. Hammer and Yousem had no relevant disclosures.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. He is also an MIT Knight Science Journalism fellow. Email: [email protected].

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

Chest CT is being ordered too often for incidental pulmonary nodules found on neck imaging, according to a study at one US health system.

It’s not uncommon for neck CT or MRI to show nodules in the lung apices, but there’s been no data on how often those incidental findings turn out to be lung cancer.

For the new study, researchers analyzed data of 22,173 patients who underwent neck, brachial plexus, or parathyroid imaging at the Massachusetts General Brigham in Boston.

Of those patients, 273 (1.2%) had requests for supplemental chest CTs due to incidental lung findings. Ultimately, only one new lung cancer was detected — an indolent adenocarcinoma — yielding a 2-year incidence rate of 0.40%.

The results suggest that recommendations for chest CT “should likely be substantially decreased,” the researchers conclude in the Journal of the American College of Radiology — though they also acknowledge a need for studies of larger datasets.

As for what drives such CT requests, study co-author Mark Hammer, MD, a thoracic radiologist at Brigham and Women’s Hospital, Harvard Medical School in Boston, offered one possibility: Neuroradiologists, who typically interpret neck imaging, might be less familiar with lung nodule follow-up guidelines.

At his institution, Hammer told Medscape Medical News, thoracic radiologists generally follow the Fleischner Society guidelines on management of incidentally detected pulmonary nodules.

“The reality is that neuroradiologists are often unfamiliar with those guidelines and may recommend follow-up for nodules that do not require it,” he said.

The Fleischner guidelines don’t recommend imaging nodules smaller than 6 mm given the very low cancer risk. For nodules of 6-8 mm, they recommend follow-up chest CTs at 3-12 months to see if the nodule has grown or changed. For larger or otherwise suspicious lesions, they advise prompt evaluation.

But while guidelines exist, follow-up decisions after neck imaging are largely at the discretion of the provider, said Dave Yousem, MD, MBA, a neuroradiologist at Johns Hopkins University in Baltimore.

According to Yousem, some physicians might be comfortable with the possibility of missing a low-risk indolent cancer to spare many patients from unnecessary CTs. But there’s also concern that overlooking even one tumor could trigger litigation, he said.

Hammer’s team found that of all patients with chest CT recommendations, only 171 (62.6%) underwent scanning — a rate consistent with previous reports of incidentaloma follow-up.

Hammer said, thoracic radiologists might have been applying the Fleischner guidelines, but some patients might simply have been lost to follow-up, among other possibilities.

He and his colleagues said recommendations for additional imaging should be evidence-based and judicious to ensure “appropriate follow-up and early detection of lung cancer.”

Potential solutions, they added, include incidentaloma tracking systems, improved communication between providers, and AI-assisted image interpretation.

The study was funded by the Association of University Radiologists and the Agency for Healthcare Research and Quality. Hammer and Yousem had no relevant disclosures.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. He is also an MIT Knight Science Journalism fellow. Email: [email protected].

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

Several newly identified biomarkers can help distinguish invasive aspergillosis from aspergillus colonization in lung transplant recipients, according to data from a new study presented at the annual meeting of the International Society for Heart and Lung Transplantation.

Aspergillus, a common environmental mold, can cause potentially serious infection or asymptomatic colonization in patients who have significant lung disease or are immunosuppressed, said Aaron Mishkin, MD, associate professor of medicine at the Lewis Katz School of Medicine at Temple University, Philadelphia, who was not involved in the study.

“Determining if the aspergillus that is present is a colonizing organism vs disease is challenging clinically,” Mishkin said. Clinicians currently rely on criteria including a compatible patient, imaging findings, and a laboratory-based diagnostic such as tissue from a biopsy, cultures, polymerase chain reaction (PCR), or fungal antigen detection, said Mishkin. “Fungal antigen detection has variable specificity and sensitivity,” he noted. New biomarkers that look for an immune response could help differentiate between colonization and infection by assessing an immune-mediated inflammatory response, the hallmark of infection, he said.

To tease out potential biomarkers associated with invasive aspergillosis, Christine Ng, MS, a researcher at the University Health Network, Toronto, Ontario, Canada, and colleagues performed RNA sequencing on samples from 14 control lung transplant patients, 34 with aspergillus colonization, and seven with invasive aspergillosis. They identified potential candidate genes in 15 control samples, 17 aspergillus colonization samples, and 15 invasive aspergillosis samples.

Overall, signaling pathway analysis showed robust immune response, T-cell immunity, and leukocyte immunity in patients with invasive aspergillosis. By contrast, patients with aspergillus colonization showed enriched cellular responses (response to stimuli, epithelium development).

In a real-time quantitative PCR analysis, the researchers validated three biomarkers specific to invasive aspergillosis (IRF7, ZBP1, CYP27B1). Biomarkers AKR1C2, FGF10, and VGLL3 demonstrated specificity for aspergillus colonization. Additionally, biomarkers PTGER3, LPAR3, and COL14A1 were significant when aspergillus colonization was compared to controls but not in comparisons between invasive aspergillosis and aspergillus colonization. 

The study findings were limited by the small sample size, and larger studies are needed before they can be implemented in clinical practice, the researchers wrote. However, the results suggest that the new biomarkers reveal distinct host immune patterns and may improve differentiation of aspergillosis from colonization in lung transplant recipients, they concluded.

Clinical Implications and Next Steps

RNA testing can help differentiate colonization vs infection, Mishkin said. “Colonization is not typically treated, whereas infection would be treated with an anti-fungal and, in the case of a transplant recipient, a reduction in immunosuppression,” he said. “In lung transplantation, a delicate equilibrium must be maintained between achieving optimal immunosuppression and minimizing or treating infection. Any tools that can aid in this decision-making have the potential to enhance patient outcomes,” he added.

The current study was limited by the use of data only from a single center, and the broader applicability to additional populations, broader geographic areas, and a larger number of organisms remains unknown, Mishkin said. “This type of assay does have the possibility of applicability to a larger number of fungal and even bacterial species,” he noted.

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

Several newly identified biomarkers can help distinguish invasive aspergillosis from aspergillus colonization in lung transplant recipients, according to data from a new study presented at the annual meeting of the International Society for Heart and Lung Transplantation.

Aspergillus, a common environmental mold, can cause potentially serious infection or asymptomatic colonization in patients who have significant lung disease or are immunosuppressed, said Aaron Mishkin, MD, associate professor of medicine at the Lewis Katz School of Medicine at Temple University, Philadelphia, who was not involved in the study.

“Determining if the aspergillus that is present is a colonizing organism vs disease is challenging clinically,” Mishkin said. Clinicians currently rely on criteria including a compatible patient, imaging findings, and a laboratory-based diagnostic such as tissue from a biopsy, cultures, polymerase chain reaction (PCR), or fungal antigen detection, said Mishkin. “Fungal antigen detection has variable specificity and sensitivity,” he noted. New biomarkers that look for an immune response could help differentiate between colonization and infection by assessing an immune-mediated inflammatory response, the hallmark of infection, he said.

To tease out potential biomarkers associated with invasive aspergillosis, Christine Ng, MS, a researcher at the University Health Network, Toronto, Ontario, Canada, and colleagues performed RNA sequencing on samples from 14 control lung transplant patients, 34 with aspergillus colonization, and seven with invasive aspergillosis. They identified potential candidate genes in 15 control samples, 17 aspergillus colonization samples, and 15 invasive aspergillosis samples.

Overall, signaling pathway analysis showed robust immune response, T-cell immunity, and leukocyte immunity in patients with invasive aspergillosis. By contrast, patients with aspergillus colonization showed enriched cellular responses (response to stimuli, epithelium development).

In a real-time quantitative PCR analysis, the researchers validated three biomarkers specific to invasive aspergillosis (IRF7, ZBP1, CYP27B1). Biomarkers AKR1C2, FGF10, and VGLL3 demonstrated specificity for aspergillus colonization. Additionally, biomarkers PTGER3, LPAR3, and COL14A1 were significant when aspergillus colonization was compared to controls but not in comparisons between invasive aspergillosis and aspergillus colonization. 

The study findings were limited by the small sample size, and larger studies are needed before they can be implemented in clinical practice, the researchers wrote. However, the results suggest that the new biomarkers reveal distinct host immune patterns and may improve differentiation of aspergillosis from colonization in lung transplant recipients, they concluded.

Clinical Implications and Next Steps

RNA testing can help differentiate colonization vs infection, Mishkin said. “Colonization is not typically treated, whereas infection would be treated with an anti-fungal and, in the case of a transplant recipient, a reduction in immunosuppression,” he said. “In lung transplantation, a delicate equilibrium must be maintained between achieving optimal immunosuppression and minimizing or treating infection. Any tools that can aid in this decision-making have the potential to enhance patient outcomes,” he added.

The current study was limited by the use of data only from a single center, and the broader applicability to additional populations, broader geographic areas, and a larger number of organisms remains unknown, Mishkin said. “This type of assay does have the possibility of applicability to a larger number of fungal and even bacterial species,” he noted.

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

Several newly identified biomarkers can help distinguish invasive aspergillosis from aspergillus colonization in lung transplant recipients, according to data from a new study presented at the annual meeting of the International Society for Heart and Lung Transplantation.

Aspergillus, a common environmental mold, can cause potentially serious infection or asymptomatic colonization in patients who have significant lung disease or are immunosuppressed, said Aaron Mishkin, MD, associate professor of medicine at the Lewis Katz School of Medicine at Temple University, Philadelphia, who was not involved in the study.

“Determining if the aspergillus that is present is a colonizing organism vs disease is challenging clinically,” Mishkin said. Clinicians currently rely on criteria including a compatible patient, imaging findings, and a laboratory-based diagnostic such as tissue from a biopsy, cultures, polymerase chain reaction (PCR), or fungal antigen detection, said Mishkin. “Fungal antigen detection has variable specificity and sensitivity,” he noted. New biomarkers that look for an immune response could help differentiate between colonization and infection by assessing an immune-mediated inflammatory response, the hallmark of infection, he said.

To tease out potential biomarkers associated with invasive aspergillosis, Christine Ng, MS, a researcher at the University Health Network, Toronto, Ontario, Canada, and colleagues performed RNA sequencing on samples from 14 control lung transplant patients, 34 with aspergillus colonization, and seven with invasive aspergillosis. They identified potential candidate genes in 15 control samples, 17 aspergillus colonization samples, and 15 invasive aspergillosis samples.

Overall, signaling pathway analysis showed robust immune response, T-cell immunity, and leukocyte immunity in patients with invasive aspergillosis. By contrast, patients with aspergillus colonization showed enriched cellular responses (response to stimuli, epithelium development).

In a real-time quantitative PCR analysis, the researchers validated three biomarkers specific to invasive aspergillosis (IRF7, ZBP1, CYP27B1). Biomarkers AKR1C2, FGF10, and VGLL3 demonstrated specificity for aspergillus colonization. Additionally, biomarkers PTGER3, LPAR3, and COL14A1 were significant when aspergillus colonization was compared to controls but not in comparisons between invasive aspergillosis and aspergillus colonization. 

The study findings were limited by the small sample size, and larger studies are needed before they can be implemented in clinical practice, the researchers wrote. However, the results suggest that the new biomarkers reveal distinct host immune patterns and may improve differentiation of aspergillosis from colonization in lung transplant recipients, they concluded.

Clinical Implications and Next Steps

RNA testing can help differentiate colonization vs infection, Mishkin said. “Colonization is not typically treated, whereas infection would be treated with an anti-fungal and, in the case of a transplant recipient, a reduction in immunosuppression,” he said. “In lung transplantation, a delicate equilibrium must be maintained between achieving optimal immunosuppression and minimizing or treating infection. Any tools that can aid in this decision-making have the potential to enhance patient outcomes,” he added.

The current study was limited by the use of data only from a single center, and the broader applicability to additional populations, broader geographic areas, and a larger number of organisms remains unknown, Mishkin said. “This type of assay does have the possibility of applicability to a larger number of fungal and even bacterial species,” he noted.

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

Blast exposure has been associated with a wide range of negative outcomes, including alterations in brain structure and function, poorer cognitive functioning, and increased severity of psychiatric and health symptoms. Long-term effects also include chronic secondary downstream effects, such as neuroinflammation, neurotoxicity, cellular senescence, and neurodegeneration.

Now, a recent US Department of Veterans Affairs (VA) study of 114 post-9/11 combat veterans suggests that lifetime blast exposure severity is independently associated with accelerated epigenetic aging, even after accounting for PTSD and TBI. The field of epigenetics refers to how environment influences genes by changing the chemicals attached to them. 

This cross-sectional study analyzed participants enrolled in 2 coordinated VA research protocols: the Chronic Effects of Neurotrauma Consortium Study 34 and the Post-Deployment Mental Health Study. Researchers measured biological aging using DunedinPACE, an epigenetic biomarker derived from whole-blood DNA methylation data.

Greater blast exposure severity was significantly associated with faster DunedinPACE. Mild TBI history was also independently associated with faster aging, whereas PTSD diagnosis was not. No significant interaction effects were observed. Exploratory analyses suggested that higher-intensity and more frequent blast exposures contributed to more accelerated aging. 

The researchers said their findings suggest that accelerated biological aging may represent a pathway linking blast exposure to increased vulnerability for age-related disease and could inform early identification of at-risk veterans. 

Preclinical work has “undeniably demonstrated that primary blast forces can directly induce neurotrauma with associated, ongoing symptoms,” according to the authors of a 2024 study. “[H]owever, these findings have not translated into clinical work.” Most human studies of blast exposure use data obtained from assessments of TBI. That approach is limited, they said, because blast exposure does not always result in symptoms of concussion or TBI, and clinical symptoms of TBI are not necessary for blast-induced neurotrauma to occur. 

Moreover, understanding how and why blast exposure often results in negative consequences is still lagging, and interventions and treatments have lagged comparatively, the researchers noted. In large part, they added, this is because there is no broadly endorsed definition of blast exposure. They illustrated their point with examples of terms used in earlier research: blast TBI, primary blast TBI, pressure severity, distance from the blast, and frequency of exposure. The lack of standardized language, they suggested, “prevents synthesis of existing literature into a cohesive understanding of the field.”

Those researchers called for concerted and collaborative efforts to advance the study of blast exposure, including developing a standardized definition of blast exposure and curating an empirical literature base allowing clear comparisons of results across studies. They also urged raising awareness about blast-related negative outcomes with education at all levels: continuing education opportunities, round tables at annual conference meetings, grand rounds in hospital or academic medical center settings, and journal clubs.

Blast exposure has been associated with a wide range of negative outcomes, including alterations in brain structure and function, poorer cognitive functioning, and increased severity of psychiatric and health symptoms. Long-term effects also include chronic secondary downstream effects, such as neuroinflammation, neurotoxicity, cellular senescence, and neurodegeneration.

Now, a recent US Department of Veterans Affairs (VA) study of 114 post-9/11 combat veterans suggests that lifetime blast exposure severity is independently associated with accelerated epigenetic aging, even after accounting for PTSD and TBI. The field of epigenetics refers to how environment influences genes by changing the chemicals attached to them. 

This cross-sectional study analyzed participants enrolled in 2 coordinated VA research protocols: the Chronic Effects of Neurotrauma Consortium Study 34 and the Post-Deployment Mental Health Study. Researchers measured biological aging using DunedinPACE, an epigenetic biomarker derived from whole-blood DNA methylation data.

Greater blast exposure severity was significantly associated with faster DunedinPACE. Mild TBI history was also independently associated with faster aging, whereas PTSD diagnosis was not. No significant interaction effects were observed. Exploratory analyses suggested that higher-intensity and more frequent blast exposures contributed to more accelerated aging. 

The researchers said their findings suggest that accelerated biological aging may represent a pathway linking blast exposure to increased vulnerability for age-related disease and could inform early identification of at-risk veterans. 

Preclinical work has “undeniably demonstrated that primary blast forces can directly induce neurotrauma with associated, ongoing symptoms,” according to the authors of a 2024 study. “[H]owever, these findings have not translated into clinical work.” Most human studies of blast exposure use data obtained from assessments of TBI. That approach is limited, they said, because blast exposure does not always result in symptoms of concussion or TBI, and clinical symptoms of TBI are not necessary for blast-induced neurotrauma to occur. 

Moreover, understanding how and why blast exposure often results in negative consequences is still lagging, and interventions and treatments have lagged comparatively, the researchers noted. In large part, they added, this is because there is no broadly endorsed definition of blast exposure. They illustrated their point with examples of terms used in earlier research: blast TBI, primary blast TBI, pressure severity, distance from the blast, and frequency of exposure. The lack of standardized language, they suggested, “prevents synthesis of existing literature into a cohesive understanding of the field.”

Those researchers called for concerted and collaborative efforts to advance the study of blast exposure, including developing a standardized definition of blast exposure and curating an empirical literature base allowing clear comparisons of results across studies. They also urged raising awareness about blast-related negative outcomes with education at all levels: continuing education opportunities, round tables at annual conference meetings, grand rounds in hospital or academic medical center settings, and journal clubs.

Blast exposure has been associated with a wide range of negative outcomes, including alterations in brain structure and function, poorer cognitive functioning, and increased severity of psychiatric and health symptoms. Long-term effects also include chronic secondary downstream effects, such as neuroinflammation, neurotoxicity, cellular senescence, and neurodegeneration.

Now, a recent US Department of Veterans Affairs (VA) study of 114 post-9/11 combat veterans suggests that lifetime blast exposure severity is independently associated with accelerated epigenetic aging, even after accounting for PTSD and TBI. The field of epigenetics refers to how environment influences genes by changing the chemicals attached to them. 

This cross-sectional study analyzed participants enrolled in 2 coordinated VA research protocols: the Chronic Effects of Neurotrauma Consortium Study 34 and the Post-Deployment Mental Health Study. Researchers measured biological aging using DunedinPACE, an epigenetic biomarker derived from whole-blood DNA methylation data.

Greater blast exposure severity was significantly associated with faster DunedinPACE. Mild TBI history was also independently associated with faster aging, whereas PTSD diagnosis was not. No significant interaction effects were observed. Exploratory analyses suggested that higher-intensity and more frequent blast exposures contributed to more accelerated aging. 

The researchers said their findings suggest that accelerated biological aging may represent a pathway linking blast exposure to increased vulnerability for age-related disease and could inform early identification of at-risk veterans. 

Preclinical work has “undeniably demonstrated that primary blast forces can directly induce neurotrauma with associated, ongoing symptoms,” according to the authors of a 2024 study. “[H]owever, these findings have not translated into clinical work.” Most human studies of blast exposure use data obtained from assessments of TBI. That approach is limited, they said, because blast exposure does not always result in symptoms of concussion or TBI, and clinical symptoms of TBI are not necessary for blast-induced neurotrauma to occur. 

Moreover, understanding how and why blast exposure often results in negative consequences is still lagging, and interventions and treatments have lagged comparatively, the researchers noted. In large part, they added, this is because there is no broadly endorsed definition of blast exposure. They illustrated their point with examples of terms used in earlier research: blast TBI, primary blast TBI, pressure severity, distance from the blast, and frequency of exposure. The lack of standardized language, they suggested, “prevents synthesis of existing literature into a cohesive understanding of the field.”

Those researchers called for concerted and collaborative efforts to advance the study of blast exposure, including developing a standardized definition of blast exposure and curating an empirical literature base allowing clear comparisons of results across studies. They also urged raising awareness about blast-related negative outcomes with education at all levels: continuing education opportunities, round tables at annual conference meetings, grand rounds in hospital or academic medical center settings, and journal clubs.

Women veterans who live in rural areas face multifaceted challenges in managing chronic pain. Some barriers are logistical, including distance from health care facilities and the time required to get there, while others are financial, such as the cost of gas. Researchers from the Veterans Rural Health Resource Center and the Iowa City Veterans Affairs (VA) Health Care System designed a telehealth intervention specifically for rural women. What the study revealed was that social interactions and camaraderie may be just as important in reducing pain as gentle exercise and behavioral changes.

The participants, recruited from a Midwestern VA health care system, were dealing with chronic pain. In baseline measurements, average scores on the Pain, Enjoyment of Life, and General Activity three-item scale (PEG-3) indicated severe pain and functional interference. Notably, the researchers point out, rural women veterans with chronic pain are less likely than urban veterans to receive specialty pain care.

The researchers designed a program of pain self-management options, allowing the participants to sample from a range of empirically supported approaches in one easily accessible format. The program was primarily delivered over video, to support group processes as well as access to video-based components of the intervention (such as yoga lessons) or to display pages from the participant manual for in-session review. The researchers planned it as a women-only space, to provide a “psychologically safe, gender-sensitive, empowering environment.” 

Eight weekly 90-minute sessions featured mindful movement (gentle yoga, graduated walking), peer connection and support, and an introduction to an evidence-based pain or lifestyle self-management topic such as nutrition. The program also included content based on previous work in chronic pain including acceptance and commitment therapy, cognitive behavioral therapy, and dialectical behavior therapy.

Of the 44 participants, 84% completed the intervention. About half of treatment completers (47%) were deemed responders, reporting a ≥ 30% reduction on their PEG-3 total scores. On the Global Impression of Change scale, 87% reported improvement. 

Of the 30 participants who provided follow-up data, 94% were satisfied or very satisfied; no one reported being dissatisfied with the intervention. 

In qualitative interviews, though, the researchers say a clear theme emerged, reflecting the impact and benefit of the balance of three social and psychological components: rapport with facilitators, connection with other women veterans, and maintenance of individuality. 

In fact, the social support elements of the current intervention may have directly contributed to the observed improvements in pain severity and interference, the researchers suggest. They also cite another potential mechanism: impacting loneliness. Other studies have found that loneliness is prevalent among rural-dwelling women with chronic illnesses; research in rural settings also suggests that interventions focused on shared interests and common experiences might reduce loneliness. Moreover, reducing loneliness may have an independent benefit: In that research, loneliness was a risk factor for developing the pain, depression, and fatigue symptom cluster. 

The women in the telehealth study often spoke about the emotional benefits and camaraderie of the group sessions. They reported feeling understood. “The most memorable thing was that I just felt good,” one participant said. “…They helped me approach what was going on in my life. …[T]hey never grouped us together. We were all individuals with similar problems.”

Social support might help to buffer stress, which in turn may improve the experience of pain, via its effect on stressor appraisals and coping resources. Thus, their findings pair well, the researchers say, with the creation of the Women Veterans Network (WoVeN), a national peer-facilitated social support intervention aimed at ameliorating loneliness and increasing support among women veterans. Ultimately, they suggest, their findings may lead to help for women veterans living with chronic pain—whether they live in the country or the city.

Women veterans who live in rural areas face multifaceted challenges in managing chronic pain. Some barriers are logistical, including distance from health care facilities and the time required to get there, while others are financial, such as the cost of gas. Researchers from the Veterans Rural Health Resource Center and the Iowa City Veterans Affairs (VA) Health Care System designed a telehealth intervention specifically for rural women. What the study revealed was that social interactions and camaraderie may be just as important in reducing pain as gentle exercise and behavioral changes.

The participants, recruited from a Midwestern VA health care system, were dealing with chronic pain. In baseline measurements, average scores on the Pain, Enjoyment of Life, and General Activity three-item scale (PEG-3) indicated severe pain and functional interference. Notably, the researchers point out, rural women veterans with chronic pain are less likely than urban veterans to receive specialty pain care.

The researchers designed a program of pain self-management options, allowing the participants to sample from a range of empirically supported approaches in one easily accessible format. The program was primarily delivered over video, to support group processes as well as access to video-based components of the intervention (such as yoga lessons) or to display pages from the participant manual for in-session review. The researchers planned it as a women-only space, to provide a “psychologically safe, gender-sensitive, empowering environment.” 

Eight weekly 90-minute sessions featured mindful movement (gentle yoga, graduated walking), peer connection and support, and an introduction to an evidence-based pain or lifestyle self-management topic such as nutrition. The program also included content based on previous work in chronic pain including acceptance and commitment therapy, cognitive behavioral therapy, and dialectical behavior therapy.

Of the 44 participants, 84% completed the intervention. About half of treatment completers (47%) were deemed responders, reporting a ≥ 30% reduction on their PEG-3 total scores. On the Global Impression of Change scale, 87% reported improvement. 

Of the 30 participants who provided follow-up data, 94% were satisfied or very satisfied; no one reported being dissatisfied with the intervention. 

In qualitative interviews, though, the researchers say a clear theme emerged, reflecting the impact and benefit of the balance of three social and psychological components: rapport with facilitators, connection with other women veterans, and maintenance of individuality. 

In fact, the social support elements of the current intervention may have directly contributed to the observed improvements in pain severity and interference, the researchers suggest. They also cite another potential mechanism: impacting loneliness. Other studies have found that loneliness is prevalent among rural-dwelling women with chronic illnesses; research in rural settings also suggests that interventions focused on shared interests and common experiences might reduce loneliness. Moreover, reducing loneliness may have an independent benefit: In that research, loneliness was a risk factor for developing the pain, depression, and fatigue symptom cluster. 

The women in the telehealth study often spoke about the emotional benefits and camaraderie of the group sessions. They reported feeling understood. “The most memorable thing was that I just felt good,” one participant said. “…They helped me approach what was going on in my life. …[T]hey never grouped us together. We were all individuals with similar problems.”

Social support might help to buffer stress, which in turn may improve the experience of pain, via its effect on stressor appraisals and coping resources. Thus, their findings pair well, the researchers say, with the creation of the Women Veterans Network (WoVeN), a national peer-facilitated social support intervention aimed at ameliorating loneliness and increasing support among women veterans. Ultimately, they suggest, their findings may lead to help for women veterans living with chronic pain—whether they live in the country or the city.

Women veterans who live in rural areas face multifaceted challenges in managing chronic pain. Some barriers are logistical, including distance from health care facilities and the time required to get there, while others are financial, such as the cost of gas. Researchers from the Veterans Rural Health Resource Center and the Iowa City Veterans Affairs (VA) Health Care System designed a telehealth intervention specifically for rural women. What the study revealed was that social interactions and camaraderie may be just as important in reducing pain as gentle exercise and behavioral changes.

The participants, recruited from a Midwestern VA health care system, were dealing with chronic pain. In baseline measurements, average scores on the Pain, Enjoyment of Life, and General Activity three-item scale (PEG-3) indicated severe pain and functional interference. Notably, the researchers point out, rural women veterans with chronic pain are less likely than urban veterans to receive specialty pain care.

The researchers designed a program of pain self-management options, allowing the participants to sample from a range of empirically supported approaches in one easily accessible format. The program was primarily delivered over video, to support group processes as well as access to video-based components of the intervention (such as yoga lessons) or to display pages from the participant manual for in-session review. The researchers planned it as a women-only space, to provide a “psychologically safe, gender-sensitive, empowering environment.” 

Eight weekly 90-minute sessions featured mindful movement (gentle yoga, graduated walking), peer connection and support, and an introduction to an evidence-based pain or lifestyle self-management topic such as nutrition. The program also included content based on previous work in chronic pain including acceptance and commitment therapy, cognitive behavioral therapy, and dialectical behavior therapy.

Of the 44 participants, 84% completed the intervention. About half of treatment completers (47%) were deemed responders, reporting a ≥ 30% reduction on their PEG-3 total scores. On the Global Impression of Change scale, 87% reported improvement. 

Of the 30 participants who provided follow-up data, 94% were satisfied or very satisfied; no one reported being dissatisfied with the intervention. 

In qualitative interviews, though, the researchers say a clear theme emerged, reflecting the impact and benefit of the balance of three social and psychological components: rapport with facilitators, connection with other women veterans, and maintenance of individuality. 

In fact, the social support elements of the current intervention may have directly contributed to the observed improvements in pain severity and interference, the researchers suggest. They also cite another potential mechanism: impacting loneliness. Other studies have found that loneliness is prevalent among rural-dwelling women with chronic illnesses; research in rural settings also suggests that interventions focused on shared interests and common experiences might reduce loneliness. Moreover, reducing loneliness may have an independent benefit: In that research, loneliness was a risk factor for developing the pain, depression, and fatigue symptom cluster. 

The women in the telehealth study often spoke about the emotional benefits and camaraderie of the group sessions. They reported feeling understood. “The most memorable thing was that I just felt good,” one participant said. “…They helped me approach what was going on in my life. …[T]hey never grouped us together. We were all individuals with similar problems.”

Social support might help to buffer stress, which in turn may improve the experience of pain, via its effect on stressor appraisals and coping resources. Thus, their findings pair well, the researchers say, with the creation of the Women Veterans Network (WoVeN), a national peer-facilitated social support intervention aimed at ameliorating loneliness and increasing support among women veterans. Ultimately, they suggest, their findings may lead to help for women veterans living with chronic pain—whether they live in the country or the city.

Immune checkpoint inhibitors (ICIs) have become important in oncology and represent an evolving area of therapeutics. Since their approval by the US Food and Drug Administration (FDA) in 2011, ICIs have been increasingly used as modalities in neoadjuvant and adjuvant treatment for resectable solid malignancies and in unresectable disease, such as advanced melanoma, and are associated with improved survival.¹

Immune checkpoints are present on the cell surface of activated T cells as well as other immune cells like B cells and natural killer cells. By regulating the length and amplitude of the body’s innate immune response, they maintain immune homeostasis and prevent its overactivation. Immune checkpoints are often thought of as the brakes on the immune system.²

Two glycoproteins that act as immune checkpoints and are targeted by ICIs are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 is upregulated on activated T cells. PD-1 is also expressed on activated T cells, as well as macrophages, B cells, and dendritic cells. Cancer cells can evade immune surveillance by exploiting immune checkpoint pathways. Inhibition of these checkpoints with ICIs reactivates T cells and enables the immune system to recognize and attack cancer cells more effectively. Ipilimumab blocks the activity of CTLA-4 on T cells. Nivolumab and pembrolizumab block the interaction between PD-1 on T cells and its ligand PD-L1 on cancer cells.^3,4

Inhibition of these checkpoints is often effective in cancer treatment but can result in the loss of immunologic tolerance with resultant immune-related adverse events (irAEs) and potentially permanent autoimmune disorders. Autoreactive T cells can damage host cell tissues including the colon, lungs, liver, pituitary gland, thyroid, and skin. Severe irAEs include type 1 diabetes mellitus, myositis, nephritis, colitis, pneumonitis, hepatitis, uveitis, hypophysitis, and adrenalitis.⁴

Hypophysitis is inflammation of the pituitary gland, often with thickening of the pituitary stalk, resulting in dysfunction and hormone deficiencies. While primary hypophysitis is idiopathic, secondary hypophysitis is the result of an underlying condition such as exposure to an ICI. Immune-mediated inflammation of the pituitary gland in hypophysitis may disrupt corticotroph function, leading to adrenocorticotropic hormone (ACTH) deficiency. Early warning features are often vague and nonspecific, such as headache, fatigue, and weakness, which makes diagnosis challenging.^3,5

CASE PRESENTATION

A 73-year-old male veteran with a history of metastatic melanoma on ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks (a standard combination regimen for advanced melanoma) presented to the emergency department (ED) with 2 weeks of cough, nausea, and severe headache 3 weeks after cycle 2 of combination ICI therapy. The patient had undergone excision of multiple sites of melanoma in situ with recurrence and disease progression after 5 cycles of pembrolizumab. He was subsequently started on combination ICI therapy.

On ED arrival, the patient was afebrile and saturating well on room air. He was normotensive but found to have orthostatic blood pressure. Physical examination was remarkable for dry oral mucosa and decreased skin turgor. Initial laboratory results were significant for hyponatremia of 123 mmol/L (reference range, 136-145 mmol/L), low-normal free thyroxine (T4) level of 0.5 ng/dL (reference range, 0.6-1.2 ng/dL), a low total triiodothyronine level of 32.14 ng/dL (reference range, 85-178 ng/dL), and a low thyrotropin level of 0.19 mIU/L (reference range, 0.35-5.50 mIU/L). Serum osmolarity was low at 259 mOsm/kg (reference range, 285-315 mOsm/kg), urine sodium was high at 168 mEq/L (reference, 20 mEq/L), and urine osmolarity was inappropriately concentrated at 726 mOsm/kg (reference range, 250-1000 mOsm/kg). The patient was admitted for additional testing. His morning cortisol level was within normal limits at 15 mcg/dL (reference range, 6.7-22.5 mcg/dL).

Computed tomography (CT) of the patient’s head revealed no acute findings. Chest CT revealed posterior right lower lobe mild ground-glass opacities, with possible ICI-induced pneumonitis. The patient received fluid resuscitation. Given concern for syndrome of inappropriate antidiuretic hormone secretion, the patient was started on 3 g salt tablets 3 times a day and urea 30 g powder daily. The etiology of the abnormal thyroid levels was unclear to endocrinology at that time. The differential diagnosis included a nonthyroidal illness or central hypothyroidism.

The patient started levothyroxine 75 mcg due to abnormal thyroid levels and persistent fatigue and fludrocortisone 0.1 mg daily to manage orthostatic hypotension. His sodium levels improved to 132 mmol/L over 6 days and he was discharged with levothyroxine 75 mcg daily, fludrocortisone 0.1 mg daily, 3 g salt tabs 3 times a day, urea 30 g powder daily, as well as oral cefpodoxime 500 mg twice daily for 3 days and azithromycin 500 mg once daily for 2 days (for a total of 10 days of antibiotic therapy) to treat potential occult pneumonia.

The patient returned to the ED 3 days after discharge following an outpatient oncology appointment with ongoing severe headaches and persistent nausea. There was concern for recurrent hyponatremia. His sodium level was within normal limits at 133 mmol/L. Repeat morning cortisol was low-normal at 9 mcg/dL. Magnetic resonance imaging (MRI) of the brain was negative for metastatic disease, but showed a slight interval increase in size of the pituitary gland compared with an MRI from 6 months prior, with mild fullness and a slightly convex superior margin near homogeneous enhancement, raising concern for infection or hypophysitis (Figure 1).

The patient was readmitted to the general medicine service and was given intravenous hydrocortisone 100 mg every 8 hours because of concern for central adrenal insufficiency due to grade 3 hypophysitis in the setting of MRI imaging and severe headaches (Table 1). He was not hypotensive at the time of hydrocortisone initiation and other vital signs were stable. A cosyntropin stimulation test—a standard diagnostic test for central adrenal insufficiency—was not performed because the patient had already started high-dose hydrocortisone. The patient’s free T4 on this admission remained low at 0.6 ng/dL.

No adjustments were made to his levothyroxine dose given that he recently began the medication and levels may lag after initiation. After a 4-day hospitalization, the decision was made to continue with the steroid taper and follow up with outpatient endocrinology to obtain a cosyntropin stimulation test to complete a full assessment of his pituitary axis (Figure 2). Repeat thyroid function testing for levothyroxine titration was arranged. The levothyroxine dosage was later increased to 88 mcg daily, but the patient discontinued the medication and remained euthyroid. Endocrinology attributed a nonthyroidal illness as the etiology of his hypothyroidism, likely euthyroid sick syndrome in the setting of illness. His hydrocortisone was tapered during outpatient care and fludrocortisone was discontinued due to hypertension.

One month after his second discharge, the patient presented to the ED with 2 weeks of dizziness, associated lightheadedness, and blurred vision when standing from a sitting position. Upon assessment, symptoms were attributed to poor oral intake. The patient’s vital signs were again positive for orthostatic hypotension, though refractory to adequate fluid replacement. Laboratory testing was significant for a low ACTH level of 3.0 pg/mL (reference range, 7.2-63.3 pg/mL). Given that the patient had not received steroids for 1 week, he underwent a cosyntropin stimulation test, which revealed a blunted response supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis (Table 2).

The patient was again readmitted to the general medicine service. A brain MRI showed interval shrinkage of the pituitary gland compared to imaging one month prior, which was attributed to hydrocortisone treatment during this month. CT of the patient’s abdomen demonstrated normal-sized adrenal glands. Positron emission tomography (PET)/CT showed no evidence of pituitary or adrenal metastases. Endocrinology recommended reinitiating oral hydrocortisone 50 mg in the morning and 50 mg around 3 pm daily with fludrocortisone 0.2 mg once daily, which resulted in near resolution of the patient’s symptoms. He was discharged after a 14-day hospitalization with home physical therapy services and endocrinology, nephrology, and oncology follow-up appointments.

The patient was readmitted twice to the general medicine service over the next 6 months for complications from hydrocortisone and fludrocortisone treatment including hypokalemia. He followed up with outpatient clinicians until his death 14 months later. He did not restart ICI therapy, and eventually joined a clinical trial for other advanced melanoma treatments at another institution. The patient’s family consented to the publication of this case report with the accompanying images.

DISCUSSION

The combination of ipilimumab (anti-CTLA-4 monoclonal antibody) and nivolumab (anti-PD-1 monoclonal antibody) is FDA-approved for treatment of advanced melanoma with the goal of harnessing complementary and synergistic mechanisms of dual therapy.^6-8 Combination therapy, however, can increase the incidence of irAEs, which are often endocrine-related and more common in patients treated with dual immunotherapy than with monotherapy.⁹ Hypophysitis has the lowest reported fatality rate among ICI-related irAEs (< 1%), compared with higher mortality rates seen in myocarditis (25%-50%) and pneumonitis (10%-20%).^4,10

The patient initially presented with ICI-related hypothyroidism, later identified as secondary (central) hypothyroidism. He was treated with levothyroxine until central hypothyroidism was confirmed. Subsequently, the patient developed headache, poor appetite, and lightheadedness, with MRI findings suggestive of hypophysitis, for which he was started on hydrocortisone. A component of primary adrenal insufficiency was initially considered, given the low ACTH level and blunted response to cosyntropin stimulation following prior high-dose steroid therapy. However, CT imaging demonstrated normal adrenal morphology without atrophy, supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis.

The estimated incidence of ICI-induced hypophysitis is 1.5% to 13.3% with anti-CTLA-4 agents, 0.3% to 3.0% with anti-PD-1 agents, and can be as high as 12.8% with combination therapy.¹ ICI-induced hypophysitis is believed to arise from the direct binding of ICI antibodies to their targets on anterior pituitary cells, such as corticotrophs, thyrotrophs, and gonadotrophs, triggering an immune response. One theory for targeting these cells is high CTLA-4 expression in the anterior pituitary gland.¹¹ PD-1 therapies tend to manifest as either hypothyroidism, hyperthyroidism, Graves’ disease, diabetes, or adrenal insufficiency.¹⁰

A concern in patients with advanced melanoma is metastasis. Melanoma has a high propensity for brain metastasis.¹² There was moderate suspicion for pituitary gland metastasis in this case, though pituitary metastasis more often manifests with symptoms of posterior pituitary gland deficiency, such as polyuria and polydipsia.¹³ The adrenal gland is the fourth-most common site for melanoma metastases, after the lung, liver, and bone.¹⁴ This patient had no evidence of pituitary or adrenal metastases on PET/CT. Therefore, his symptoms were most likely due to ICI therapy. Cases of ≥ 1 endocrine dysfunction have been reported as an ICI therapy irAE.¹⁵ In these situations, diagnosing primary and central adrenal insufficiency in the same patient is complex because hormone profiles are intertwined.

Many patients who develop hypophysitis from ICI therapy will require permanent replacement therapy. It is unclear whether low-dose replacement steroids have a significant effect on the efficacy of ICIs. Given that ICI treatment works by enhancing the immune system, medications that suppress the body’s immune system, such as steroids, could interfere with treatment efficacy. However, there are speculations that the development of irAEs is an indicator of effective treatment. In a phase 1 trial of a CTLA-4 blocker in patients with metastatic melanoma, there was a correlation between reduced CTLA-4 expression as well as low rates of melanoma recurrence and a higher incidence of irAEs.¹⁶

When assessing patients on ICI treatment, clinicians must remain vigilant for all potential irAEs, especially in patients receiving combination therapy. ICI-induced irAEs can present with vague and nonspecific symptoms. Concurrent endocrine irAEs, such as hypophysitis with thyroiditis or adrenalitis, are not uncommon in combination therapy and can complicate interpretation of hormone profiles. It is prudent for clinicians to review known risk factors. Hypophysitis is typically associated with older adult male patients.^17,18

The irAEs of ICI therapy deeply affected the quality of life of the patient in this case, as he was often experiencing many of the clinical symptoms of his hormone insufficiencies as well as the treatment modalities, thus requiring repeated hospital admissions. The risks and benefits of continuing ICI therapy should be an ongoing discussion between the physician and patient and should take into account the acuity and severity of irAEs and oncological disease burden, among other variables. Given the severity of his AEs, the patient stopped ICI therapy and instead opted to enroll in a clinical trial at another institution for continued alternative treatments.

CONCLUSIONS

This case offers a lesson in the diagnostic challenges of vague symptoms in patients with cancer who are receiving ICI therapy. ICI therapy is widely used in the treatment of solid malignancies, and as its use increases, it is expected that clinicians will likely see more cases of irAEs in hospitalized patients. The vague presentation of irAEs can often lead to treatment delays, especially when > 1 irAE presents concurrently. There are ongoing studies researching potential ways to predict the likelihood of developing these irAEs. It is imperative that clinicians are aware of these ICI-related complications and that more research be conducted to understand patient quality of life and treatment guidance based on irAE severity and disease burden.

Immune checkpoint inhibitors (ICIs) have become important in oncology and represent an evolving area of therapeutics. Since their approval by the US Food and Drug Administration (FDA) in 2011, ICIs have been increasingly used as modalities in neoadjuvant and adjuvant treatment for resectable solid malignancies and in unresectable disease, such as advanced melanoma, and are associated with improved survival.¹

Immune checkpoints are present on the cell surface of activated T cells as well as other immune cells like B cells and natural killer cells. By regulating the length and amplitude of the body’s innate immune response, they maintain immune homeostasis and prevent its overactivation. Immune checkpoints are often thought of as the brakes on the immune system.²

Two glycoproteins that act as immune checkpoints and are targeted by ICIs are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 is upregulated on activated T cells. PD-1 is also expressed on activated T cells, as well as macrophages, B cells, and dendritic cells. Cancer cells can evade immune surveillance by exploiting immune checkpoint pathways. Inhibition of these checkpoints with ICIs reactivates T cells and enables the immune system to recognize and attack cancer cells more effectively. Ipilimumab blocks the activity of CTLA-4 on T cells. Nivolumab and pembrolizumab block the interaction between PD-1 on T cells and its ligand PD-L1 on cancer cells.^3,4

Inhibition of these checkpoints is often effective in cancer treatment but can result in the loss of immunologic tolerance with resultant immune-related adverse events (irAEs) and potentially permanent autoimmune disorders. Autoreactive T cells can damage host cell tissues including the colon, lungs, liver, pituitary gland, thyroid, and skin. Severe irAEs include type 1 diabetes mellitus, myositis, nephritis, colitis, pneumonitis, hepatitis, uveitis, hypophysitis, and adrenalitis.⁴

Hypophysitis is inflammation of the pituitary gland, often with thickening of the pituitary stalk, resulting in dysfunction and hormone deficiencies. While primary hypophysitis is idiopathic, secondary hypophysitis is the result of an underlying condition such as exposure to an ICI. Immune-mediated inflammation of the pituitary gland in hypophysitis may disrupt corticotroph function, leading to adrenocorticotropic hormone (ACTH) deficiency. Early warning features are often vague and nonspecific, such as headache, fatigue, and weakness, which makes diagnosis challenging.^3,5

CASE PRESENTATION

A 73-year-old male veteran with a history of metastatic melanoma on ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks (a standard combination regimen for advanced melanoma) presented to the emergency department (ED) with 2 weeks of cough, nausea, and severe headache 3 weeks after cycle 2 of combination ICI therapy. The patient had undergone excision of multiple sites of melanoma in situ with recurrence and disease progression after 5 cycles of pembrolizumab. He was subsequently started on combination ICI therapy.

On ED arrival, the patient was afebrile and saturating well on room air. He was normotensive but found to have orthostatic blood pressure. Physical examination was remarkable for dry oral mucosa and decreased skin turgor. Initial laboratory results were significant for hyponatremia of 123 mmol/L (reference range, 136-145 mmol/L), low-normal free thyroxine (T4) level of 0.5 ng/dL (reference range, 0.6-1.2 ng/dL), a low total triiodothyronine level of 32.14 ng/dL (reference range, 85-178 ng/dL), and a low thyrotropin level of 0.19 mIU/L (reference range, 0.35-5.50 mIU/L). Serum osmolarity was low at 259 mOsm/kg (reference range, 285-315 mOsm/kg), urine sodium was high at 168 mEq/L (reference, 20 mEq/L), and urine osmolarity was inappropriately concentrated at 726 mOsm/kg (reference range, 250-1000 mOsm/kg). The patient was admitted for additional testing. His morning cortisol level was within normal limits at 15 mcg/dL (reference range, 6.7-22.5 mcg/dL).

Computed tomography (CT) of the patient’s head revealed no acute findings. Chest CT revealed posterior right lower lobe mild ground-glass opacities, with possible ICI-induced pneumonitis. The patient received fluid resuscitation. Given concern for syndrome of inappropriate antidiuretic hormone secretion, the patient was started on 3 g salt tablets 3 times a day and urea 30 g powder daily. The etiology of the abnormal thyroid levels was unclear to endocrinology at that time. The differential diagnosis included a nonthyroidal illness or central hypothyroidism.

The patient started levothyroxine 75 mcg due to abnormal thyroid levels and persistent fatigue and fludrocortisone 0.1 mg daily to manage orthostatic hypotension. His sodium levels improved to 132 mmol/L over 6 days and he was discharged with levothyroxine 75 mcg daily, fludrocortisone 0.1 mg daily, 3 g salt tabs 3 times a day, urea 30 g powder daily, as well as oral cefpodoxime 500 mg twice daily for 3 days and azithromycin 500 mg once daily for 2 days (for a total of 10 days of antibiotic therapy) to treat potential occult pneumonia.

The patient returned to the ED 3 days after discharge following an outpatient oncology appointment with ongoing severe headaches and persistent nausea. There was concern for recurrent hyponatremia. His sodium level was within normal limits at 133 mmol/L. Repeat morning cortisol was low-normal at 9 mcg/dL. Magnetic resonance imaging (MRI) of the brain was negative for metastatic disease, but showed a slight interval increase in size of the pituitary gland compared with an MRI from 6 months prior, with mild fullness and a slightly convex superior margin near homogeneous enhancement, raising concern for infection or hypophysitis (Figure 1).

The patient was readmitted to the general medicine service and was given intravenous hydrocortisone 100 mg every 8 hours because of concern for central adrenal insufficiency due to grade 3 hypophysitis in the setting of MRI imaging and severe headaches (Table 1). He was not hypotensive at the time of hydrocortisone initiation and other vital signs were stable. A cosyntropin stimulation test—a standard diagnostic test for central adrenal insufficiency—was not performed because the patient had already started high-dose hydrocortisone. The patient’s free T4 on this admission remained low at 0.6 ng/dL.

No adjustments were made to his levothyroxine dose given that he recently began the medication and levels may lag after initiation. After a 4-day hospitalization, the decision was made to continue with the steroid taper and follow up with outpatient endocrinology to obtain a cosyntropin stimulation test to complete a full assessment of his pituitary axis (Figure 2). Repeat thyroid function testing for levothyroxine titration was arranged. The levothyroxine dosage was later increased to 88 mcg daily, but the patient discontinued the medication and remained euthyroid. Endocrinology attributed a nonthyroidal illness as the etiology of his hypothyroidism, likely euthyroid sick syndrome in the setting of illness. His hydrocortisone was tapered during outpatient care and fludrocortisone was discontinued due to hypertension.

One month after his second discharge, the patient presented to the ED with 2 weeks of dizziness, associated lightheadedness, and blurred vision when standing from a sitting position. Upon assessment, symptoms were attributed to poor oral intake. The patient’s vital signs were again positive for orthostatic hypotension, though refractory to adequate fluid replacement. Laboratory testing was significant for a low ACTH level of 3.0 pg/mL (reference range, 7.2-63.3 pg/mL). Given that the patient had not received steroids for 1 week, he underwent a cosyntropin stimulation test, which revealed a blunted response supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis (Table 2).

The patient was again readmitted to the general medicine service. A brain MRI showed interval shrinkage of the pituitary gland compared to imaging one month prior, which was attributed to hydrocortisone treatment during this month. CT of the patient’s abdomen demonstrated normal-sized adrenal glands. Positron emission tomography (PET)/CT showed no evidence of pituitary or adrenal metastases. Endocrinology recommended reinitiating oral hydrocortisone 50 mg in the morning and 50 mg around 3 pm daily with fludrocortisone 0.2 mg once daily, which resulted in near resolution of the patient’s symptoms. He was discharged after a 14-day hospitalization with home physical therapy services and endocrinology, nephrology, and oncology follow-up appointments.

The patient was readmitted twice to the general medicine service over the next 6 months for complications from hydrocortisone and fludrocortisone treatment including hypokalemia. He followed up with outpatient clinicians until his death 14 months later. He did not restart ICI therapy, and eventually joined a clinical trial for other advanced melanoma treatments at another institution. The patient’s family consented to the publication of this case report with the accompanying images.

DISCUSSION

The combination of ipilimumab (anti-CTLA-4 monoclonal antibody) and nivolumab (anti-PD-1 monoclonal antibody) is FDA-approved for treatment of advanced melanoma with the goal of harnessing complementary and synergistic mechanisms of dual therapy.^6-8 Combination therapy, however, can increase the incidence of irAEs, which are often endocrine-related and more common in patients treated with dual immunotherapy than with monotherapy.⁹ Hypophysitis has the lowest reported fatality rate among ICI-related irAEs (< 1%), compared with higher mortality rates seen in myocarditis (25%-50%) and pneumonitis (10%-20%).^4,10

The patient initially presented with ICI-related hypothyroidism, later identified as secondary (central) hypothyroidism. He was treated with levothyroxine until central hypothyroidism was confirmed. Subsequently, the patient developed headache, poor appetite, and lightheadedness, with MRI findings suggestive of hypophysitis, for which he was started on hydrocortisone. A component of primary adrenal insufficiency was initially considered, given the low ACTH level and blunted response to cosyntropin stimulation following prior high-dose steroid therapy. However, CT imaging demonstrated normal adrenal morphology without atrophy, supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis.

The estimated incidence of ICI-induced hypophysitis is 1.5% to 13.3% with anti-CTLA-4 agents, 0.3% to 3.0% with anti-PD-1 agents, and can be as high as 12.8% with combination therapy.¹ ICI-induced hypophysitis is believed to arise from the direct binding of ICI antibodies to their targets on anterior pituitary cells, such as corticotrophs, thyrotrophs, and gonadotrophs, triggering an immune response. One theory for targeting these cells is high CTLA-4 expression in the anterior pituitary gland.¹¹ PD-1 therapies tend to manifest as either hypothyroidism, hyperthyroidism, Graves’ disease, diabetes, or adrenal insufficiency.¹⁰

A concern in patients with advanced melanoma is metastasis. Melanoma has a high propensity for brain metastasis.¹² There was moderate suspicion for pituitary gland metastasis in this case, though pituitary metastasis more often manifests with symptoms of posterior pituitary gland deficiency, such as polyuria and polydipsia.¹³ The adrenal gland is the fourth-most common site for melanoma metastases, after the lung, liver, and bone.¹⁴ This patient had no evidence of pituitary or adrenal metastases on PET/CT. Therefore, his symptoms were most likely due to ICI therapy. Cases of ≥ 1 endocrine dysfunction have been reported as an ICI therapy irAE.¹⁵ In these situations, diagnosing primary and central adrenal insufficiency in the same patient is complex because hormone profiles are intertwined.

Many patients who develop hypophysitis from ICI therapy will require permanent replacement therapy. It is unclear whether low-dose replacement steroids have a significant effect on the efficacy of ICIs. Given that ICI treatment works by enhancing the immune system, medications that suppress the body’s immune system, such as steroids, could interfere with treatment efficacy. However, there are speculations that the development of irAEs is an indicator of effective treatment. In a phase 1 trial of a CTLA-4 blocker in patients with metastatic melanoma, there was a correlation between reduced CTLA-4 expression as well as low rates of melanoma recurrence and a higher incidence of irAEs.¹⁶

When assessing patients on ICI treatment, clinicians must remain vigilant for all potential irAEs, especially in patients receiving combination therapy. ICI-induced irAEs can present with vague and nonspecific symptoms. Concurrent endocrine irAEs, such as hypophysitis with thyroiditis or adrenalitis, are not uncommon in combination therapy and can complicate interpretation of hormone profiles. It is prudent for clinicians to review known risk factors. Hypophysitis is typically associated with older adult male patients.^17,18

The irAEs of ICI therapy deeply affected the quality of life of the patient in this case, as he was often experiencing many of the clinical symptoms of his hormone insufficiencies as well as the treatment modalities, thus requiring repeated hospital admissions. The risks and benefits of continuing ICI therapy should be an ongoing discussion between the physician and patient and should take into account the acuity and severity of irAEs and oncological disease burden, among other variables. Given the severity of his AEs, the patient stopped ICI therapy and instead opted to enroll in a clinical trial at another institution for continued alternative treatments.

CONCLUSIONS

This case offers a lesson in the diagnostic challenges of vague symptoms in patients with cancer who are receiving ICI therapy. ICI therapy is widely used in the treatment of solid malignancies, and as its use increases, it is expected that clinicians will likely see more cases of irAEs in hospitalized patients. The vague presentation of irAEs can often lead to treatment delays, especially when > 1 irAE presents concurrently. There are ongoing studies researching potential ways to predict the likelihood of developing these irAEs. It is imperative that clinicians are aware of these ICI-related complications and that more research be conducted to understand patient quality of life and treatment guidance based on irAE severity and disease burden.

Immune checkpoint inhibitors (ICIs) have become important in oncology and represent an evolving area of therapeutics. Since their approval by the US Food and Drug Administration (FDA) in 2011, ICIs have been increasingly used as modalities in neoadjuvant and adjuvant treatment for resectable solid malignancies and in unresectable disease, such as advanced melanoma, and are associated with improved survival.¹

Immune checkpoints are present on the cell surface of activated T cells as well as other immune cells like B cells and natural killer cells. By regulating the length and amplitude of the body’s innate immune response, they maintain immune homeostasis and prevent its overactivation. Immune checkpoints are often thought of as the brakes on the immune system.²

Two glycoproteins that act as immune checkpoints and are targeted by ICIs are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 is upregulated on activated T cells. PD-1 is also expressed on activated T cells, as well as macrophages, B cells, and dendritic cells. Cancer cells can evade immune surveillance by exploiting immune checkpoint pathways. Inhibition of these checkpoints with ICIs reactivates T cells and enables the immune system to recognize and attack cancer cells more effectively. Ipilimumab blocks the activity of CTLA-4 on T cells. Nivolumab and pembrolizumab block the interaction between PD-1 on T cells and its ligand PD-L1 on cancer cells.^3,4

Inhibition of these checkpoints is often effective in cancer treatment but can result in the loss of immunologic tolerance with resultant immune-related adverse events (irAEs) and potentially permanent autoimmune disorders. Autoreactive T cells can damage host cell tissues including the colon, lungs, liver, pituitary gland, thyroid, and skin. Severe irAEs include type 1 diabetes mellitus, myositis, nephritis, colitis, pneumonitis, hepatitis, uveitis, hypophysitis, and adrenalitis.⁴

Hypophysitis is inflammation of the pituitary gland, often with thickening of the pituitary stalk, resulting in dysfunction and hormone deficiencies. While primary hypophysitis is idiopathic, secondary hypophysitis is the result of an underlying condition such as exposure to an ICI. Immune-mediated inflammation of the pituitary gland in hypophysitis may disrupt corticotroph function, leading to adrenocorticotropic hormone (ACTH) deficiency. Early warning features are often vague and nonspecific, such as headache, fatigue, and weakness, which makes diagnosis challenging.^3,5

CASE PRESENTATION

A 73-year-old male veteran with a history of metastatic melanoma on ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks (a standard combination regimen for advanced melanoma) presented to the emergency department (ED) with 2 weeks of cough, nausea, and severe headache 3 weeks after cycle 2 of combination ICI therapy. The patient had undergone excision of multiple sites of melanoma in situ with recurrence and disease progression after 5 cycles of pembrolizumab. He was subsequently started on combination ICI therapy.

On ED arrival, the patient was afebrile and saturating well on room air. He was normotensive but found to have orthostatic blood pressure. Physical examination was remarkable for dry oral mucosa and decreased skin turgor. Initial laboratory results were significant for hyponatremia of 123 mmol/L (reference range, 136-145 mmol/L), low-normal free thyroxine (T4) level of 0.5 ng/dL (reference range, 0.6-1.2 ng/dL), a low total triiodothyronine level of 32.14 ng/dL (reference range, 85-178 ng/dL), and a low thyrotropin level of 0.19 mIU/L (reference range, 0.35-5.50 mIU/L). Serum osmolarity was low at 259 mOsm/kg (reference range, 285-315 mOsm/kg), urine sodium was high at 168 mEq/L (reference, 20 mEq/L), and urine osmolarity was inappropriately concentrated at 726 mOsm/kg (reference range, 250-1000 mOsm/kg). The patient was admitted for additional testing. His morning cortisol level was within normal limits at 15 mcg/dL (reference range, 6.7-22.5 mcg/dL).

Computed tomography (CT) of the patient’s head revealed no acute findings. Chest CT revealed posterior right lower lobe mild ground-glass opacities, with possible ICI-induced pneumonitis. The patient received fluid resuscitation. Given concern for syndrome of inappropriate antidiuretic hormone secretion, the patient was started on 3 g salt tablets 3 times a day and urea 30 g powder daily. The etiology of the abnormal thyroid levels was unclear to endocrinology at that time. The differential diagnosis included a nonthyroidal illness or central hypothyroidism.

The patient started levothyroxine 75 mcg due to abnormal thyroid levels and persistent fatigue and fludrocortisone 0.1 mg daily to manage orthostatic hypotension. His sodium levels improved to 132 mmol/L over 6 days and he was discharged with levothyroxine 75 mcg daily, fludrocortisone 0.1 mg daily, 3 g salt tabs 3 times a day, urea 30 g powder daily, as well as oral cefpodoxime 500 mg twice daily for 3 days and azithromycin 500 mg once daily for 2 days (for a total of 10 days of antibiotic therapy) to treat potential occult pneumonia.

The patient returned to the ED 3 days after discharge following an outpatient oncology appointment with ongoing severe headaches and persistent nausea. There was concern for recurrent hyponatremia. His sodium level was within normal limits at 133 mmol/L. Repeat morning cortisol was low-normal at 9 mcg/dL. Magnetic resonance imaging (MRI) of the brain was negative for metastatic disease, but showed a slight interval increase in size of the pituitary gland compared with an MRI from 6 months prior, with mild fullness and a slightly convex superior margin near homogeneous enhancement, raising concern for infection or hypophysitis (Figure 1).

The patient was readmitted to the general medicine service and was given intravenous hydrocortisone 100 mg every 8 hours because of concern for central adrenal insufficiency due to grade 3 hypophysitis in the setting of MRI imaging and severe headaches (Table 1). He was not hypotensive at the time of hydrocortisone initiation and other vital signs were stable. A cosyntropin stimulation test—a standard diagnostic test for central adrenal insufficiency—was not performed because the patient had already started high-dose hydrocortisone. The patient’s free T4 on this admission remained low at 0.6 ng/dL.

No adjustments were made to his levothyroxine dose given that he recently began the medication and levels may lag after initiation. After a 4-day hospitalization, the decision was made to continue with the steroid taper and follow up with outpatient endocrinology to obtain a cosyntropin stimulation test to complete a full assessment of his pituitary axis (Figure 2). Repeat thyroid function testing for levothyroxine titration was arranged. The levothyroxine dosage was later increased to 88 mcg daily, but the patient discontinued the medication and remained euthyroid. Endocrinology attributed a nonthyroidal illness as the etiology of his hypothyroidism, likely euthyroid sick syndrome in the setting of illness. His hydrocortisone was tapered during outpatient care and fludrocortisone was discontinued due to hypertension.

One month after his second discharge, the patient presented to the ED with 2 weeks of dizziness, associated lightheadedness, and blurred vision when standing from a sitting position. Upon assessment, symptoms were attributed to poor oral intake. The patient’s vital signs were again positive for orthostatic hypotension, though refractory to adequate fluid replacement. Laboratory testing was significant for a low ACTH level of 3.0 pg/mL (reference range, 7.2-63.3 pg/mL). Given that the patient had not received steroids for 1 week, he underwent a cosyntropin stimulation test, which revealed a blunted response supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis (Table 2).

The patient was again readmitted to the general medicine service. A brain MRI showed interval shrinkage of the pituitary gland compared to imaging one month prior, which was attributed to hydrocortisone treatment during this month. CT of the patient’s abdomen demonstrated normal-sized adrenal glands. Positron emission tomography (PET)/CT showed no evidence of pituitary or adrenal metastases. Endocrinology recommended reinitiating oral hydrocortisone 50 mg in the morning and 50 mg around 3 pm daily with fludrocortisone 0.2 mg once daily, which resulted in near resolution of the patient’s symptoms. He was discharged after a 14-day hospitalization with home physical therapy services and endocrinology, nephrology, and oncology follow-up appointments.

The patient was readmitted twice to the general medicine service over the next 6 months for complications from hydrocortisone and fludrocortisone treatment including hypokalemia. He followed up with outpatient clinicians until his death 14 months later. He did not restart ICI therapy, and eventually joined a clinical trial for other advanced melanoma treatments at another institution. The patient’s family consented to the publication of this case report with the accompanying images.

DISCUSSION

The combination of ipilimumab (anti-CTLA-4 monoclonal antibody) and nivolumab (anti-PD-1 monoclonal antibody) is FDA-approved for treatment of advanced melanoma with the goal of harnessing complementary and synergistic mechanisms of dual therapy.^6-8 Combination therapy, however, can increase the incidence of irAEs, which are often endocrine-related and more common in patients treated with dual immunotherapy than with monotherapy.⁹ Hypophysitis has the lowest reported fatality rate among ICI-related irAEs (< 1%), compared with higher mortality rates seen in myocarditis (25%-50%) and pneumonitis (10%-20%).^4,10

The patient initially presented with ICI-related hypothyroidism, later identified as secondary (central) hypothyroidism. He was treated with levothyroxine until central hypothyroidism was confirmed. Subsequently, the patient developed headache, poor appetite, and lightheadedness, with MRI findings suggestive of hypophysitis, for which he was started on hydrocortisone. A component of primary adrenal insufficiency was initially considered, given the low ACTH level and blunted response to cosyntropin stimulation following prior high-dose steroid therapy. However, CT imaging demonstrated normal adrenal morphology without atrophy, supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis.

The estimated incidence of ICI-induced hypophysitis is 1.5% to 13.3% with anti-CTLA-4 agents, 0.3% to 3.0% with anti-PD-1 agents, and can be as high as 12.8% with combination therapy.¹ ICI-induced hypophysitis is believed to arise from the direct binding of ICI antibodies to their targets on anterior pituitary cells, such as corticotrophs, thyrotrophs, and gonadotrophs, triggering an immune response. One theory for targeting these cells is high CTLA-4 expression in the anterior pituitary gland.¹¹ PD-1 therapies tend to manifest as either hypothyroidism, hyperthyroidism, Graves’ disease, diabetes, or adrenal insufficiency.¹⁰

A concern in patients with advanced melanoma is metastasis. Melanoma has a high propensity for brain metastasis.¹² There was moderate suspicion for pituitary gland metastasis in this case, though pituitary metastasis more often manifests with symptoms of posterior pituitary gland deficiency, such as polyuria and polydipsia.¹³ The adrenal gland is the fourth-most common site for melanoma metastases, after the lung, liver, and bone.¹⁴ This patient had no evidence of pituitary or adrenal metastases on PET/CT. Therefore, his symptoms were most likely due to ICI therapy. Cases of ≥ 1 endocrine dysfunction have been reported as an ICI therapy irAE.¹⁵ In these situations, diagnosing primary and central adrenal insufficiency in the same patient is complex because hormone profiles are intertwined.

Many patients who develop hypophysitis from ICI therapy will require permanent replacement therapy. It is unclear whether low-dose replacement steroids have a significant effect on the efficacy of ICIs. Given that ICI treatment works by enhancing the immune system, medications that suppress the body’s immune system, such as steroids, could interfere with treatment efficacy. However, there are speculations that the development of irAEs is an indicator of effective treatment. In a phase 1 trial of a CTLA-4 blocker in patients with metastatic melanoma, there was a correlation between reduced CTLA-4 expression as well as low rates of melanoma recurrence and a higher incidence of irAEs.¹⁶

When assessing patients on ICI treatment, clinicians must remain vigilant for all potential irAEs, especially in patients receiving combination therapy. ICI-induced irAEs can present with vague and nonspecific symptoms. Concurrent endocrine irAEs, such as hypophysitis with thyroiditis or adrenalitis, are not uncommon in combination therapy and can complicate interpretation of hormone profiles. It is prudent for clinicians to review known risk factors. Hypophysitis is typically associated with older adult male patients.^17,18

The irAEs of ICI therapy deeply affected the quality of life of the patient in this case, as he was often experiencing many of the clinical symptoms of his hormone insufficiencies as well as the treatment modalities, thus requiring repeated hospital admissions. The risks and benefits of continuing ICI therapy should be an ongoing discussion between the physician and patient and should take into account the acuity and severity of irAEs and oncological disease burden, among other variables. Given the severity of his AEs, the patient stopped ICI therapy and instead opted to enroll in a clinical trial at another institution for continued alternative treatments.

CONCLUSIONS

This case offers a lesson in the diagnostic challenges of vague symptoms in patients with cancer who are receiving ICI therapy. ICI therapy is widely used in the treatment of solid malignancies, and as its use increases, it is expected that clinicians will likely see more cases of irAEs in hospitalized patients. The vague presentation of irAEs can often lead to treatment delays, especially when > 1 irAE presents concurrently. There are ongoing studies researching potential ways to predict the likelihood of developing these irAEs. It is imperative that clinicians are aware of these ICI-related complications and that more research be conducted to understand patient quality of life and treatment guidance based on irAE severity and disease burden.