Mixed Topics

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.

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.

Hypergammaglobulinemic purpura of Waldenström (HGPW) is a rare chronic skin condition characterized by recurrent petechiae and purpura on the lower legs, elevated erythrocyte sedimentation rate (ESR), polyclonal hypergammaglobulinemia, and elevated titers of IgG and IgA rheumatoid factor (RF).^1,2 This condition can be a primary (idiopathic) syndrome or secondary to an autoimmune connective tissue disease. We report 2 cases of patients with episodic skin eruptions that were consistent with HGPW.

Patient 1

A 41-year-old woman presented to our clinic with a rash on the legs of 20 years’ duration. She had first been evaluated at an outside dermatology clinic 5 years prior, and a biopsy performed at the time led to a diagnosis of leukocytoclastic vasculitis (LCV). The rash affected her ability to work, as her job involved standing for prolonged periods of time. If she stood for more than 2 hours, she experienced leg pain and worsening of the rash. The rash also was exacerbated by nonsteroidal anti-inflammatory drugs but improved with multiple days of rest. She had been on dapsone 75 mg daily, but the dose was reduced to 50 mg daily after elevated liver enzymes were noted. This regimen had improved her rash for 4 years until she experienced breakthrough symptoms, leading to her re-evaluation. Prior outside therapies included systemic steroids with limited response, then oral dapsone.

Upon our initial evaluation, laboratory tests were notable for an elevated ESR of 43 mm/h. Results of antinuclear antibody (ANA), anti–double-stranded DNA, extractable nuclear antigen, RF, HIV, cryoglobulin, hepatitis panel, serum protein electrophoresis, complete blood count, basic metabolic panel, urinalysis, and thyroid-stimulating hormone testing were within reference range. Physical examination revealed scattered pinpoint violaceous papules on the lower extremities. Photographs on the patient’s phone from 2 months prior showed a more robust manifestation with diffuse palpable purpura on the lower extremities.

At 3-year follow-up, laboratory evaluation including ESR, IgA, IgG, IgM, serum protein electrophoresis with reflex immunofixation, and Mycoplasma pneumoniae IgM/IgG showed elevated ESR (29 mm/h) and IgG (1654 mg), with otherwise unremarkable results. Because of the extended period of time since the previous biopsy, a repeat biopsy with hematoxylin and eosin staining and direct immunofluorescence was performed. Biopsy from the left calf demonstrated a perivascular and interstitial infiltrate with lymphocytes and neutrophils with nuclear debris and hemorrhage (Figure 1). Direct immunofluorescence was positive for IgA, C3, and fibrin within vessel walls (Figure 2).

Overall the features of recurrent dependent palpable purpura and the pathology findings were consistent with evolving LCV. Given the chronic nature of her symptoms; flares with prolonged standing; presence of polyclonol hypergammaglobulinemia; and negative evaluation for underling autoimmune disease, infection, and malignancy, the clinicopathologic correlation was most consistent with primary HGPW. The patient was treated with colchicine 0.6 mg twice daily and continued on dapsone 50 mg daily. The colchicine was reduced to once daily due to diarrhea. Nonetheless, the patient had less frequent and less intense flares. On follow-up examination 4 months later, she was satisfied with her current level of control and did not wish to escalate her treatment.

Patient 2

A 53-year-old woman with a 1-year history of sicca symptoms presented for evaluation of a transient rash on the legs and feet of 2 months’ duration. At that time, the heels began to feel swollen. The rash was painful on the feet and caused calf myalgias. She did not endorse pruritus or pain elsewhere. The rash was not associated with prolonged standing, walking, or wearing tight socks. She had no fevers, chills, or joint pain. Flares would come and go within a week.

Laboratory evaluation was notable for an ANA of 1:1280 (reference range, 1:80) with positive anti-Ro/SS-A and anti-La/SS-B. Rheumatology evaluation confirmed the diagnosis of Sjögren syndrome. Physical examination revealed minimal petechiae on the heel of the left foot. Photographs from the previous month provided by the patient revealed linear petechiae of the lower extremities with postinflammatory hyperpigmentation (Figure 3). An additional photograph from the prior week revealed more diffuse erythematous plaques without secondary changes on the feet up to the ankles (Figure 4).

The patient experienced a recurrence of the rash within a month and had an expedited visit for biopsies, which demonstrated mixed inflammation with neutrophils, nuclear debris, hemorrhage, and C3 and fibrin immunoreactants within vessel walls. As with patient 1, the features were consistent with LCV.

In the context of Sjögren syndrome and elevated IgG and RF, the patient’s symptoms were consistent with secondary HGPW. Rheumatology prescribed hydroxychloroquine 400 mg daily alternating every other day with 300 mg and 0.6 mg of colchicine. The rash cleared within approximately 1 month.

Comment

Also known as benign hypergammaglobulinemic purpura, HGPW is a rare purpuric eruption that is exacerbated with prolonged standing and increased hydrostatic pressure.³ First described in 1943, HGPW is characterized by recurrent petechiae, purpuric macules, or palpable purpura, depending on the degree of inflammation.^1,4,5 It typically is distributed on the bilateral lower extremities or trunk. Chronic postinflammatory hyperpigmentation with hemosiderin deposition also can be observed. The lesions last for up to 1 week at a time and are frequently asymmetrically distributed.²

Patient 1 demonstrated the typical clinical manifestations and laboratory findings of HGPW. The eruption often is asymptomatic, and patients report that the skin worsens with prolonged immobilization, walking, and wearing of tight clothing.^2,6-8 Increased hydrostatic pressure is thought to cause the erythrocyte extravasation, resulting in the purpuric lesions. However, patient 2 was less typical, presenting with prominent skin pain and myalgias. Some patients experience discomfort, burning dysesthesia, pruritus, and swelling of the affected area.¹ Hypergammaglobulinemic purpura of Waldenström is a chronic condition. Recurrent episodes can occur yearly or as frequently as multiple times per week.⁸

Women are most commonly diagnosed with HGPW, but many cases have been reported in children.^9,10 In spite of the “condition being considered largely benign,” women with a diagnosis of HGPW require preconception counseling due to risks for congenital heart block, neonatal lupus, intrauterine growth restriction, intrauterine demise, and preterm birth.^7,9,11,12

The etiology of the rash remains undefined. It is hypothesized that it develops due to underlying immune dysregulation with associated immune complex formation and deposition in the blood vessel wall.¹ Small circulating immune complexes containing IgG or IgA RF are a specific finding in patients with HGPW. These highly soluble autoantibodies are hypothesized to influence the rapid appearance and disappearance of lesions.¹

The role of hypergammaglobulinemia in the pathogenesis of HGPW is unknown.¹³ Serum IgG levels do not correlate with the appearance and regression of lesions.¹³ Additionally, hypergammaglobulinemia can be found in autoimmune connective tissue diseases such as Sjögren syndrome without resulting cutaneous vasculitis.¹³

Characteristic laboratory abnormalities include polyclonal hypergammaglobulinemia, elevated ESR, and elevated IgA and IgG RF. Positive ANA and anti-Ro/SS-A and anti-La/SS-B indicate a potential to develop autoimmune connective tissue diseases, including Sjögren syndrome, systemic lupus erythematosus, and rheumatoid arthritis.^1,14 Additional recommended workup includes complete blood counts, metabolic panel, complement levels, urinalysis, and urine protein/creatinine ratio.⁹ Repeat monitoring for antibodies, inflammatory markers, immunoglobulins, and RF should be completed 3 months after initial evaluation. Patients with symptoms of systemic disease should have laboratory evaluation repeated.

Erythrocyte sedimentation rate abnormalities are a defining feature of HGPW. Erythrocyte sedimentation rate is an inexpensive and commonly ordered inflammatory marker that measures settling of erythrocytes within 1 hour and can be elevated by plasma proteins such as gamma globulins. Erythrocyte sedimentation rate is nonspecific and is not sensitive as a general screening test. It can be elevated by autoimmune connective tissue disease, infection, and malignancy.¹⁵ Notably, ESR is not specific to inflammation. Confounding factors include red blood cell abnormalities, physiologic factors, and the quantity of plasma proteins such as fibrinogen.¹⁶ These positively charged plasma proteins neutralize the negative surface charge of erythrocytes, resulting in erythrocytes that are prone to rouleaux formation.¹⁷

The utility of the ESR is to expedite the diagnostic process and indicate the need for further workup.¹⁶ Patients with mild to moderate elevation in ESR without an identified etiology should have repeat testing to confirm the validity of the laboratory value. Patients with an ESR higher than 100 mm/h are more likely have an infectious cause, collagen vascular disease, or underlying malignancy.¹⁵ Elevation of ESR in HGPW is likely a result of increased immunoglobulins and acute phase proteins.¹⁷

The histopathology of HGPW is nonspecific and may show LCV or erythrocyte extravasation with mild perivascular lymphocytic infiltrates.^1,9 Direct immunofluorescence testing may show immune-complex deposition.⁵ For patients with evidence of LCV, the biopsy of a fresh but well-developed lesion is important in confirming the presence of vasculitis.¹ Incorrect sampling may lead to underreporting of LCV with HGPW.³

Associated underlying conditions include Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis, hepatitis C, and hematologic malignancies.^1,3 Our patients demonstrated primary and secondary causes of HGPW. Patient 1’s case was not associated with any autoimmune disease but demonstrated chronic recurrence. Patient 2’s case was secondary to Sjögren syndrome.

In patients with suspected HGPW, differential diagnoses to consider include IgA vasculitis, cutaneous small vessel vasculitis, pigmented purpuric dermatoses, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, and scurvy.^1,4

For patients with primary disease, treatment is focused on symptom management with compression stockings and avoidance of triggers. Compression stockings may exacerbate purpura but can provide symptom relief in some individuals.¹⁴ Patients with frequent or painful episodes can benefit from systemic treatment. In patients with an underlying disease, systemic therapies include prednisone, hydroxychloroquine, indomethacin, colchicine, chlorambucil, mycophenolate mofetil, rituximab, and plasmapheresis. Dapsone, a treatment for LCV, has been reported to be beneficial in patients with a neutrophilic infiltrate.¹⁸

Hypergammaglobulinemic purpura of Waldenström requires a thorough evaluation due to its association with underlying systemic disease. Patients without evidence of systemic disease should receive long-term monitoring and coordination of care with rheumatology, as systemic manifestations can develop years after the initial cutaneous manifestation. Dermatologists should consider HGPW in the differential diagnosis for cutaneous vasculitides.

Hypergammaglobulinemic purpura of Waldenström (HGPW) is a rare chronic skin condition characterized by recurrent petechiae and purpura on the lower legs, elevated erythrocyte sedimentation rate (ESR), polyclonal hypergammaglobulinemia, and elevated titers of IgG and IgA rheumatoid factor (RF).^1,2 This condition can be a primary (idiopathic) syndrome or secondary to an autoimmune connective tissue disease. We report 2 cases of patients with episodic skin eruptions that were consistent with HGPW.

Patient 1

A 41-year-old woman presented to our clinic with a rash on the legs of 20 years’ duration. She had first been evaluated at an outside dermatology clinic 5 years prior, and a biopsy performed at the time led to a diagnosis of leukocytoclastic vasculitis (LCV). The rash affected her ability to work, as her job involved standing for prolonged periods of time. If she stood for more than 2 hours, she experienced leg pain and worsening of the rash. The rash also was exacerbated by nonsteroidal anti-inflammatory drugs but improved with multiple days of rest. She had been on dapsone 75 mg daily, but the dose was reduced to 50 mg daily after elevated liver enzymes were noted. This regimen had improved her rash for 4 years until she experienced breakthrough symptoms, leading to her re-evaluation. Prior outside therapies included systemic steroids with limited response, then oral dapsone.

Upon our initial evaluation, laboratory tests were notable for an elevated ESR of 43 mm/h. Results of antinuclear antibody (ANA), anti–double-stranded DNA, extractable nuclear antigen, RF, HIV, cryoglobulin, hepatitis panel, serum protein electrophoresis, complete blood count, basic metabolic panel, urinalysis, and thyroid-stimulating hormone testing were within reference range. Physical examination revealed scattered pinpoint violaceous papules on the lower extremities. Photographs on the patient’s phone from 2 months prior showed a more robust manifestation with diffuse palpable purpura on the lower extremities.

At 3-year follow-up, laboratory evaluation including ESR, IgA, IgG, IgM, serum protein electrophoresis with reflex immunofixation, and Mycoplasma pneumoniae IgM/IgG showed elevated ESR (29 mm/h) and IgG (1654 mg), with otherwise unremarkable results. Because of the extended period of time since the previous biopsy, a repeat biopsy with hematoxylin and eosin staining and direct immunofluorescence was performed. Biopsy from the left calf demonstrated a perivascular and interstitial infiltrate with lymphocytes and neutrophils with nuclear debris and hemorrhage (Figure 1). Direct immunofluorescence was positive for IgA, C3, and fibrin within vessel walls (Figure 2).

Overall the features of recurrent dependent palpable purpura and the pathology findings were consistent with evolving LCV. Given the chronic nature of her symptoms; flares with prolonged standing; presence of polyclonol hypergammaglobulinemia; and negative evaluation for underling autoimmune disease, infection, and malignancy, the clinicopathologic correlation was most consistent with primary HGPW. The patient was treated with colchicine 0.6 mg twice daily and continued on dapsone 50 mg daily. The colchicine was reduced to once daily due to diarrhea. Nonetheless, the patient had less frequent and less intense flares. On follow-up examination 4 months later, she was satisfied with her current level of control and did not wish to escalate her treatment.

Patient 2

A 53-year-old woman with a 1-year history of sicca symptoms presented for evaluation of a transient rash on the legs and feet of 2 months’ duration. At that time, the heels began to feel swollen. The rash was painful on the feet and caused calf myalgias. She did not endorse pruritus or pain elsewhere. The rash was not associated with prolonged standing, walking, or wearing tight socks. She had no fevers, chills, or joint pain. Flares would come and go within a week.

Laboratory evaluation was notable for an ANA of 1:1280 (reference range, 1:80) with positive anti-Ro/SS-A and anti-La/SS-B. Rheumatology evaluation confirmed the diagnosis of Sjögren syndrome. Physical examination revealed minimal petechiae on the heel of the left foot. Photographs from the previous month provided by the patient revealed linear petechiae of the lower extremities with postinflammatory hyperpigmentation (Figure 3). An additional photograph from the prior week revealed more diffuse erythematous plaques without secondary changes on the feet up to the ankles (Figure 4).

The patient experienced a recurrence of the rash within a month and had an expedited visit for biopsies, which demonstrated mixed inflammation with neutrophils, nuclear debris, hemorrhage, and C3 and fibrin immunoreactants within vessel walls. As with patient 1, the features were consistent with LCV.

In the context of Sjögren syndrome and elevated IgG and RF, the patient’s symptoms were consistent with secondary HGPW. Rheumatology prescribed hydroxychloroquine 400 mg daily alternating every other day with 300 mg and 0.6 mg of colchicine. The rash cleared within approximately 1 month.

Comment

Also known as benign hypergammaglobulinemic purpura, HGPW is a rare purpuric eruption that is exacerbated with prolonged standing and increased hydrostatic pressure.³ First described in 1943, HGPW is characterized by recurrent petechiae, purpuric macules, or palpable purpura, depending on the degree of inflammation.^1,4,5 It typically is distributed on the bilateral lower extremities or trunk. Chronic postinflammatory hyperpigmentation with hemosiderin deposition also can be observed. The lesions last for up to 1 week at a time and are frequently asymmetrically distributed.²

Patient 1 demonstrated the typical clinical manifestations and laboratory findings of HGPW. The eruption often is asymptomatic, and patients report that the skin worsens with prolonged immobilization, walking, and wearing of tight clothing.^2,6-8 Increased hydrostatic pressure is thought to cause the erythrocyte extravasation, resulting in the purpuric lesions. However, patient 2 was less typical, presenting with prominent skin pain and myalgias. Some patients experience discomfort, burning dysesthesia, pruritus, and swelling of the affected area.¹ Hypergammaglobulinemic purpura of Waldenström is a chronic condition. Recurrent episodes can occur yearly or as frequently as multiple times per week.⁸

Women are most commonly diagnosed with HGPW, but many cases have been reported in children.^9,10 In spite of the “condition being considered largely benign,” women with a diagnosis of HGPW require preconception counseling due to risks for congenital heart block, neonatal lupus, intrauterine growth restriction, intrauterine demise, and preterm birth.^7,9,11,12

The etiology of the rash remains undefined. It is hypothesized that it develops due to underlying immune dysregulation with associated immune complex formation and deposition in the blood vessel wall.¹ Small circulating immune complexes containing IgG or IgA RF are a specific finding in patients with HGPW. These highly soluble autoantibodies are hypothesized to influence the rapid appearance and disappearance of lesions.¹

The role of hypergammaglobulinemia in the pathogenesis of HGPW is unknown.¹³ Serum IgG levels do not correlate with the appearance and regression of lesions.¹³ Additionally, hypergammaglobulinemia can be found in autoimmune connective tissue diseases such as Sjögren syndrome without resulting cutaneous vasculitis.¹³

Characteristic laboratory abnormalities include polyclonal hypergammaglobulinemia, elevated ESR, and elevated IgA and IgG RF. Positive ANA and anti-Ro/SS-A and anti-La/SS-B indicate a potential to develop autoimmune connective tissue diseases, including Sjögren syndrome, systemic lupus erythematosus, and rheumatoid arthritis.^1,14 Additional recommended workup includes complete blood counts, metabolic panel, complement levels, urinalysis, and urine protein/creatinine ratio.⁹ Repeat monitoring for antibodies, inflammatory markers, immunoglobulins, and RF should be completed 3 months after initial evaluation. Patients with symptoms of systemic disease should have laboratory evaluation repeated.

Erythrocyte sedimentation rate abnormalities are a defining feature of HGPW. Erythrocyte sedimentation rate is an inexpensive and commonly ordered inflammatory marker that measures settling of erythrocytes within 1 hour and can be elevated by plasma proteins such as gamma globulins. Erythrocyte sedimentation rate is nonspecific and is not sensitive as a general screening test. It can be elevated by autoimmune connective tissue disease, infection, and malignancy.¹⁵ Notably, ESR is not specific to inflammation. Confounding factors include red blood cell abnormalities, physiologic factors, and the quantity of plasma proteins such as fibrinogen.¹⁶ These positively charged plasma proteins neutralize the negative surface charge of erythrocytes, resulting in erythrocytes that are prone to rouleaux formation.¹⁷

The utility of the ESR is to expedite the diagnostic process and indicate the need for further workup.¹⁶ Patients with mild to moderate elevation in ESR without an identified etiology should have repeat testing to confirm the validity of the laboratory value. Patients with an ESR higher than 100 mm/h are more likely have an infectious cause, collagen vascular disease, or underlying malignancy.¹⁵ Elevation of ESR in HGPW is likely a result of increased immunoglobulins and acute phase proteins.¹⁷

The histopathology of HGPW is nonspecific and may show LCV or erythrocyte extravasation with mild perivascular lymphocytic infiltrates.^1,9 Direct immunofluorescence testing may show immune-complex deposition.⁵ For patients with evidence of LCV, the biopsy of a fresh but well-developed lesion is important in confirming the presence of vasculitis.¹ Incorrect sampling may lead to underreporting of LCV with HGPW.³

Associated underlying conditions include Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis, hepatitis C, and hematologic malignancies.^1,3 Our patients demonstrated primary and secondary causes of HGPW. Patient 1’s case was not associated with any autoimmune disease but demonstrated chronic recurrence. Patient 2’s case was secondary to Sjögren syndrome.

In patients with suspected HGPW, differential diagnoses to consider include IgA vasculitis, cutaneous small vessel vasculitis, pigmented purpuric dermatoses, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, and scurvy.^1,4

For patients with primary disease, treatment is focused on symptom management with compression stockings and avoidance of triggers. Compression stockings may exacerbate purpura but can provide symptom relief in some individuals.¹⁴ Patients with frequent or painful episodes can benefit from systemic treatment. In patients with an underlying disease, systemic therapies include prednisone, hydroxychloroquine, indomethacin, colchicine, chlorambucil, mycophenolate mofetil, rituximab, and plasmapheresis. Dapsone, a treatment for LCV, has been reported to be beneficial in patients with a neutrophilic infiltrate.¹⁸

Hypergammaglobulinemic purpura of Waldenström requires a thorough evaluation due to its association with underlying systemic disease. Patients without evidence of systemic disease should receive long-term monitoring and coordination of care with rheumatology, as systemic manifestations can develop years after the initial cutaneous manifestation. Dermatologists should consider HGPW in the differential diagnosis for cutaneous vasculitides.

Hypergammaglobulinemic purpura of Waldenström (HGPW) is a rare chronic skin condition characterized by recurrent petechiae and purpura on the lower legs, elevated erythrocyte sedimentation rate (ESR), polyclonal hypergammaglobulinemia, and elevated titers of IgG and IgA rheumatoid factor (RF).^1,2 This condition can be a primary (idiopathic) syndrome or secondary to an autoimmune connective tissue disease. We report 2 cases of patients with episodic skin eruptions that were consistent with HGPW.

Patient 1

A 41-year-old woman presented to our clinic with a rash on the legs of 20 years’ duration. She had first been evaluated at an outside dermatology clinic 5 years prior, and a biopsy performed at the time led to a diagnosis of leukocytoclastic vasculitis (LCV). The rash affected her ability to work, as her job involved standing for prolonged periods of time. If she stood for more than 2 hours, she experienced leg pain and worsening of the rash. The rash also was exacerbated by nonsteroidal anti-inflammatory drugs but improved with multiple days of rest. She had been on dapsone 75 mg daily, but the dose was reduced to 50 mg daily after elevated liver enzymes were noted. This regimen had improved her rash for 4 years until she experienced breakthrough symptoms, leading to her re-evaluation. Prior outside therapies included systemic steroids with limited response, then oral dapsone.

Upon our initial evaluation, laboratory tests were notable for an elevated ESR of 43 mm/h. Results of antinuclear antibody (ANA), anti–double-stranded DNA, extractable nuclear antigen, RF, HIV, cryoglobulin, hepatitis panel, serum protein electrophoresis, complete blood count, basic metabolic panel, urinalysis, and thyroid-stimulating hormone testing were within reference range. Physical examination revealed scattered pinpoint violaceous papules on the lower extremities. Photographs on the patient’s phone from 2 months prior showed a more robust manifestation with diffuse palpable purpura on the lower extremities.

At 3-year follow-up, laboratory evaluation including ESR, IgA, IgG, IgM, serum protein electrophoresis with reflex immunofixation, and Mycoplasma pneumoniae IgM/IgG showed elevated ESR (29 mm/h) and IgG (1654 mg), with otherwise unremarkable results. Because of the extended period of time since the previous biopsy, a repeat biopsy with hematoxylin and eosin staining and direct immunofluorescence was performed. Biopsy from the left calf demonstrated a perivascular and interstitial infiltrate with lymphocytes and neutrophils with nuclear debris and hemorrhage (Figure 1). Direct immunofluorescence was positive for IgA, C3, and fibrin within vessel walls (Figure 2).

Overall the features of recurrent dependent palpable purpura and the pathology findings were consistent with evolving LCV. Given the chronic nature of her symptoms; flares with prolonged standing; presence of polyclonol hypergammaglobulinemia; and negative evaluation for underling autoimmune disease, infection, and malignancy, the clinicopathologic correlation was most consistent with primary HGPW. The patient was treated with colchicine 0.6 mg twice daily and continued on dapsone 50 mg daily. The colchicine was reduced to once daily due to diarrhea. Nonetheless, the patient had less frequent and less intense flares. On follow-up examination 4 months later, she was satisfied with her current level of control and did not wish to escalate her treatment.

Patient 2

A 53-year-old woman with a 1-year history of sicca symptoms presented for evaluation of a transient rash on the legs and feet of 2 months’ duration. At that time, the heels began to feel swollen. The rash was painful on the feet and caused calf myalgias. She did not endorse pruritus or pain elsewhere. The rash was not associated with prolonged standing, walking, or wearing tight socks. She had no fevers, chills, or joint pain. Flares would come and go within a week.

Laboratory evaluation was notable for an ANA of 1:1280 (reference range, 1:80) with positive anti-Ro/SS-A and anti-La/SS-B. Rheumatology evaluation confirmed the diagnosis of Sjögren syndrome. Physical examination revealed minimal petechiae on the heel of the left foot. Photographs from the previous month provided by the patient revealed linear petechiae of the lower extremities with postinflammatory hyperpigmentation (Figure 3). An additional photograph from the prior week revealed more diffuse erythematous plaques without secondary changes on the feet up to the ankles (Figure 4).

The patient experienced a recurrence of the rash within a month and had an expedited visit for biopsies, which demonstrated mixed inflammation with neutrophils, nuclear debris, hemorrhage, and C3 and fibrin immunoreactants within vessel walls. As with patient 1, the features were consistent with LCV.

In the context of Sjögren syndrome and elevated IgG and RF, the patient’s symptoms were consistent with secondary HGPW. Rheumatology prescribed hydroxychloroquine 400 mg daily alternating every other day with 300 mg and 0.6 mg of colchicine. The rash cleared within approximately 1 month.

Comment

Also known as benign hypergammaglobulinemic purpura, HGPW is a rare purpuric eruption that is exacerbated with prolonged standing and increased hydrostatic pressure.³ First described in 1943, HGPW is characterized by recurrent petechiae, purpuric macules, or palpable purpura, depending on the degree of inflammation.^1,4,5 It typically is distributed on the bilateral lower extremities or trunk. Chronic postinflammatory hyperpigmentation with hemosiderin deposition also can be observed. The lesions last for up to 1 week at a time and are frequently asymmetrically distributed.²

Patient 1 demonstrated the typical clinical manifestations and laboratory findings of HGPW. The eruption often is asymptomatic, and patients report that the skin worsens with prolonged immobilization, walking, and wearing of tight clothing.^2,6-8 Increased hydrostatic pressure is thought to cause the erythrocyte extravasation, resulting in the purpuric lesions. However, patient 2 was less typical, presenting with prominent skin pain and myalgias. Some patients experience discomfort, burning dysesthesia, pruritus, and swelling of the affected area.¹ Hypergammaglobulinemic purpura of Waldenström is a chronic condition. Recurrent episodes can occur yearly or as frequently as multiple times per week.⁸

Women are most commonly diagnosed with HGPW, but many cases have been reported in children.^9,10 In spite of the “condition being considered largely benign,” women with a diagnosis of HGPW require preconception counseling due to risks for congenital heart block, neonatal lupus, intrauterine growth restriction, intrauterine demise, and preterm birth.^7,9,11,12

The etiology of the rash remains undefined. It is hypothesized that it develops due to underlying immune dysregulation with associated immune complex formation and deposition in the blood vessel wall.¹ Small circulating immune complexes containing IgG or IgA RF are a specific finding in patients with HGPW. These highly soluble autoantibodies are hypothesized to influence the rapid appearance and disappearance of lesions.¹

The role of hypergammaglobulinemia in the pathogenesis of HGPW is unknown.¹³ Serum IgG levels do not correlate with the appearance and regression of lesions.¹³ Additionally, hypergammaglobulinemia can be found in autoimmune connective tissue diseases such as Sjögren syndrome without resulting cutaneous vasculitis.¹³

Characteristic laboratory abnormalities include polyclonal hypergammaglobulinemia, elevated ESR, and elevated IgA and IgG RF. Positive ANA and anti-Ro/SS-A and anti-La/SS-B indicate a potential to develop autoimmune connective tissue diseases, including Sjögren syndrome, systemic lupus erythematosus, and rheumatoid arthritis.^1,14 Additional recommended workup includes complete blood counts, metabolic panel, complement levels, urinalysis, and urine protein/creatinine ratio.⁹ Repeat monitoring for antibodies, inflammatory markers, immunoglobulins, and RF should be completed 3 months after initial evaluation. Patients with symptoms of systemic disease should have laboratory evaluation repeated.

Erythrocyte sedimentation rate abnormalities are a defining feature of HGPW. Erythrocyte sedimentation rate is an inexpensive and commonly ordered inflammatory marker that measures settling of erythrocytes within 1 hour and can be elevated by plasma proteins such as gamma globulins. Erythrocyte sedimentation rate is nonspecific and is not sensitive as a general screening test. It can be elevated by autoimmune connective tissue disease, infection, and malignancy.¹⁵ Notably, ESR is not specific to inflammation. Confounding factors include red blood cell abnormalities, physiologic factors, and the quantity of plasma proteins such as fibrinogen.¹⁶ These positively charged plasma proteins neutralize the negative surface charge of erythrocytes, resulting in erythrocytes that are prone to rouleaux formation.¹⁷

The utility of the ESR is to expedite the diagnostic process and indicate the need for further workup.¹⁶ Patients with mild to moderate elevation in ESR without an identified etiology should have repeat testing to confirm the validity of the laboratory value. Patients with an ESR higher than 100 mm/h are more likely have an infectious cause, collagen vascular disease, or underlying malignancy.¹⁵ Elevation of ESR in HGPW is likely a result of increased immunoglobulins and acute phase proteins.¹⁷

The histopathology of HGPW is nonspecific and may show LCV or erythrocyte extravasation with mild perivascular lymphocytic infiltrates.^1,9 Direct immunofluorescence testing may show immune-complex deposition.⁵ For patients with evidence of LCV, the biopsy of a fresh but well-developed lesion is important in confirming the presence of vasculitis.¹ Incorrect sampling may lead to underreporting of LCV with HGPW.³

Associated underlying conditions include Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis, hepatitis C, and hematologic malignancies.^1,3 Our patients demonstrated primary and secondary causes of HGPW. Patient 1’s case was not associated with any autoimmune disease but demonstrated chronic recurrence. Patient 2’s case was secondary to Sjögren syndrome.

In patients with suspected HGPW, differential diagnoses to consider include IgA vasculitis, cutaneous small vessel vasculitis, pigmented purpuric dermatoses, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, and scurvy.^1,4

For patients with primary disease, treatment is focused on symptom management with compression stockings and avoidance of triggers. Compression stockings may exacerbate purpura but can provide symptom relief in some individuals.¹⁴ Patients with frequent or painful episodes can benefit from systemic treatment. In patients with an underlying disease, systemic therapies include prednisone, hydroxychloroquine, indomethacin, colchicine, chlorambucil, mycophenolate mofetil, rituximab, and plasmapheresis. Dapsone, a treatment for LCV, has been reported to be beneficial in patients with a neutrophilic infiltrate.¹⁸

Hypergammaglobulinemic purpura of Waldenström requires a thorough evaluation due to its association with underlying systemic disease. Patients without evidence of systemic disease should receive long-term monitoring and coordination of care with rheumatology, as systemic manifestations can develop years after the initial cutaneous manifestation. Dermatologists should consider HGPW in the differential diagnosis for cutaneous vasculitides.

THE DIAGNOSIS: Cutaneous Rosai-Dorfman Disease

The clinical differential diagnosis in our patient included a broad array of soft-tissue neoplasms ranging from benign entities to sarcomas. Histology was notable for a dense, dermal-based, lymphohistiocytic infiltrate with alternating hypocellular and hypercellular areas imparting a marbled appearance on low-power view (Figure, A). Further immunohistochemical staining revealed large, S100-positive histiocytes containing intact inflammatory cells (emperipolesis), which confirmed a diagnosis of cutaneous Rosai-Dorfman disease (RDD)(Figure, B). Our patient elected to undergo surgical removal of the mass, and he will be monitored for recurrence.

Rosai-Dorfman disease is a non–Langerhans cell histiocytosis that most commonly affects the lymph nodes but can affect other organs including the skin. Rosai-Dorfman disease initially was documented in the medical literature in 1969 by Rosai and Dorfman¹ as benign sinus histiocytosis with massive lymphadenopathy. Classic RDD usually manifests with painless cervical lymphadenopathy in children or young adults along with fever, leukocytosis, anemia, polyclonal hypergammaglobulinemia, and elevated inflammatory markers.^2,3 Extranodal involvement has been reported in up to 43% of cases, with common sites including the skin, central nervous system, and gastrointestinal tract.^3,4

Cutaneous RDD is a distinct, less common clinical entity that is limited to the skin and shows no nodal involvement or systemic symptoms such as fever, night sweats, or weight loss.⁵ Cutaneous RDD classically manifests with localized indurated papules and plaques, but it can manifest with tumorlike lesions in the subcutaneous tissues.⁶ Cutaneous RDD is very rare, with fewer than 200 known case reports in the literature as of 2014; in comparison to classic forms of RDD, cutaneous RDD has a female predominance.^7,8 There are few reports of isolated cutaneous disease manifesting as soft-tissue masses, and our case represents a rare case of cutaneous RDD manifesting as a solitary soft-tissue mass in the axilla.^9-11 Diagnosis of cutaneous RDD is challenging due to its variable clinical manifestations and nonspecific imaging findings, requiring clinicopathologic correlation.

Imaging of subcutaneous RDD lesions typically shows well-defined, irregularly shaped masses with homogenous enhancement on computed tomography/ magnetic resonance imaging. Additional imaging with positron emission tomography/computed tomography is recommended to examine for organ involvement, as RDD lesions have avid uptake.^12,13 Imaging may help differentiate RDD lesions from malignant neoplasms prior to biopsy. Additional workup includes baseline laboratory testing with inflammatory markers and a complete blood count for evaluation of laboratory abnormalities seen in classic RDD, including leukocytosis, anemia, or systemic inflammation.¹² Following imaging and laboratory testing, definitive diagnosis of RDD necessitates histopathologic examination.

Although cutaneous RDD is clinically distinct from its classic RDD counterpart, the conditions share the same characteristic histologic features.⁵ Histology is notable for a dense mixed inflammatory infiltrate comprised of large pale histiocytes exhibiting emperipolesis, lymphocytes, plasma cells, and occasional eosinophils and neutrophils. Histiocytes stain positive for CD68, CD163, and S100 and are negative for Langerhans cell markers CD1a and CD207.⁶

The etiology of RDD remains poorly understood. Classic RDD has been associated with both sporadic and familial forms, with somatic mutations identified in the mitogen-activated protein kinase/KRAS pathway in up to one-third of cases, and less frequently in the BRAF gene.^14,15 Germline mutations in familial cases of RDD have been identified in the SLC29A3 gene; mutations in this gene are associated with a spectrum of syndromes with histiocytosis and lymphadenopathy.^14,15 In contrast, molecular drivers have yet to be identified in cutaneous RDD lesions, and the current predominant hypothesis is that cutaneous RDD has a reactive or immunologic pathophysiology. Autoimmune diseases, infections, and lymphomas have been reported to co-occur with both classic and cutaneous RDD.¹⁵ While subclinical viral infections such as Epstein-Barr virus and human herpesvirus 6 have been identified in RDD cases, studies have failed to prove their role as pathogenic drivers of the disease.^14,16,17 Commonly reported comorbidities include systemic lupus erythematous, diabetes, hemolytic anemia, acute/chronic uveitis (though it is controversial whether these cases represent orbital involvement in systemic RDD), and Crohn disease.^7,8,18,19 Immunohistochemical findings have supported that cells within RDD are activated monocytes responding to T-cell cytokine signaling following an infectious or immunologic insult.^20,21

Consensus guidelines on treatment for cutaneous RDD recommend either observation for asymptomatic disease or surgical excision for unifocal lesions with consideration of systemic therapy for refractory cutaneous disease.^22,23 Most patients with cutaneous RDD have self-limited disease, but long-term follow-up is recommended following surgical excision to monitor for recurrence, especially if there is a residual positive margin.²⁴ Radiation therapy also may have to be utilized for residual or recurrent disease that becomes symptomatic; however, further studies are needed to determine its efficacy in limiting recurrence.^4,12,25 Systemic treatment options include immunosuppressive or immunomodulatory agents such as corticosteroids, methotrexate, and rituximab.⁵ There currently are no guidelines on length of follow-up, but surveillance is recommended initially at 4 months, followed by 6- to 12-month intervals.²²

THE DIAGNOSIS: Cutaneous Rosai-Dorfman Disease

The clinical differential diagnosis in our patient included a broad array of soft-tissue neoplasms ranging from benign entities to sarcomas. Histology was notable for a dense, dermal-based, lymphohistiocytic infiltrate with alternating hypocellular and hypercellular areas imparting a marbled appearance on low-power view (Figure, A). Further immunohistochemical staining revealed large, S100-positive histiocytes containing intact inflammatory cells (emperipolesis), which confirmed a diagnosis of cutaneous Rosai-Dorfman disease (RDD)(Figure, B). Our patient elected to undergo surgical removal of the mass, and he will be monitored for recurrence.

Rosai-Dorfman disease is a non–Langerhans cell histiocytosis that most commonly affects the lymph nodes but can affect other organs including the skin. Rosai-Dorfman disease initially was documented in the medical literature in 1969 by Rosai and Dorfman¹ as benign sinus histiocytosis with massive lymphadenopathy. Classic RDD usually manifests with painless cervical lymphadenopathy in children or young adults along with fever, leukocytosis, anemia, polyclonal hypergammaglobulinemia, and elevated inflammatory markers.^2,3 Extranodal involvement has been reported in up to 43% of cases, with common sites including the skin, central nervous system, and gastrointestinal tract.^3,4

Cutaneous RDD is a distinct, less common clinical entity that is limited to the skin and shows no nodal involvement or systemic symptoms such as fever, night sweats, or weight loss.⁵ Cutaneous RDD classically manifests with localized indurated papules and plaques, but it can manifest with tumorlike lesions in the subcutaneous tissues.⁶ Cutaneous RDD is very rare, with fewer than 200 known case reports in the literature as of 2014; in comparison to classic forms of RDD, cutaneous RDD has a female predominance.^7,8 There are few reports of isolated cutaneous disease manifesting as soft-tissue masses, and our case represents a rare case of cutaneous RDD manifesting as a solitary soft-tissue mass in the axilla.^9-11 Diagnosis of cutaneous RDD is challenging due to its variable clinical manifestations and nonspecific imaging findings, requiring clinicopathologic correlation.

Imaging of subcutaneous RDD lesions typically shows well-defined, irregularly shaped masses with homogenous enhancement on computed tomography/ magnetic resonance imaging. Additional imaging with positron emission tomography/computed tomography is recommended to examine for organ involvement, as RDD lesions have avid uptake.^12,13 Imaging may help differentiate RDD lesions from malignant neoplasms prior to biopsy. Additional workup includes baseline laboratory testing with inflammatory markers and a complete blood count for evaluation of laboratory abnormalities seen in classic RDD, including leukocytosis, anemia, or systemic inflammation.¹² Following imaging and laboratory testing, definitive diagnosis of RDD necessitates histopathologic examination.

Although cutaneous RDD is clinically distinct from its classic RDD counterpart, the conditions share the same characteristic histologic features.⁵ Histology is notable for a dense mixed inflammatory infiltrate comprised of large pale histiocytes exhibiting emperipolesis, lymphocytes, plasma cells, and occasional eosinophils and neutrophils. Histiocytes stain positive for CD68, CD163, and S100 and are negative for Langerhans cell markers CD1a and CD207.⁶

The etiology of RDD remains poorly understood. Classic RDD has been associated with both sporadic and familial forms, with somatic mutations identified in the mitogen-activated protein kinase/KRAS pathway in up to one-third of cases, and less frequently in the BRAF gene.^14,15 Germline mutations in familial cases of RDD have been identified in the SLC29A3 gene; mutations in this gene are associated with a spectrum of syndromes with histiocytosis and lymphadenopathy.^14,15 In contrast, molecular drivers have yet to be identified in cutaneous RDD lesions, and the current predominant hypothesis is that cutaneous RDD has a reactive or immunologic pathophysiology. Autoimmune diseases, infections, and lymphomas have been reported to co-occur with both classic and cutaneous RDD.¹⁵ While subclinical viral infections such as Epstein-Barr virus and human herpesvirus 6 have been identified in RDD cases, studies have failed to prove their role as pathogenic drivers of the disease.^14,16,17 Commonly reported comorbidities include systemic lupus erythematous, diabetes, hemolytic anemia, acute/chronic uveitis (though it is controversial whether these cases represent orbital involvement in systemic RDD), and Crohn disease.^7,8,18,19 Immunohistochemical findings have supported that cells within RDD are activated monocytes responding to T-cell cytokine signaling following an infectious or immunologic insult.^20,21

Consensus guidelines on treatment for cutaneous RDD recommend either observation for asymptomatic disease or surgical excision for unifocal lesions with consideration of systemic therapy for refractory cutaneous disease.^22,23 Most patients with cutaneous RDD have self-limited disease, but long-term follow-up is recommended following surgical excision to monitor for recurrence, especially if there is a residual positive margin.²⁴ Radiation therapy also may have to be utilized for residual or recurrent disease that becomes symptomatic; however, further studies are needed to determine its efficacy in limiting recurrence.^4,12,25 Systemic treatment options include immunosuppressive or immunomodulatory agents such as corticosteroids, methotrexate, and rituximab.⁵ There currently are no guidelines on length of follow-up, but surveillance is recommended initially at 4 months, followed by 6- to 12-month intervals.²²

THE DIAGNOSIS: Cutaneous Rosai-Dorfman Disease

The clinical differential diagnosis in our patient included a broad array of soft-tissue neoplasms ranging from benign entities to sarcomas. Histology was notable for a dense, dermal-based, lymphohistiocytic infiltrate with alternating hypocellular and hypercellular areas imparting a marbled appearance on low-power view (Figure, A). Further immunohistochemical staining revealed large, S100-positive histiocytes containing intact inflammatory cells (emperipolesis), which confirmed a diagnosis of cutaneous Rosai-Dorfman disease (RDD)(Figure, B). Our patient elected to undergo surgical removal of the mass, and he will be monitored for recurrence.

Rosai-Dorfman disease is a non–Langerhans cell histiocytosis that most commonly affects the lymph nodes but can affect other organs including the skin. Rosai-Dorfman disease initially was documented in the medical literature in 1969 by Rosai and Dorfman¹ as benign sinus histiocytosis with massive lymphadenopathy. Classic RDD usually manifests with painless cervical lymphadenopathy in children or young adults along with fever, leukocytosis, anemia, polyclonal hypergammaglobulinemia, and elevated inflammatory markers.^2,3 Extranodal involvement has been reported in up to 43% of cases, with common sites including the skin, central nervous system, and gastrointestinal tract.^3,4

Cutaneous RDD is a distinct, less common clinical entity that is limited to the skin and shows no nodal involvement or systemic symptoms such as fever, night sweats, or weight loss.⁵ Cutaneous RDD classically manifests with localized indurated papules and plaques, but it can manifest with tumorlike lesions in the subcutaneous tissues.⁶ Cutaneous RDD is very rare, with fewer than 200 known case reports in the literature as of 2014; in comparison to classic forms of RDD, cutaneous RDD has a female predominance.^7,8 There are few reports of isolated cutaneous disease manifesting as soft-tissue masses, and our case represents a rare case of cutaneous RDD manifesting as a solitary soft-tissue mass in the axilla.^9-11 Diagnosis of cutaneous RDD is challenging due to its variable clinical manifestations and nonspecific imaging findings, requiring clinicopathologic correlation.

Imaging of subcutaneous RDD lesions typically shows well-defined, irregularly shaped masses with homogenous enhancement on computed tomography/ magnetic resonance imaging. Additional imaging with positron emission tomography/computed tomography is recommended to examine for organ involvement, as RDD lesions have avid uptake.^12,13 Imaging may help differentiate RDD lesions from malignant neoplasms prior to biopsy. Additional workup includes baseline laboratory testing with inflammatory markers and a complete blood count for evaluation of laboratory abnormalities seen in classic RDD, including leukocytosis, anemia, or systemic inflammation.¹² Following imaging and laboratory testing, definitive diagnosis of RDD necessitates histopathologic examination.

Although cutaneous RDD is clinically distinct from its classic RDD counterpart, the conditions share the same characteristic histologic features.⁵ Histology is notable for a dense mixed inflammatory infiltrate comprised of large pale histiocytes exhibiting emperipolesis, lymphocytes, plasma cells, and occasional eosinophils and neutrophils. Histiocytes stain positive for CD68, CD163, and S100 and are negative for Langerhans cell markers CD1a and CD207.⁶

The etiology of RDD remains poorly understood. Classic RDD has been associated with both sporadic and familial forms, with somatic mutations identified in the mitogen-activated protein kinase/KRAS pathway in up to one-third of cases, and less frequently in the BRAF gene.^14,15 Germline mutations in familial cases of RDD have been identified in the SLC29A3 gene; mutations in this gene are associated with a spectrum of syndromes with histiocytosis and lymphadenopathy.^14,15 In contrast, molecular drivers have yet to be identified in cutaneous RDD lesions, and the current predominant hypothesis is that cutaneous RDD has a reactive or immunologic pathophysiology. Autoimmune diseases, infections, and lymphomas have been reported to co-occur with both classic and cutaneous RDD.¹⁵ While subclinical viral infections such as Epstein-Barr virus and human herpesvirus 6 have been identified in RDD cases, studies have failed to prove their role as pathogenic drivers of the disease.^14,16,17 Commonly reported comorbidities include systemic lupus erythematous, diabetes, hemolytic anemia, acute/chronic uveitis (though it is controversial whether these cases represent orbital involvement in systemic RDD), and Crohn disease.^7,8,18,19 Immunohistochemical findings have supported that cells within RDD are activated monocytes responding to T-cell cytokine signaling following an infectious or immunologic insult.^20,21

Consensus guidelines on treatment for cutaneous RDD recommend either observation for asymptomatic disease or surgical excision for unifocal lesions with consideration of systemic therapy for refractory cutaneous disease.^22,23 Most patients with cutaneous RDD have self-limited disease, but long-term follow-up is recommended following surgical excision to monitor for recurrence, especially if there is a residual positive margin.²⁴ Radiation therapy also may have to be utilized for residual or recurrent disease that becomes symptomatic; however, further studies are needed to determine its efficacy in limiting recurrence.^4,12,25 Systemic treatment options include immunosuppressive or immunomodulatory agents such as corticosteroids, methotrexate, and rituximab.⁵ There currently are no guidelines on length of follow-up, but surveillance is recommended initially at 4 months, followed by 6- to 12-month intervals.²²

To the Editor:

Xylazine, commonly referred to by its street name tranq, is a veterinary tranquilizer that has recently gained attention due to its increasing misuse in human populations. It often is combined with recreational drugs like fentanyl to extend the duration of drug effects. As a partial α₂ receptor agonist, xylazine acts by reducing dopamine and norepinephrine release, resulting in sedative effects. This case report highlights xylazine skin necrosis manifesting as wrist drop and chronic wounds in a patient with a history of intravenous (IV) drug use.

A 35-year-old man with a history of IV drug use presented to the emergency department with a nonprogressive right wrist drop that had persisted for 2 weeks, along with new-onset left wrist drop of 1 day’s duration. The patient did not report any sensory symptoms or pain. Physical examination revealed an ulcerated necrotic plaque with hemorrhagic crust and focal areas of scarring on the right posterior forearm (Figure 1). The left hand exhibited a well-healed pink scar symmetric to the ulcer on the right forearm. The patient reported a history of a similar ulcer on the left hand that had resolved after discontinuation of IV drug use in that arm. He denied any history of trauma to the area.

The patient’s laboratory results demonstrated elevated inflammatory markers, including an erythrocyte sedimentation rate of 105 mm/h (reference range, <15 mm/h in men younger than 50 years) and a C-reactive protein level of 7.7 mg/dL (reference range, <0.9 mg/dL). Additionally, antinuclear antibody and antineutrophil cytoplasmic antibody tests were positive. A urine drug screen returned positive results for various substances, including cocaine, cocaine metabolites, fentanyl, norfentanyl, β-hydroxyfentanyl or fentanyl metabolite, caffeine, caffeine metabolite or theophylline, nicotine metabolite, and xylazine. Magnetic resonance imaging of the right upper extremity excluded osteomyelitis but revealed multiple subepidermal abscesses.

A punch biopsy from the right forearm demonstrated an ulcer with a mixed infiltrate, dermal necrosis, and clusters of Gram-positive cocci, indicating a bacterial infection. There was no evidence of leukocytoclastic vasculitis (Figures 2 and 3). Electromyography confirmed mononeuritis multiplex as the cause of the right wrist drop. The patient was found to have cytoplasmic antineutrophil cytoplasmic antibody–positive vasculitis in the setting of levamisole-adulterated cocaine use. Since no vasculitis was identified on histopathology of the ulcer and xylazine was detected on drug screening, a diagnosis of xylazine-induced skin necrosis was made. In our case, the patient did not show evidence of active osteomyelitis or sepsis and left the hospital against medical advice without adequate wound debridement.

Our case highlights xylazine-induced skin necrosis that can occur in individuals who use IV drugs. The combination of xylazine with other recreational drugs such as fentanyl poses unique challenges for clinicians. Xylazine has been increasingly found in cases of overdose-related mortality¹ and recently has been reported to induce skin ulcers.² Xylazine intoxication, though uncommon, can result in distinct clinical presentations, including recalcitrant skin ulcers and deep necrotizing wounds.

The precise mechanism behind these wounds remains unclear. Xylazine is a partial α₂ receptor agonist, and it is postulated that the necrotic wounds develop secondary to local vasoconstriction, leading to decreased skin perfusion.³ A recent study found that xylazine used in combination with cocaine or an active metabolite in heroin can cause cytotoxicity to vascular endothelial cells, which can lead to dysregulation of vascular tone.⁴ Decreased perfusion and impaired wound healing put patients at risk for secondary infections, infected ulcers, osteomyelitis, and sepsis.

In patients with known fentanyl use in conjunction with skin necrosis, a high degree of suspicion for xylazine intoxication should be employed. Ruling out vasculitis (via serologic markers and skin biopsy) as well as atypical skin infections is important in these patients to identify potential cases of xylazine-induced skin necrosis. Other IV drugs such as krokodil (desomorphine) can cause severe skin necrosis and therefore should be considered in these patients. Early detection of these skin ulcers is imperative, as delayed diagnosis increases the risk for osteomyelitis and/or the need for amputation.

This case emphasizes the importance of health care providers remaining vigilant about emerging trends in drug misuse. Early recognition of xylazine intoxication and its potential complications is crucial for timely intervention and appropriate management, which may include wound debridement and antibiotic therapy. In addition, proper counseling regarding discontinuation of drug use is important in wound healing, though this poses a challenging conversation with the patient. Increased awareness among health care professionals and continued research in illicit drug–induced skin necrosis will aid in better understanding and addressing the growing issue of xylazine misuse.

To the Editor:

Xylazine, commonly referred to by its street name tranq, is a veterinary tranquilizer that has recently gained attention due to its increasing misuse in human populations. It often is combined with recreational drugs like fentanyl to extend the duration of drug effects. As a partial α₂ receptor agonist, xylazine acts by reducing dopamine and norepinephrine release, resulting in sedative effects. This case report highlights xylazine skin necrosis manifesting as wrist drop and chronic wounds in a patient with a history of intravenous (IV) drug use.

A 35-year-old man with a history of IV drug use presented to the emergency department with a nonprogressive right wrist drop that had persisted for 2 weeks, along with new-onset left wrist drop of 1 day’s duration. The patient did not report any sensory symptoms or pain. Physical examination revealed an ulcerated necrotic plaque with hemorrhagic crust and focal areas of scarring on the right posterior forearm (Figure 1). The left hand exhibited a well-healed pink scar symmetric to the ulcer on the right forearm. The patient reported a history of a similar ulcer on the left hand that had resolved after discontinuation of IV drug use in that arm. He denied any history of trauma to the area.

The patient’s laboratory results demonstrated elevated inflammatory markers, including an erythrocyte sedimentation rate of 105 mm/h (reference range, <15 mm/h in men younger than 50 years) and a C-reactive protein level of 7.7 mg/dL (reference range, <0.9 mg/dL). Additionally, antinuclear antibody and antineutrophil cytoplasmic antibody tests were positive. A urine drug screen returned positive results for various substances, including cocaine, cocaine metabolites, fentanyl, norfentanyl, β-hydroxyfentanyl or fentanyl metabolite, caffeine, caffeine metabolite or theophylline, nicotine metabolite, and xylazine. Magnetic resonance imaging of the right upper extremity excluded osteomyelitis but revealed multiple subepidermal abscesses.

A punch biopsy from the right forearm demonstrated an ulcer with a mixed infiltrate, dermal necrosis, and clusters of Gram-positive cocci, indicating a bacterial infection. There was no evidence of leukocytoclastic vasculitis (Figures 2 and 3). Electromyography confirmed mononeuritis multiplex as the cause of the right wrist drop. The patient was found to have cytoplasmic antineutrophil cytoplasmic antibody–positive vasculitis in the setting of levamisole-adulterated cocaine use. Since no vasculitis was identified on histopathology of the ulcer and xylazine was detected on drug screening, a diagnosis of xylazine-induced skin necrosis was made. In our case, the patient did not show evidence of active osteomyelitis or sepsis and left the hospital against medical advice without adequate wound debridement.

Our case highlights xylazine-induced skin necrosis that can occur in individuals who use IV drugs. The combination of xylazine with other recreational drugs such as fentanyl poses unique challenges for clinicians. Xylazine has been increasingly found in cases of overdose-related mortality¹ and recently has been reported to induce skin ulcers.² Xylazine intoxication, though uncommon, can result in distinct clinical presentations, including recalcitrant skin ulcers and deep necrotizing wounds.

The precise mechanism behind these wounds remains unclear. Xylazine is a partial α₂ receptor agonist, and it is postulated that the necrotic wounds develop secondary to local vasoconstriction, leading to decreased skin perfusion.³ A recent study found that xylazine used in combination with cocaine or an active metabolite in heroin can cause cytotoxicity to vascular endothelial cells, which can lead to dysregulation of vascular tone.⁴ Decreased perfusion and impaired wound healing put patients at risk for secondary infections, infected ulcers, osteomyelitis, and sepsis.

In patients with known fentanyl use in conjunction with skin necrosis, a high degree of suspicion for xylazine intoxication should be employed. Ruling out vasculitis (via serologic markers and skin biopsy) as well as atypical skin infections is important in these patients to identify potential cases of xylazine-induced skin necrosis. Other IV drugs such as krokodil (desomorphine) can cause severe skin necrosis and therefore should be considered in these patients. Early detection of these skin ulcers is imperative, as delayed diagnosis increases the risk for osteomyelitis and/or the need for amputation.

This case emphasizes the importance of health care providers remaining vigilant about emerging trends in drug misuse. Early recognition of xylazine intoxication and its potential complications is crucial for timely intervention and appropriate management, which may include wound debridement and antibiotic therapy. In addition, proper counseling regarding discontinuation of drug use is important in wound healing, though this poses a challenging conversation with the patient. Increased awareness among health care professionals and continued research in illicit drug–induced skin necrosis will aid in better understanding and addressing the growing issue of xylazine misuse.

To the Editor:

Xylazine, commonly referred to by its street name tranq, is a veterinary tranquilizer that has recently gained attention due to its increasing misuse in human populations. It often is combined with recreational drugs like fentanyl to extend the duration of drug effects. As a partial α₂ receptor agonist, xylazine acts by reducing dopamine and norepinephrine release, resulting in sedative effects. This case report highlights xylazine skin necrosis manifesting as wrist drop and chronic wounds in a patient with a history of intravenous (IV) drug use.

A 35-year-old man with a history of IV drug use presented to the emergency department with a nonprogressive right wrist drop that had persisted for 2 weeks, along with new-onset left wrist drop of 1 day’s duration. The patient did not report any sensory symptoms or pain. Physical examination revealed an ulcerated necrotic plaque with hemorrhagic crust and focal areas of scarring on the right posterior forearm (Figure 1). The left hand exhibited a well-healed pink scar symmetric to the ulcer on the right forearm. The patient reported a history of a similar ulcer on the left hand that had resolved after discontinuation of IV drug use in that arm. He denied any history of trauma to the area.

The patient’s laboratory results demonstrated elevated inflammatory markers, including an erythrocyte sedimentation rate of 105 mm/h (reference range, <15 mm/h in men younger than 50 years) and a C-reactive protein level of 7.7 mg/dL (reference range, <0.9 mg/dL). Additionally, antinuclear antibody and antineutrophil cytoplasmic antibody tests were positive. A urine drug screen returned positive results for various substances, including cocaine, cocaine metabolites, fentanyl, norfentanyl, β-hydroxyfentanyl or fentanyl metabolite, caffeine, caffeine metabolite or theophylline, nicotine metabolite, and xylazine. Magnetic resonance imaging of the right upper extremity excluded osteomyelitis but revealed multiple subepidermal abscesses.

A punch biopsy from the right forearm demonstrated an ulcer with a mixed infiltrate, dermal necrosis, and clusters of Gram-positive cocci, indicating a bacterial infection. There was no evidence of leukocytoclastic vasculitis (Figures 2 and 3). Electromyography confirmed mononeuritis multiplex as the cause of the right wrist drop. The patient was found to have cytoplasmic antineutrophil cytoplasmic antibody–positive vasculitis in the setting of levamisole-adulterated cocaine use. Since no vasculitis was identified on histopathology of the ulcer and xylazine was detected on drug screening, a diagnosis of xylazine-induced skin necrosis was made. In our case, the patient did not show evidence of active osteomyelitis or sepsis and left the hospital against medical advice without adequate wound debridement.

Our case highlights xylazine-induced skin necrosis that can occur in individuals who use IV drugs. The combination of xylazine with other recreational drugs such as fentanyl poses unique challenges for clinicians. Xylazine has been increasingly found in cases of overdose-related mortality¹ and recently has been reported to induce skin ulcers.² Xylazine intoxication, though uncommon, can result in distinct clinical presentations, including recalcitrant skin ulcers and deep necrotizing wounds.

The precise mechanism behind these wounds remains unclear. Xylazine is a partial α₂ receptor agonist, and it is postulated that the necrotic wounds develop secondary to local vasoconstriction, leading to decreased skin perfusion.³ A recent study found that xylazine used in combination with cocaine or an active metabolite in heroin can cause cytotoxicity to vascular endothelial cells, which can lead to dysregulation of vascular tone.⁴ Decreased perfusion and impaired wound healing put patients at risk for secondary infections, infected ulcers, osteomyelitis, and sepsis.

In patients with known fentanyl use in conjunction with skin necrosis, a high degree of suspicion for xylazine intoxication should be employed. Ruling out vasculitis (via serologic markers and skin biopsy) as well as atypical skin infections is important in these patients to identify potential cases of xylazine-induced skin necrosis. Other IV drugs such as krokodil (desomorphine) can cause severe skin necrosis and therefore should be considered in these patients. Early detection of these skin ulcers is imperative, as delayed diagnosis increases the risk for osteomyelitis and/or the need for amputation.

This case emphasizes the importance of health care providers remaining vigilant about emerging trends in drug misuse. Early recognition of xylazine intoxication and its potential complications is crucial for timely intervention and appropriate management, which may include wound debridement and antibiotic therapy. In addition, proper counseling regarding discontinuation of drug use is important in wound healing, though this poses a challenging conversation with the patient. Increased awareness among health care professionals and continued research in illicit drug–induced skin necrosis will aid in better understanding and addressing the growing issue of xylazine misuse.