Federal Practitioner

It is a great honor and privilege to care for the men and women who have bravely served our country, and to give a hero’s Final Salute in recognition of the veteran’s service and sacrifices. US Department of Veterans Affairs (VA) and other non-VA health care facilities caring for veterans find meaning and take pride in providing a Final Salute to veterans who spend their last days of life at their facilities. The Final Salute aligns with the mission of the VA: To fulfill President Lincoln’s promise “To care for him who shall have borne the battle, and for his widow, and his orphan” by serving and honoring the people who are America’s veterans.¹ As health care professionals, we feel and grieve the loss when a veteran dies within our facilities. While some VA and community health care facilities honor veterans at the time of death, others have yet to implement a Final Salute program.² How can we ensure that veterans at the time of death receive a hero’s Final Salute?

There are 26 million veterans alive today, representing about 8% of the total US adult population.³ Yet more than 1800 veterans die every day, representing about a quarter of all US deaths.^4,5 Most veterans die in the community; only 4% of veteran deaths occur in VA facilities.^5,6 This article highlights the unique tradition that a few VA and community health care facilities have launched to honor veterans whose journeys end under their care. This article also is a call to action to raise awareness of the importance of instituting the Final Salute program that is part of the end-of-life protocol for veterans.

A Final Salute ceremony (also called Honors Escort or Honor Walk) takes place when a veteran who dies in the hospital or nursing home is transported on the gurney from the location of their passing to the funeral home vehicle or the morgue. Staff, family members, visitors, and other veterans silently line the hallways from the veteran’s room to the health care facility exit and pay their respects to the deceased veteran. A Final Salute is a quiet, yet profound and powerful way for care teams to ensure that the deceased veteran does not leave alone.

VA-Based Ceremonies

There are many acts of remembrance at the bedside from the time of death to the time when the veteran’s body approaches the funeral home vehicle or the doors of the morgue. Tonya Ross, social worker and Honors Escort program manager at the Robert J. Dole VA Medical Center (VAMC) in Wichita, Kansas, reported that following the death of a veteran, there is a bedside remembrance that begins with a flag ceremony. Afterward, the veteran’s gurney is draped with the American flag, and as the procession moves through the medical center, the veterans salute, and all others place their hands over their hearts

Chaplain Michael Halyard at the Ozarks VAMC in Fayetteville, Arkansas, reported that following the death of a veteran, the chaplain greets family members with condolences and allows them to grieve and reflect on their life with the deceased veteran. On arrival of the funeral home team, an announcement for an Honor Walk is made. Staff, visitors, and family are lined up on the first floor of the hospital waiting to pay their final respects to the veteran. A slow processional of the veteran covered by a handmade quilt is escorted by a VA police officer and the chaplain. The processional stops in the middle and the chaplain announces, “Let us pause for a moment of silence as we honor one of our own US Army veterans who has completed the journey of life.”

The Final Salute at the VA Wilkes-Barre Community Living Center (CLC) in Pennsylvania begins with a bedside flag ceremony. Afterward, the veteran’s gurney is draped with the flag, and as the procession moves through the CLC, all who are standing along the route offer their respects. Throughout the ceremony, a team member remains with the family of the deceased, providing comfort and support. Once the ceremony is completed, the team member remains with the family to ensure all issues are addressed and all questions or concerns are answered.

Residents of the Philadelphia VAMC CLC in Pennsylvania have found a way to say a last goodbye to fellow veterans in a unique and dignified manner. Bettyanne Corkery, nurse manager for the Heroes’ Crossing hospice and palliative care unit explains, “Our Honor Guard evolved from our residents’ requests. We used to drape a flag over the body of veterans leaving us for the last time, but our residents came to us and said they wanted to do more.” CLC residents wanted to form an Honor Guard and say goodbye with dignity and grace. Gerry Donlon, a US Army Vietnam veteran and president of the residents council and chief program coordinator, explained that Honor Guard members are called to the deceased’s room and stand guard until the hearse comes. Donlon adds, “We proceed forward, along with the family, and the speaker system for the hospital plays patriotic songs, including Taps. When we get to the lobby, we stop, and I say a prayer. We fold the flag military style and hand it over to the family members, we render a Final Salute, and then the veteran is taken to the hearse.”⁷

Community Cermeonies

Texas Health Arlington Memorial Hospital (THAM) has honored 531 veterans with Final Salutes since 2015. Before the official procession begins, designated employees drape the patient’s body with the flag. Physicians, nurses, and volunteers escort the body in a silent procession along with the family. On leaving, the veteran’s family receives the flag in honor of their loved one. A specially designed medallion has been placed in the lobby floor at the location where the Final Salute is rendered. Christi Evans, RN, BSN, ACM, manager for care
coordination at AnMed Health, Anderson, South Carolina, witnessed a Final Salute at THAM for a relative and took the idea to Mike Johnston, Director of Spiritual Care to establish the program at AnMed Health, which has provided 118 Final Salutes since 2018.

Central Maine Healthcare (CMH), which operates 3 hospitals, provides 2 ceremonies. The Final Salute occurs prior to the veteran’s passing and the Honor Walk gathers hospital personnel outside the patient’s room as they are moved. During the Final Salute, with the approval of a veteran’s family, a veteran employed by CMF presents the veteran with a folded flag and certificate and thanks them for their service and hospital employee salute. After the veteran dies, staff members gather in the hallway for the Honor Walk. Ascension Sacred Heart (ASH), Florida, where on average 260 veterans look for treatment every month, has taken the Final Salute to all 4 of their hospitals. Sabrina Granese, BSN, RN, Military Service Line Director at ASH explains, “Patients that are active duty or veterans are identified at the time of admission. When a veteran passes away, with the approval of a veteran’s family, ‘Code veteran’ will be heard over the hospital intercom. Staff members will have 5 minutes to make their way to the main hospital entrance for the Honor Walk.” Similarly, the skilled nursing facilities operated by Bethesda Health Group, St. Louis, Missouri, have implemented the Veteran Escort Ceremony. Employees, volunteers, family members, and residents line the hallways during the procession to salute and honor the passing of the veteran’s body.

Closure For Families

Simple yet magnificent, a Final Salute shows that a veteran is “gone but not forgotten” and also shows families they are not alone as they too made sacrifices to allow their loved ones to serve in the Armed Forces; it signals the hope of healing and closure.⁸ “The staff came to pay their respects,” recalled Cindy Roberts, a social worker at the VA Bay Pines, when her relative died at the Ozarks VAMC. She explained, I wasn’t expecting as much because it was 2 AM. I have never in my life had an experience like that. I wish there were words to describe it; I wish every VAMC in the country did that.”

Hope Danishanko, social worker at the VA Wilkes-Barre CLC, said veterans are appreciative of the program. “I have had many CLC residents tell me that the Honors Escort allows them to have closure. They also feel it provides respect to the veteran who has passed.”

Bettyanne Corkery noted that the Philadelphia CLC Honor Guard program is unique because it is veteran driven. “They have sessions in which they talk about what works and what doesn’t, and they recruit new volunteers themselves,” she said. “It has evolved into the most beautiful ceremony, and they are constantly tweaking it.” According to Gerry Donlon, “When you see all 8 members of the Honor Guard get a call at 2 AM, and everyone shows up, you know there’s personal satisfaction. I’d like to see every CLC [throughout VA] do this. I really would.”⁷

“Family members tell us they feel blessed and honored to be a part of the program. They are so grateful for the way we pay tribute to their veteran loved one,” says Leslie Schaeffer, support services manager and bereavement coordinator and coordinator of the Veteran Escort Ceremony at Bethesda Health Group communities.

Privileged and humbled—that is how staff and family members describe feeling after participating in a Final Salute. Its impact on the families has been amazing. Between the tears, there are thanks for the recognition of the sacrifices their loved ones made. When one family was informed of the ceremony by Reverend Tricia Lytle, Manager of Spiritual Care at AnMed Health, the “whole family responded by explaining how much that meant at such a difficult time. They began sharing stories about his service and how proud he was to be a veteran,” she reported. “As I [Rev. Lytle] leaned over to present the flag at the bedside, the wife reached up and took hold as she tearfully accepted it and embraced it close to her heart. The staff in the hallway looked on respectfully also in tears.”

Conclusions

The Final Salute is a brief ceremonial procession demonstrating that the mission to care for America’s veterans does not end at the bedside. It ensures that no veteran’s body is alone when led out of the health facility room to the exit. With these Final Salute practices, I hope that the rest of VA and community health facilities caring for veterans will implement a Final Salute program to better honor veterans who depart in their care.

Acknowledgments
The author would like to express gratitude to everyone who so openly shared their stories—your insight, advice, and encouragement are inspiring and invaluable. Thank you to all the facilities that consented to be featured in this article.

It is a great honor and privilege to care for the men and women who have bravely served our country, and to give a hero’s Final Salute in recognition of the veteran’s service and sacrifices. US Department of Veterans Affairs (VA) and other non-VA health care facilities caring for veterans find meaning and take pride in providing a Final Salute to veterans who spend their last days of life at their facilities. The Final Salute aligns with the mission of the VA: To fulfill President Lincoln’s promise “To care for him who shall have borne the battle, and for his widow, and his orphan” by serving and honoring the people who are America’s veterans.¹ As health care professionals, we feel and grieve the loss when a veteran dies within our facilities. While some VA and community health care facilities honor veterans at the time of death, others have yet to implement a Final Salute program.² How can we ensure that veterans at the time of death receive a hero’s Final Salute?

There are 26 million veterans alive today, representing about 8% of the total US adult population.³ Yet more than 1800 veterans die every day, representing about a quarter of all US deaths.^4,5 Most veterans die in the community; only 4% of veteran deaths occur in VA facilities.^5,6 This article highlights the unique tradition that a few VA and community health care facilities have launched to honor veterans whose journeys end under their care. This article also is a call to action to raise awareness of the importance of instituting the Final Salute program that is part of the end-of-life protocol for veterans.

A Final Salute ceremony (also called Honors Escort or Honor Walk) takes place when a veteran who dies in the hospital or nursing home is transported on the gurney from the location of their passing to the funeral home vehicle or the morgue. Staff, family members, visitors, and other veterans silently line the hallways from the veteran’s room to the health care facility exit and pay their respects to the deceased veteran. A Final Salute is a quiet, yet profound and powerful way for care teams to ensure that the deceased veteran does not leave alone.

VA-Based Ceremonies

There are many acts of remembrance at the bedside from the time of death to the time when the veteran’s body approaches the funeral home vehicle or the doors of the morgue. Tonya Ross, social worker and Honors Escort program manager at the Robert J. Dole VA Medical Center (VAMC) in Wichita, Kansas, reported that following the death of a veteran, there is a bedside remembrance that begins with a flag ceremony. Afterward, the veteran’s gurney is draped with the American flag, and as the procession moves through the medical center, the veterans salute, and all others place their hands over their hearts

Chaplain Michael Halyard at the Ozarks VAMC in Fayetteville, Arkansas, reported that following the death of a veteran, the chaplain greets family members with condolences and allows them to grieve and reflect on their life with the deceased veteran. On arrival of the funeral home team, an announcement for an Honor Walk is made. Staff, visitors, and family are lined up on the first floor of the hospital waiting to pay their final respects to the veteran. A slow processional of the veteran covered by a handmade quilt is escorted by a VA police officer and the chaplain. The processional stops in the middle and the chaplain announces, “Let us pause for a moment of silence as we honor one of our own US Army veterans who has completed the journey of life.”

The Final Salute at the VA Wilkes-Barre Community Living Center (CLC) in Pennsylvania begins with a bedside flag ceremony. Afterward, the veteran’s gurney is draped with the flag, and as the procession moves through the CLC, all who are standing along the route offer their respects. Throughout the ceremony, a team member remains with the family of the deceased, providing comfort and support. Once the ceremony is completed, the team member remains with the family to ensure all issues are addressed and all questions or concerns are answered.

Residents of the Philadelphia VAMC CLC in Pennsylvania have found a way to say a last goodbye to fellow veterans in a unique and dignified manner. Bettyanne Corkery, nurse manager for the Heroes’ Crossing hospice and palliative care unit explains, “Our Honor Guard evolved from our residents’ requests. We used to drape a flag over the body of veterans leaving us for the last time, but our residents came to us and said they wanted to do more.” CLC residents wanted to form an Honor Guard and say goodbye with dignity and grace. Gerry Donlon, a US Army Vietnam veteran and president of the residents council and chief program coordinator, explained that Honor Guard members are called to the deceased’s room and stand guard until the hearse comes. Donlon adds, “We proceed forward, along with the family, and the speaker system for the hospital plays patriotic songs, including Taps. When we get to the lobby, we stop, and I say a prayer. We fold the flag military style and hand it over to the family members, we render a Final Salute, and then the veteran is taken to the hearse.”⁷

Community Cermeonies

Texas Health Arlington Memorial Hospital (THAM) has honored 531 veterans with Final Salutes since 2015. Before the official procession begins, designated employees drape the patient’s body with the flag. Physicians, nurses, and volunteers escort the body in a silent procession along with the family. On leaving, the veteran’s family receives the flag in honor of their loved one. A specially designed medallion has been placed in the lobby floor at the location where the Final Salute is rendered. Christi Evans, RN, BSN, ACM, manager for care
coordination at AnMed Health, Anderson, South Carolina, witnessed a Final Salute at THAM for a relative and took the idea to Mike Johnston, Director of Spiritual Care to establish the program at AnMed Health, which has provided 118 Final Salutes since 2018.

Central Maine Healthcare (CMH), which operates 3 hospitals, provides 2 ceremonies. The Final Salute occurs prior to the veteran’s passing and the Honor Walk gathers hospital personnel outside the patient’s room as they are moved. During the Final Salute, with the approval of a veteran’s family, a veteran employed by CMF presents the veteran with a folded flag and certificate and thanks them for their service and hospital employee salute. After the veteran dies, staff members gather in the hallway for the Honor Walk. Ascension Sacred Heart (ASH), Florida, where on average 260 veterans look for treatment every month, has taken the Final Salute to all 4 of their hospitals. Sabrina Granese, BSN, RN, Military Service Line Director at ASH explains, “Patients that are active duty or veterans are identified at the time of admission. When a veteran passes away, with the approval of a veteran’s family, ‘Code veteran’ will be heard over the hospital intercom. Staff members will have 5 minutes to make their way to the main hospital entrance for the Honor Walk.” Similarly, the skilled nursing facilities operated by Bethesda Health Group, St. Louis, Missouri, have implemented the Veteran Escort Ceremony. Employees, volunteers, family members, and residents line the hallways during the procession to salute and honor the passing of the veteran’s body.

Closure For Families

Simple yet magnificent, a Final Salute shows that a veteran is “gone but not forgotten” and also shows families they are not alone as they too made sacrifices to allow their loved ones to serve in the Armed Forces; it signals the hope of healing and closure.⁸ “The staff came to pay their respects,” recalled Cindy Roberts, a social worker at the VA Bay Pines, when her relative died at the Ozarks VAMC. She explained, I wasn’t expecting as much because it was 2 AM. I have never in my life had an experience like that. I wish there were words to describe it; I wish every VAMC in the country did that.”

Hope Danishanko, social worker at the VA Wilkes-Barre CLC, said veterans are appreciative of the program. “I have had many CLC residents tell me that the Honors Escort allows them to have closure. They also feel it provides respect to the veteran who has passed.”

Bettyanne Corkery noted that the Philadelphia CLC Honor Guard program is unique because it is veteran driven. “They have sessions in which they talk about what works and what doesn’t, and they recruit new volunteers themselves,” she said. “It has evolved into the most beautiful ceremony, and they are constantly tweaking it.” According to Gerry Donlon, “When you see all 8 members of the Honor Guard get a call at 2 AM, and everyone shows up, you know there’s personal satisfaction. I’d like to see every CLC [throughout VA] do this. I really would.”⁷

“Family members tell us they feel blessed and honored to be a part of the program. They are so grateful for the way we pay tribute to their veteran loved one,” says Leslie Schaeffer, support services manager and bereavement coordinator and coordinator of the Veteran Escort Ceremony at Bethesda Health Group communities.

Privileged and humbled—that is how staff and family members describe feeling after participating in a Final Salute. Its impact on the families has been amazing. Between the tears, there are thanks for the recognition of the sacrifices their loved ones made. When one family was informed of the ceremony by Reverend Tricia Lytle, Manager of Spiritual Care at AnMed Health, the “whole family responded by explaining how much that meant at such a difficult time. They began sharing stories about his service and how proud he was to be a veteran,” she reported. “As I [Rev. Lytle] leaned over to present the flag at the bedside, the wife reached up and took hold as she tearfully accepted it and embraced it close to her heart. The staff in the hallway looked on respectfully also in tears.”

Conclusions

The Final Salute is a brief ceremonial procession demonstrating that the mission to care for America’s veterans does not end at the bedside. It ensures that no veteran’s body is alone when led out of the health facility room to the exit. With these Final Salute practices, I hope that the rest of VA and community health facilities caring for veterans will implement a Final Salute program to better honor veterans who depart in their care.

Acknowledgments
The author would like to express gratitude to everyone who so openly shared their stories—your insight, advice, and encouragement are inspiring and invaluable. Thank you to all the facilities that consented to be featured in this article.

It is a great honor and privilege to care for the men and women who have bravely served our country, and to give a hero’s Final Salute in recognition of the veteran’s service and sacrifices. US Department of Veterans Affairs (VA) and other non-VA health care facilities caring for veterans find meaning and take pride in providing a Final Salute to veterans who spend their last days of life at their facilities. The Final Salute aligns with the mission of the VA: To fulfill President Lincoln’s promise “To care for him who shall have borne the battle, and for his widow, and his orphan” by serving and honoring the people who are America’s veterans.¹ As health care professionals, we feel and grieve the loss when a veteran dies within our facilities. While some VA and community health care facilities honor veterans at the time of death, others have yet to implement a Final Salute program.² How can we ensure that veterans at the time of death receive a hero’s Final Salute?

There are 26 million veterans alive today, representing about 8% of the total US adult population.³ Yet more than 1800 veterans die every day, representing about a quarter of all US deaths.^4,5 Most veterans die in the community; only 4% of veteran deaths occur in VA facilities.^5,6 This article highlights the unique tradition that a few VA and community health care facilities have launched to honor veterans whose journeys end under their care. This article also is a call to action to raise awareness of the importance of instituting the Final Salute program that is part of the end-of-life protocol for veterans.

A Final Salute ceremony (also called Honors Escort or Honor Walk) takes place when a veteran who dies in the hospital or nursing home is transported on the gurney from the location of their passing to the funeral home vehicle or the morgue. Staff, family members, visitors, and other veterans silently line the hallways from the veteran’s room to the health care facility exit and pay their respects to the deceased veteran. A Final Salute is a quiet, yet profound and powerful way for care teams to ensure that the deceased veteran does not leave alone.

VA-Based Ceremonies

There are many acts of remembrance at the bedside from the time of death to the time when the veteran’s body approaches the funeral home vehicle or the doors of the morgue. Tonya Ross, social worker and Honors Escort program manager at the Robert J. Dole VA Medical Center (VAMC) in Wichita, Kansas, reported that following the death of a veteran, there is a bedside remembrance that begins with a flag ceremony. Afterward, the veteran’s gurney is draped with the American flag, and as the procession moves through the medical center, the veterans salute, and all others place their hands over their hearts

Chaplain Michael Halyard at the Ozarks VAMC in Fayetteville, Arkansas, reported that following the death of a veteran, the chaplain greets family members with condolences and allows them to grieve and reflect on their life with the deceased veteran. On arrival of the funeral home team, an announcement for an Honor Walk is made. Staff, visitors, and family are lined up on the first floor of the hospital waiting to pay their final respects to the veteran. A slow processional of the veteran covered by a handmade quilt is escorted by a VA police officer and the chaplain. The processional stops in the middle and the chaplain announces, “Let us pause for a moment of silence as we honor one of our own US Army veterans who has completed the journey of life.”

The Final Salute at the VA Wilkes-Barre Community Living Center (CLC) in Pennsylvania begins with a bedside flag ceremony. Afterward, the veteran’s gurney is draped with the flag, and as the procession moves through the CLC, all who are standing along the route offer their respects. Throughout the ceremony, a team member remains with the family of the deceased, providing comfort and support. Once the ceremony is completed, the team member remains with the family to ensure all issues are addressed and all questions or concerns are answered.

Residents of the Philadelphia VAMC CLC in Pennsylvania have found a way to say a last goodbye to fellow veterans in a unique and dignified manner. Bettyanne Corkery, nurse manager for the Heroes’ Crossing hospice and palliative care unit explains, “Our Honor Guard evolved from our residents’ requests. We used to drape a flag over the body of veterans leaving us for the last time, but our residents came to us and said they wanted to do more.” CLC residents wanted to form an Honor Guard and say goodbye with dignity and grace. Gerry Donlon, a US Army Vietnam veteran and president of the residents council and chief program coordinator, explained that Honor Guard members are called to the deceased’s room and stand guard until the hearse comes. Donlon adds, “We proceed forward, along with the family, and the speaker system for the hospital plays patriotic songs, including Taps. When we get to the lobby, we stop, and I say a prayer. We fold the flag military style and hand it over to the family members, we render a Final Salute, and then the veteran is taken to the hearse.”⁷

Community Cermeonies

Texas Health Arlington Memorial Hospital (THAM) has honored 531 veterans with Final Salutes since 2015. Before the official procession begins, designated employees drape the patient’s body with the flag. Physicians, nurses, and volunteers escort the body in a silent procession along with the family. On leaving, the veteran’s family receives the flag in honor of their loved one. A specially designed medallion has been placed in the lobby floor at the location where the Final Salute is rendered. Christi Evans, RN, BSN, ACM, manager for care
coordination at AnMed Health, Anderson, South Carolina, witnessed a Final Salute at THAM for a relative and took the idea to Mike Johnston, Director of Spiritual Care to establish the program at AnMed Health, which has provided 118 Final Salutes since 2018.

Central Maine Healthcare (CMH), which operates 3 hospitals, provides 2 ceremonies. The Final Salute occurs prior to the veteran’s passing and the Honor Walk gathers hospital personnel outside the patient’s room as they are moved. During the Final Salute, with the approval of a veteran’s family, a veteran employed by CMF presents the veteran with a folded flag and certificate and thanks them for their service and hospital employee salute. After the veteran dies, staff members gather in the hallway for the Honor Walk. Ascension Sacred Heart (ASH), Florida, where on average 260 veterans look for treatment every month, has taken the Final Salute to all 4 of their hospitals. Sabrina Granese, BSN, RN, Military Service Line Director at ASH explains, “Patients that are active duty or veterans are identified at the time of admission. When a veteran passes away, with the approval of a veteran’s family, ‘Code veteran’ will be heard over the hospital intercom. Staff members will have 5 minutes to make their way to the main hospital entrance for the Honor Walk.” Similarly, the skilled nursing facilities operated by Bethesda Health Group, St. Louis, Missouri, have implemented the Veteran Escort Ceremony. Employees, volunteers, family members, and residents line the hallways during the procession to salute and honor the passing of the veteran’s body.

Closure For Families

Simple yet magnificent, a Final Salute shows that a veteran is “gone but not forgotten” and also shows families they are not alone as they too made sacrifices to allow their loved ones to serve in the Armed Forces; it signals the hope of healing and closure.⁸ “The staff came to pay their respects,” recalled Cindy Roberts, a social worker at the VA Bay Pines, when her relative died at the Ozarks VAMC. She explained, I wasn’t expecting as much because it was 2 AM. I have never in my life had an experience like that. I wish there were words to describe it; I wish every VAMC in the country did that.”

Hope Danishanko, social worker at the VA Wilkes-Barre CLC, said veterans are appreciative of the program. “I have had many CLC residents tell me that the Honors Escort allows them to have closure. They also feel it provides respect to the veteran who has passed.”

Bettyanne Corkery noted that the Philadelphia CLC Honor Guard program is unique because it is veteran driven. “They have sessions in which they talk about what works and what doesn’t, and they recruit new volunteers themselves,” she said. “It has evolved into the most beautiful ceremony, and they are constantly tweaking it.” According to Gerry Donlon, “When you see all 8 members of the Honor Guard get a call at 2 AM, and everyone shows up, you know there’s personal satisfaction. I’d like to see every CLC [throughout VA] do this. I really would.”⁷

“Family members tell us they feel blessed and honored to be a part of the program. They are so grateful for the way we pay tribute to their veteran loved one,” says Leslie Schaeffer, support services manager and bereavement coordinator and coordinator of the Veteran Escort Ceremony at Bethesda Health Group communities.

Privileged and humbled—that is how staff and family members describe feeling after participating in a Final Salute. Its impact on the families has been amazing. Between the tears, there are thanks for the recognition of the sacrifices their loved ones made. When one family was informed of the ceremony by Reverend Tricia Lytle, Manager of Spiritual Care at AnMed Health, the “whole family responded by explaining how much that meant at such a difficult time. They began sharing stories about his service and how proud he was to be a veteran,” she reported. “As I [Rev. Lytle] leaned over to present the flag at the bedside, the wife reached up and took hold as she tearfully accepted it and embraced it close to her heart. The staff in the hallway looked on respectfully also in tears.”

Conclusions

The Final Salute is a brief ceremonial procession demonstrating that the mission to care for America’s veterans does not end at the bedside. It ensures that no veteran’s body is alone when led out of the health facility room to the exit. With these Final Salute practices, I hope that the rest of VA and community health facilities caring for veterans will implement a Final Salute program to better honor veterans who depart in their care.

Acknowledgments
The author would like to express gratitude to everyone who so openly shared their stories—your insight, advice, and encouragement are inspiring and invaluable. Thank you to all the facilities that consented to be featured in this article.

I am grateful for the opportunity to clarify and correct my recent commentary.¹ I wrote that the word provider was first used to refer to health care professionals during the 1930s in Nazi Germany, when Jewish physicians were termed Behandler. The cited manuscript stated that Behandler was “freely translated” as “provider.”² However, after reading social media comments that claimed this was a mistranslation, I sought to verify the translation.

Online German-English dictionaries yielded perplexing results. The dictionary Reverso translates Behandler as “dentist,” “practitioner,” or “therapist.”³ The Past Tenses Dictionary translates Behandler as “handlers.”⁴ Although a distasteful way to refer to a clinician-patient relationship, it still doesn’t translate as “provider.” The Collins and Cambridge dictionaries do not include Behandler, and the Langenscheidt dictionary does not provide a translation, instead noting that the translation “is missing” and that they are “verifying the word in question.”^5-7 Conversely, Anbieter appears to be the commonly provided German translation for provider.

The author of the original manuscript acknowledged that although Behandler is not listed as a translation for provider, it “comes close.”² He added that Behandler is not used anymore in German medicine because of the Nazi past (Saenger P, personal communication, February 9, 2022). A native German and Professor of German Studies at the University of Kentucky shared that “My best guess is that the term Behandler was used as a short form of Krankenbehandler, the designation for Jewish doctors in Nazi Germany who were still allowed to treat Jewish patients after withdrawal of their medical license. The best translations would be (health) practitioner or health care provider.” (Hobusch H, personal communication, 2022). However, Krankenbehandler has also been translated as “practitioner of the sick.”⁸

Given this ambiguity, it is ultimately unclear whether or to what extent Behandler can be translated as provider. Despite this uncertainty, my original argument remains unchanged. It is best to refer to all health care professionals (eg, psychotherapists, physicians, nurses, phlebotomists, pharmacists, physician assistants, social workers, physical therapists, dentists, optometrists) by their credentials. Overarching terms such as clinicians, practitioners, or health care professionals also are reasonable. This ensures accurate terminology, respects individuals’ unique training and degrees, and avoids confusion within multidisciplinary health care settings.

I thank Paul Saenger, MD, and Harald Höbusch, PhD, for their helpful insights, and those individuals who raised this concern on social media.

I am grateful for the opportunity to clarify and correct my recent commentary.¹ I wrote that the word provider was first used to refer to health care professionals during the 1930s in Nazi Germany, when Jewish physicians were termed Behandler. The cited manuscript stated that Behandler was “freely translated” as “provider.”² However, after reading social media comments that claimed this was a mistranslation, I sought to verify the translation.

Online German-English dictionaries yielded perplexing results. The dictionary Reverso translates Behandler as “dentist,” “practitioner,” or “therapist.”³ The Past Tenses Dictionary translates Behandler as “handlers.”⁴ Although a distasteful way to refer to a clinician-patient relationship, it still doesn’t translate as “provider.” The Collins and Cambridge dictionaries do not include Behandler, and the Langenscheidt dictionary does not provide a translation, instead noting that the translation “is missing” and that they are “verifying the word in question.”^5-7 Conversely, Anbieter appears to be the commonly provided German translation for provider.

The author of the original manuscript acknowledged that although Behandler is not listed as a translation for provider, it “comes close.”² He added that Behandler is not used anymore in German medicine because of the Nazi past (Saenger P, personal communication, February 9, 2022). A native German and Professor of German Studies at the University of Kentucky shared that “My best guess is that the term Behandler was used as a short form of Krankenbehandler, the designation for Jewish doctors in Nazi Germany who were still allowed to treat Jewish patients after withdrawal of their medical license. The best translations would be (health) practitioner or health care provider.” (Hobusch H, personal communication, 2022). However, Krankenbehandler has also been translated as “practitioner of the sick.”⁸

Given this ambiguity, it is ultimately unclear whether or to what extent Behandler can be translated as provider. Despite this uncertainty, my original argument remains unchanged. It is best to refer to all health care professionals (eg, psychotherapists, physicians, nurses, phlebotomists, pharmacists, physician assistants, social workers, physical therapists, dentists, optometrists) by their credentials. Overarching terms such as clinicians, practitioners, or health care professionals also are reasonable. This ensures accurate terminology, respects individuals’ unique training and degrees, and avoids confusion within multidisciplinary health care settings.

I thank Paul Saenger, MD, and Harald Höbusch, PhD, for their helpful insights, and those individuals who raised this concern on social media.

I am grateful for the opportunity to clarify and correct my recent commentary.¹ I wrote that the word provider was first used to refer to health care professionals during the 1930s in Nazi Germany, when Jewish physicians were termed Behandler. The cited manuscript stated that Behandler was “freely translated” as “provider.”² However, after reading social media comments that claimed this was a mistranslation, I sought to verify the translation.

Online German-English dictionaries yielded perplexing results. The dictionary Reverso translates Behandler as “dentist,” “practitioner,” or “therapist.”³ The Past Tenses Dictionary translates Behandler as “handlers.”⁴ Although a distasteful way to refer to a clinician-patient relationship, it still doesn’t translate as “provider.” The Collins and Cambridge dictionaries do not include Behandler, and the Langenscheidt dictionary does not provide a translation, instead noting that the translation “is missing” and that they are “verifying the word in question.”^5-7 Conversely, Anbieter appears to be the commonly provided German translation for provider.

The author of the original manuscript acknowledged that although Behandler is not listed as a translation for provider, it “comes close.”² He added that Behandler is not used anymore in German medicine because of the Nazi past (Saenger P, personal communication, February 9, 2022). A native German and Professor of German Studies at the University of Kentucky shared that “My best guess is that the term Behandler was used as a short form of Krankenbehandler, the designation for Jewish doctors in Nazi Germany who were still allowed to treat Jewish patients after withdrawal of their medical license. The best translations would be (health) practitioner or health care provider.” (Hobusch H, personal communication, 2022). However, Krankenbehandler has also been translated as “practitioner of the sick.”⁸

Given this ambiguity, it is ultimately unclear whether or to what extent Behandler can be translated as provider. Despite this uncertainty, my original argument remains unchanged. It is best to refer to all health care professionals (eg, psychotherapists, physicians, nurses, phlebotomists, pharmacists, physician assistants, social workers, physical therapists, dentists, optometrists) by their credentials. Overarching terms such as clinicians, practitioners, or health care professionals also are reasonable. This ensures accurate terminology, respects individuals’ unique training and degrees, and avoids confusion within multidisciplinary health care settings.

I thank Paul Saenger, MD, and Harald Höbusch, PhD, for their helpful insights, and those individuals who raised this concern on social media.

U.K. scientists said microplastics may pose even more of a threat than previously thought after confirming their presence in lung tissue taken from living people.

Microplastics were identified in all lung regions, but significantly higher levels were found in the lower lung.

The results supported inhalation as an exposure risk, according to the team from the University of Hull and Hull York Medical School (England), who said their findings could support further investigations into the effects of airborne microplastics on respiratory health.

The study, published in Science of the Total Environment, used lung tissue collected from surgical procedures on patients during routine medical care at Castle Hill Hospital in East Yorkshire.
 

Polypropylene and polyethylene

It found 39 microplastics in 11 of the 13 lung tissue samples tested using micro-Fourier-transform infrared (μFTIR) analysis, which the scientists said was considerably higher than results from previous laboratory tests.

Of microplastics detected, 12 polymer types were identified, of which the most common were polypropylene, (23%) polyethylene terephthalate (18%), and resin (15%). The fibers are commonly found in packaging, bottles, clothing, rope and twine manufacture, and other industries, the scientists said.

Microplastics with dimensions as small as 4 μm were found, but the scientists said they were surprised to discover samples as large as greater than 2 mm within all lung region samples, with the majority being fibrous and fragmented.

The study identified 11 microplastics in the upper part of the lung, seven in the mid part, and 21 in the lower part of the lung.

Laura Sadofsky, the study’s lead author, said: “Microplastics have previously been found in human cadaver autopsy samples. This is the first robust study to show microplastics in lungs from live people. It also shows that they are in the lower parts of the lung. Lung airways are very narrow, so no one thought they could possibly get there, but they clearly have.”

There were also considerably higher levels of microplastics found in male patients, compared with female patients.
 

Future investigations into health implications

“The characterization of types and levels of microplastics we have found can now inform realistic conditions for laboratory exposure experiments with the aim of determining health impacts,” said Laura Sadofsky, who is a senior lecturer in respiratory medicine in the Centre for Atherothrombotic and Metabolic Research at Hull York Medical School.

The latest investigation followed previous research by the medical school and the University of Hull, which found high levels of atmospheric microplastics within the Humber region.

That study, published in Atmosphere, identified resins, which could have originated from degraded roads, paint marking, or tire rubber, as well as polyethylene fibers.

A version of this article first appeared on Medscape UK.

U.K. scientists said microplastics may pose even more of a threat than previously thought after confirming their presence in lung tissue taken from living people.

Microplastics were identified in all lung regions, but significantly higher levels were found in the lower lung.

The results supported inhalation as an exposure risk, according to the team from the University of Hull and Hull York Medical School (England), who said their findings could support further investigations into the effects of airborne microplastics on respiratory health.

The study, published in Science of the Total Environment, used lung tissue collected from surgical procedures on patients during routine medical care at Castle Hill Hospital in East Yorkshire.
 

Polypropylene and polyethylene

It found 39 microplastics in 11 of the 13 lung tissue samples tested using micro-Fourier-transform infrared (μFTIR) analysis, which the scientists said was considerably higher than results from previous laboratory tests.

Of microplastics detected, 12 polymer types were identified, of which the most common were polypropylene, (23%) polyethylene terephthalate (18%), and resin (15%). The fibers are commonly found in packaging, bottles, clothing, rope and twine manufacture, and other industries, the scientists said.

Microplastics with dimensions as small as 4 μm were found, but the scientists said they were surprised to discover samples as large as greater than 2 mm within all lung region samples, with the majority being fibrous and fragmented.

The study identified 11 microplastics in the upper part of the lung, seven in the mid part, and 21 in the lower part of the lung.

Laura Sadofsky, the study’s lead author, said: “Microplastics have previously been found in human cadaver autopsy samples. This is the first robust study to show microplastics in lungs from live people. It also shows that they are in the lower parts of the lung. Lung airways are very narrow, so no one thought they could possibly get there, but they clearly have.”

There were also considerably higher levels of microplastics found in male patients, compared with female patients.
 

Future investigations into health implications

“The characterization of types and levels of microplastics we have found can now inform realistic conditions for laboratory exposure experiments with the aim of determining health impacts,” said Laura Sadofsky, who is a senior lecturer in respiratory medicine in the Centre for Atherothrombotic and Metabolic Research at Hull York Medical School.

The latest investigation followed previous research by the medical school and the University of Hull, which found high levels of atmospheric microplastics within the Humber region.

That study, published in Atmosphere, identified resins, which could have originated from degraded roads, paint marking, or tire rubber, as well as polyethylene fibers.

A version of this article first appeared on Medscape UK.

U.K. scientists said microplastics may pose even more of a threat than previously thought after confirming their presence in lung tissue taken from living people.

Microplastics were identified in all lung regions, but significantly higher levels were found in the lower lung.

The results supported inhalation as an exposure risk, according to the team from the University of Hull and Hull York Medical School (England), who said their findings could support further investigations into the effects of airborne microplastics on respiratory health.

The study, published in Science of the Total Environment, used lung tissue collected from surgical procedures on patients during routine medical care at Castle Hill Hospital in East Yorkshire.
 

Polypropylene and polyethylene

It found 39 microplastics in 11 of the 13 lung tissue samples tested using micro-Fourier-transform infrared (μFTIR) analysis, which the scientists said was considerably higher than results from previous laboratory tests.

Of microplastics detected, 12 polymer types were identified, of which the most common were polypropylene, (23%) polyethylene terephthalate (18%), and resin (15%). The fibers are commonly found in packaging, bottles, clothing, rope and twine manufacture, and other industries, the scientists said.

Microplastics with dimensions as small as 4 μm were found, but the scientists said they were surprised to discover samples as large as greater than 2 mm within all lung region samples, with the majority being fibrous and fragmented.

The study identified 11 microplastics in the upper part of the lung, seven in the mid part, and 21 in the lower part of the lung.

Laura Sadofsky, the study’s lead author, said: “Microplastics have previously been found in human cadaver autopsy samples. This is the first robust study to show microplastics in lungs from live people. It also shows that they are in the lower parts of the lung. Lung airways are very narrow, so no one thought they could possibly get there, but they clearly have.”

There were also considerably higher levels of microplastics found in male patients, compared with female patients.
 

Future investigations into health implications

“The characterization of types and levels of microplastics we have found can now inform realistic conditions for laboratory exposure experiments with the aim of determining health impacts,” said Laura Sadofsky, who is a senior lecturer in respiratory medicine in the Centre for Atherothrombotic and Metabolic Research at Hull York Medical School.

The latest investigation followed previous research by the medical school and the University of Hull, which found high levels of atmospheric microplastics within the Humber region.

That study, published in Atmosphere, identified resins, which could have originated from degraded roads, paint marking, or tire rubber, as well as polyethylene fibers.

A version of this article first appeared on Medscape UK.

When Sigmund Freud claimed that “anatomy is destiny” he was referring to anatomical sex as a determinant of personality traits. Expert consensus statements have previously offered some recommendations for managing these syndromes, but clinical data are scarce, so the present review “is intended to establish a starting point for future research,”

That notion has been widely discredited, but Freud appears to be inadvertently right in one respect: When it comes to chronic obstructive pulmonary disease (COPD), anatomy really is destiny, and sex may be as well, pulmonary researchers say.

There is a growing body of evidence to indicate that COPD affects men and women differently, and that men and women patients with COPD require different clinical management. Yet women are often underdiagnosed or misdiagnosed, partly because of poorly understood sex differences, but also because of cultural biases.

But plunging any farther into the weeds, it’s important to define terms. Although various investigators have used the terms “sex” and “gender” interchangeably, sex is the preferred term when referring to biological attributes of individual patients, while gender refers to personal identity.

These distinctions are important, contended Amik Sodhi, MBBS, MPH, from the division of allergy, pulmonology, and critical care medicine at the University of Wisconsin–Madison.

“Sex is essentially a biologic construct, so it’s got to do with the sex chromosomes, the genetics of that person, and it refers to the anatomic variations that can change susceptibility to different diseases,” she said in an interview.

An example of sex differences or “sexual dimorphism” can be found in a recent meta-analysis of sex-based genetic associations by Megan Hardin, MD, MPH from Brigham & Women’s Hospital in Boston and colleagues.

They reported that CELSR1, a gene involved in fetal lung development, was expressed more among women than among men and that a single nucleotide polymorphism in the gene was associated with COPD among women smokers, but not among men smokers.

The finding points to a potential risk locus for COPD in women, and could help shed light on sexual dimorphism in COPD, Dr. Hardin and colleagues said.

In contrast to sex, “gender is more of a psychosocial construct which can impact how diseases manifest themselves, how they are potentially managed, and what outcomes might occur for that particular disease,” Dr. Sodhi said.

She and her colleagues recently published a review of sex and gender in common lung disorders and sleep in the journal CHEST, where they wrote that the “influence of sex and gender is portrayed in epidemiological data, disease pathogenesis and pathophysiology, clinical manifestations, response to treatment, access to care, and health outcomes. Hence, sex and gender should be considered in all types of research, clinical practice and educational curricula.”

For example, as previously reported at the 2021 annual meeting of the American Thoracic Society, sex-specific differences in the severity of symptoms and prevalence of comorbidities in patients with COPD may point to different criteria for diagnosing cardiac comorbidities in women and men.

Those conclusions came from a retrospective analysis of data on 795 women and 1,251 men with GOLD (Global Initiative for Chronic Obstructive Lung Disease) class 1-3 disease.

The investigators looked at the patients’ clinical history, comorbidities, lung function, COPD Assessment Test scores, and modified Medical Research Council (mMRC) dyspnea score, and found significant differences between men and women for most functional parameters and comorbidities, and for CAT items of cough, phlegm, and energy.

In logistic regression analysis, predictors for cardiac disease in men were energy, mMRC score, smoking status, body mass index, age, and spirometric lung function, but in women only age was significantly predictive for cardiac disease.

An example of gender effects on COPD differences in men and women is the increase in cigarette advertising aimed at women in the 1960s and the advent of women-targeted brands such as Virginia Slims, which in turn lead to increased smoking rates among women. In addition, in the developing world, where the sex/gender gap in COPD is narrowing, women tend to have greater exposure to wood smoke and cooking fuels in unventilated or poorly ventilated spaces, compared with men.
 

Increasing incidence among women

According to the Centers for Disease Control and Prevention, chronic lower respiratory diseases, primarily COPD, were the fourth-leading cause of death in women in the United States in 2018, following only heart disease, cancer, and accidents/injuries.

And as a CDC analysis of data from the 2013 Behavioral Risk Factor Surveillance System showed, women were more likely to report being told by a physician that they had COPD than did men (6.6%, compared with 5.4%).

Dr. Sodhi and colleagues noted that, at all time points examined from 2005 to 2014, women had a higher proportion than men of COPD hospitalizations and in-hospital deaths. They also noted that female sex is associated with a threefold risk for severe early-onset COPD, and that women with COPD have lower diffusion capacity of lungs for carbon monoxide, despite having higher predicted forced expiratory volume in 1 second, compared with men.

“Historically, COPD wasn’t a disease that was so prevalent in women. It’s been in the past 20 years that the trends have changed,” said Patricia Silveyra, MSc, PhD, ATSF, associate professor of environmental and occupational health at Indiana University, Bloomington.

The increasing prevalence of COPD among women cannot be explained by smoking alone, she said in an interview.

“It used to be thought that it was because more women smoked, but actually a lot of women who don’t smoke can develop COPD, so it appears to be probably something environmental, but because it used to be a disease of older men, in the clinic there was also a bias to diagnose men with COPD, and women with asthma, so a lot of women went underdiagnosed,” Dr. Silveyra said.

In their review, Dr. Sodhi and colleagues noted that women with COPD “may be underdiagnosed as a result of having different symptoms from those classically recognized. Reasons for underdiagnosis or a delay in diagnosis may also be due to lack of a formal evaluation with spirometry, women seeking care later in the course of disease, physician bias, or associated fatigue or depression misdirecting diagnostic strategies. Underdiagnosis may be associated with psychological distress and worse health-related quality of life.”

Although the evidence is mixed, women tend to present more frequently with the chronic bronchitis phenotype of COPD, compared with the emphysema phenotype, and women tend to have greater degrees of pulmonary function impairment when exposed to tobacco smoke, even after controlling for differences in height and weight.

“For the same amount of exposure to tobacco smoke, females are likely to develop more severe airflow limitation at an earlier age than males, and have more exacerbation,” Dr. Sodhi and colleagues wrote.

Both Dr. Silveyra and Dr. Sodhi said that reason why men and women differ in their physiological reactions to smoke are still unknown.
 

Sex differences in drug responses

There is only limited evidence to indicate that women and men respond differently to various therapeutic agents, but what is clear is that more research into this area is needed, Dr. Sodhi and Dr. Silveyra said.

For example, among the few studies that have documented sex differences, one showed no sex differences in the efficacy of salmeterol/fluticasone combination therapy for reducing exacerbations or improving quality of life, whereas another showed that women were more likely than men to experience COPD symptoms or exacerbations after stopping inhaled corticosteroids, Dr. Sodhi and colleagues noted.

Both Dr. Sodhi and Dr. Silveyra emphasized the need for clinical trials that study the effects of sex on treatment outcomes in COPD, which could lead to better, more personalized therapeutic regimens that take sex and gender into account.

Dr. Sodhi and colleagues offered the following advice to clinicians: “Interaction with female patients should take into account that their symptoms may not conform to traditionally accepted presentations. Challenges exist for female patients at all levels of health care interaction and as clinicians we need to acknowledge the bias and willfully work toward recognition and elimination of unconscious and conscious bias. Empowering our patients to have frank discussions with their health care team when they perceive bias is another step to help promote equity.”

The review by Dr. Sodhi and colleagues was supported by grants from the National Institutes of Health. Dr. Sodhi and Dr. Silveyra reported having no conflicts of interest to disclose.

When Sigmund Freud claimed that “anatomy is destiny” he was referring to anatomical sex as a determinant of personality traits. Expert consensus statements have previously offered some recommendations for managing these syndromes, but clinical data are scarce, so the present review “is intended to establish a starting point for future research,”

That notion has been widely discredited, but Freud appears to be inadvertently right in one respect: When it comes to chronic obstructive pulmonary disease (COPD), anatomy really is destiny, and sex may be as well, pulmonary researchers say.

There is a growing body of evidence to indicate that COPD affects men and women differently, and that men and women patients with COPD require different clinical management. Yet women are often underdiagnosed or misdiagnosed, partly because of poorly understood sex differences, but also because of cultural biases.

But plunging any farther into the weeds, it’s important to define terms. Although various investigators have used the terms “sex” and “gender” interchangeably, sex is the preferred term when referring to biological attributes of individual patients, while gender refers to personal identity.

These distinctions are important, contended Amik Sodhi, MBBS, MPH, from the division of allergy, pulmonology, and critical care medicine at the University of Wisconsin–Madison.

“Sex is essentially a biologic construct, so it’s got to do with the sex chromosomes, the genetics of that person, and it refers to the anatomic variations that can change susceptibility to different diseases,” she said in an interview.

An example of sex differences or “sexual dimorphism” can be found in a recent meta-analysis of sex-based genetic associations by Megan Hardin, MD, MPH from Brigham & Women’s Hospital in Boston and colleagues.

They reported that CELSR1, a gene involved in fetal lung development, was expressed more among women than among men and that a single nucleotide polymorphism in the gene was associated with COPD among women smokers, but not among men smokers.

The finding points to a potential risk locus for COPD in women, and could help shed light on sexual dimorphism in COPD, Dr. Hardin and colleagues said.

In contrast to sex, “gender is more of a psychosocial construct which can impact how diseases manifest themselves, how they are potentially managed, and what outcomes might occur for that particular disease,” Dr. Sodhi said.

She and her colleagues recently published a review of sex and gender in common lung disorders and sleep in the journal CHEST, where they wrote that the “influence of sex and gender is portrayed in epidemiological data, disease pathogenesis and pathophysiology, clinical manifestations, response to treatment, access to care, and health outcomes. Hence, sex and gender should be considered in all types of research, clinical practice and educational curricula.”

For example, as previously reported at the 2021 annual meeting of the American Thoracic Society, sex-specific differences in the severity of symptoms and prevalence of comorbidities in patients with COPD may point to different criteria for diagnosing cardiac comorbidities in women and men.

Those conclusions came from a retrospective analysis of data on 795 women and 1,251 men with GOLD (Global Initiative for Chronic Obstructive Lung Disease) class 1-3 disease.

The investigators looked at the patients’ clinical history, comorbidities, lung function, COPD Assessment Test scores, and modified Medical Research Council (mMRC) dyspnea score, and found significant differences between men and women for most functional parameters and comorbidities, and for CAT items of cough, phlegm, and energy.

In logistic regression analysis, predictors for cardiac disease in men were energy, mMRC score, smoking status, body mass index, age, and spirometric lung function, but in women only age was significantly predictive for cardiac disease.

An example of gender effects on COPD differences in men and women is the increase in cigarette advertising aimed at women in the 1960s and the advent of women-targeted brands such as Virginia Slims, which in turn lead to increased smoking rates among women. In addition, in the developing world, where the sex/gender gap in COPD is narrowing, women tend to have greater exposure to wood smoke and cooking fuels in unventilated or poorly ventilated spaces, compared with men.
 

Increasing incidence among women

According to the Centers for Disease Control and Prevention, chronic lower respiratory diseases, primarily COPD, were the fourth-leading cause of death in women in the United States in 2018, following only heart disease, cancer, and accidents/injuries.

And as a CDC analysis of data from the 2013 Behavioral Risk Factor Surveillance System showed, women were more likely to report being told by a physician that they had COPD than did men (6.6%, compared with 5.4%).

Dr. Sodhi and colleagues noted that, at all time points examined from 2005 to 2014, women had a higher proportion than men of COPD hospitalizations and in-hospital deaths. They also noted that female sex is associated with a threefold risk for severe early-onset COPD, and that women with COPD have lower diffusion capacity of lungs for carbon monoxide, despite having higher predicted forced expiratory volume in 1 second, compared with men.

“Historically, COPD wasn’t a disease that was so prevalent in women. It’s been in the past 20 years that the trends have changed,” said Patricia Silveyra, MSc, PhD, ATSF, associate professor of environmental and occupational health at Indiana University, Bloomington.

The increasing prevalence of COPD among women cannot be explained by smoking alone, she said in an interview.

“It used to be thought that it was because more women smoked, but actually a lot of women who don’t smoke can develop COPD, so it appears to be probably something environmental, but because it used to be a disease of older men, in the clinic there was also a bias to diagnose men with COPD, and women with asthma, so a lot of women went underdiagnosed,” Dr. Silveyra said.

In their review, Dr. Sodhi and colleagues noted that women with COPD “may be underdiagnosed as a result of having different symptoms from those classically recognized. Reasons for underdiagnosis or a delay in diagnosis may also be due to lack of a formal evaluation with spirometry, women seeking care later in the course of disease, physician bias, or associated fatigue or depression misdirecting diagnostic strategies. Underdiagnosis may be associated with psychological distress and worse health-related quality of life.”

Although the evidence is mixed, women tend to present more frequently with the chronic bronchitis phenotype of COPD, compared with the emphysema phenotype, and women tend to have greater degrees of pulmonary function impairment when exposed to tobacco smoke, even after controlling for differences in height and weight.

“For the same amount of exposure to tobacco smoke, females are likely to develop more severe airflow limitation at an earlier age than males, and have more exacerbation,” Dr. Sodhi and colleagues wrote.

Both Dr. Silveyra and Dr. Sodhi said that reason why men and women differ in their physiological reactions to smoke are still unknown.
 

Sex differences in drug responses

There is only limited evidence to indicate that women and men respond differently to various therapeutic agents, but what is clear is that more research into this area is needed, Dr. Sodhi and Dr. Silveyra said.

For example, among the few studies that have documented sex differences, one showed no sex differences in the efficacy of salmeterol/fluticasone combination therapy for reducing exacerbations or improving quality of life, whereas another showed that women were more likely than men to experience COPD symptoms or exacerbations after stopping inhaled corticosteroids, Dr. Sodhi and colleagues noted.

Both Dr. Sodhi and Dr. Silveyra emphasized the need for clinical trials that study the effects of sex on treatment outcomes in COPD, which could lead to better, more personalized therapeutic regimens that take sex and gender into account.

Dr. Sodhi and colleagues offered the following advice to clinicians: “Interaction with female patients should take into account that their symptoms may not conform to traditionally accepted presentations. Challenges exist for female patients at all levels of health care interaction and as clinicians we need to acknowledge the bias and willfully work toward recognition and elimination of unconscious and conscious bias. Empowering our patients to have frank discussions with their health care team when they perceive bias is another step to help promote equity.”

The review by Dr. Sodhi and colleagues was supported by grants from the National Institutes of Health. Dr. Sodhi and Dr. Silveyra reported having no conflicts of interest to disclose.

When Sigmund Freud claimed that “anatomy is destiny” he was referring to anatomical sex as a determinant of personality traits. Expert consensus statements have previously offered some recommendations for managing these syndromes, but clinical data are scarce, so the present review “is intended to establish a starting point for future research,”

That notion has been widely discredited, but Freud appears to be inadvertently right in one respect: When it comes to chronic obstructive pulmonary disease (COPD), anatomy really is destiny, and sex may be as well, pulmonary researchers say.

There is a growing body of evidence to indicate that COPD affects men and women differently, and that men and women patients with COPD require different clinical management. Yet women are often underdiagnosed or misdiagnosed, partly because of poorly understood sex differences, but also because of cultural biases.

But plunging any farther into the weeds, it’s important to define terms. Although various investigators have used the terms “sex” and “gender” interchangeably, sex is the preferred term when referring to biological attributes of individual patients, while gender refers to personal identity.

These distinctions are important, contended Amik Sodhi, MBBS, MPH, from the division of allergy, pulmonology, and critical care medicine at the University of Wisconsin–Madison.

“Sex is essentially a biologic construct, so it’s got to do with the sex chromosomes, the genetics of that person, and it refers to the anatomic variations that can change susceptibility to different diseases,” she said in an interview.

An example of sex differences or “sexual dimorphism” can be found in a recent meta-analysis of sex-based genetic associations by Megan Hardin, MD, MPH from Brigham & Women’s Hospital in Boston and colleagues.

They reported that CELSR1, a gene involved in fetal lung development, was expressed more among women than among men and that a single nucleotide polymorphism in the gene was associated with COPD among women smokers, but not among men smokers.

The finding points to a potential risk locus for COPD in women, and could help shed light on sexual dimorphism in COPD, Dr. Hardin and colleagues said.

In contrast to sex, “gender is more of a psychosocial construct which can impact how diseases manifest themselves, how they are potentially managed, and what outcomes might occur for that particular disease,” Dr. Sodhi said.

She and her colleagues recently published a review of sex and gender in common lung disorders and sleep in the journal CHEST, where they wrote that the “influence of sex and gender is portrayed in epidemiological data, disease pathogenesis and pathophysiology, clinical manifestations, response to treatment, access to care, and health outcomes. Hence, sex and gender should be considered in all types of research, clinical practice and educational curricula.”

For example, as previously reported at the 2021 annual meeting of the American Thoracic Society, sex-specific differences in the severity of symptoms and prevalence of comorbidities in patients with COPD may point to different criteria for diagnosing cardiac comorbidities in women and men.

Those conclusions came from a retrospective analysis of data on 795 women and 1,251 men with GOLD (Global Initiative for Chronic Obstructive Lung Disease) class 1-3 disease.

The investigators looked at the patients’ clinical history, comorbidities, lung function, COPD Assessment Test scores, and modified Medical Research Council (mMRC) dyspnea score, and found significant differences between men and women for most functional parameters and comorbidities, and for CAT items of cough, phlegm, and energy.

In logistic regression analysis, predictors for cardiac disease in men were energy, mMRC score, smoking status, body mass index, age, and spirometric lung function, but in women only age was significantly predictive for cardiac disease.

An example of gender effects on COPD differences in men and women is the increase in cigarette advertising aimed at women in the 1960s and the advent of women-targeted brands such as Virginia Slims, which in turn lead to increased smoking rates among women. In addition, in the developing world, where the sex/gender gap in COPD is narrowing, women tend to have greater exposure to wood smoke and cooking fuels in unventilated or poorly ventilated spaces, compared with men.
 

Increasing incidence among women

According to the Centers for Disease Control and Prevention, chronic lower respiratory diseases, primarily COPD, were the fourth-leading cause of death in women in the United States in 2018, following only heart disease, cancer, and accidents/injuries.

And as a CDC analysis of data from the 2013 Behavioral Risk Factor Surveillance System showed, women were more likely to report being told by a physician that they had COPD than did men (6.6%, compared with 5.4%).

Dr. Sodhi and colleagues noted that, at all time points examined from 2005 to 2014, women had a higher proportion than men of COPD hospitalizations and in-hospital deaths. They also noted that female sex is associated with a threefold risk for severe early-onset COPD, and that women with COPD have lower diffusion capacity of lungs for carbon monoxide, despite having higher predicted forced expiratory volume in 1 second, compared with men.

“Historically, COPD wasn’t a disease that was so prevalent in women. It’s been in the past 20 years that the trends have changed,” said Patricia Silveyra, MSc, PhD, ATSF, associate professor of environmental and occupational health at Indiana University, Bloomington.

The increasing prevalence of COPD among women cannot be explained by smoking alone, she said in an interview.

“It used to be thought that it was because more women smoked, but actually a lot of women who don’t smoke can develop COPD, so it appears to be probably something environmental, but because it used to be a disease of older men, in the clinic there was also a bias to diagnose men with COPD, and women with asthma, so a lot of women went underdiagnosed,” Dr. Silveyra said.

In their review, Dr. Sodhi and colleagues noted that women with COPD “may be underdiagnosed as a result of having different symptoms from those classically recognized. Reasons for underdiagnosis or a delay in diagnosis may also be due to lack of a formal evaluation with spirometry, women seeking care later in the course of disease, physician bias, or associated fatigue or depression misdirecting diagnostic strategies. Underdiagnosis may be associated with psychological distress and worse health-related quality of life.”

Although the evidence is mixed, women tend to present more frequently with the chronic bronchitis phenotype of COPD, compared with the emphysema phenotype, and women tend to have greater degrees of pulmonary function impairment when exposed to tobacco smoke, even after controlling for differences in height and weight.

“For the same amount of exposure to tobacco smoke, females are likely to develop more severe airflow limitation at an earlier age than males, and have more exacerbation,” Dr. Sodhi and colleagues wrote.

Both Dr. Silveyra and Dr. Sodhi said that reason why men and women differ in their physiological reactions to smoke are still unknown.
 

Sex differences in drug responses

There is only limited evidence to indicate that women and men respond differently to various therapeutic agents, but what is clear is that more research into this area is needed, Dr. Sodhi and Dr. Silveyra said.

For example, among the few studies that have documented sex differences, one showed no sex differences in the efficacy of salmeterol/fluticasone combination therapy for reducing exacerbations or improving quality of life, whereas another showed that women were more likely than men to experience COPD symptoms or exacerbations after stopping inhaled corticosteroids, Dr. Sodhi and colleagues noted.

Both Dr. Sodhi and Dr. Silveyra emphasized the need for clinical trials that study the effects of sex on treatment outcomes in COPD, which could lead to better, more personalized therapeutic regimens that take sex and gender into account.

Dr. Sodhi and colleagues offered the following advice to clinicians: “Interaction with female patients should take into account that their symptoms may not conform to traditionally accepted presentations. Challenges exist for female patients at all levels of health care interaction and as clinicians we need to acknowledge the bias and willfully work toward recognition and elimination of unconscious and conscious bias. Empowering our patients to have frank discussions with their health care team when they perceive bias is another step to help promote equity.”

The review by Dr. Sodhi and colleagues was supported by grants from the National Institutes of Health. Dr. Sodhi and Dr. Silveyra reported having no conflicts of interest to disclose.

Since the start of the pandemic, supply-chain problems have permeated just about every industry sector. While most of the media attention has focused on toilet paper and retail shipment delays, a darker, more sinister supply chain disruption has been unfolding, one that entails a sophisticated criminal enterprise that has been operating at scale to distribute and profit from counterfeit HIV drugs.

Recently, news has emerged – most notably in the Wall Street Journal – with reports of a Justice Department investigation into what appears to be a national drug trafficking network comprising more than 70 distributors and marketers.

The details read like a best-selling crime novel.

Since last year, authorities have seized 85,247 bottles of counterfeit HIV drugs, both Biktarvy (bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg tablets) and Descovy (emtricitabine 200 mg and tenofovir alafenamide 25 mg tablets). Law enforcement has conducted raids at 17 locations in eight states. Doctored supply chain papers have provided cover for the fake medicines and the individuals behind them.

But unlike the inconvenience of sparse toilet paper, this crime poses life-threatening risks to millions of patients with HIV who rely on Biktarvy to suppress the virus or Descovy to prevent infection from it. Even worse, some patients have been exposed to over-the-counter painkillers or the antipsychotic drug quetiapine fumarate masquerading as HIV drugs in legitimate but repurposed bottles.

Gilead Sciences (Foster City, Calif.), which manufactures both Biktarvy and Descovy, declined to comment when contacted, instead referring this news organization to previous press statements.
 

Falsified HIV medications, illicit purchases over 2 Years

On Aug. 5, 2021, Gilead first warned the public that it had become aware of tampered and counterfeit Biktarvy and Descovy tablets. In coordination with the Food and Drug Administration, it alerted pharmacies to “investigate the potential for counterfeit or tampered Gilead medication sold by [unauthorized] distributors that may be within their recent supply.”

On Jan. 19, 2022, Gilead issued a second statement outlining ongoing actions in coordination with U.S. marshals and local law enforcement to remove these illegal medications from circulation and prevent further distribution.

The timing of the most recent announcement was not accidental. The day before, a federal judge serving the U.S. District Court for the Eastern District of New York unsealed documents detailing the company’s lawsuit against dozens of individuals and entities who they alleged had engaged in a highly coordinated effort to defraud pharmacies and consumers. The suit followed two prior Gilead filings that ultimately resulted in court-issued ex parte seizure orders (orders that allow a court to seize property without the property owner’s consent) and the recovery of more than 1,000 bottles containing questionable Gilead medications.

The lawsuit centered on Cambridge, Mass.–based wholesale pharmaceutical distributor Safe Chain Solutions and its two cofounders. The document is peppered with terms such as “shifting series of fly-by-night corporate entities,” “gray market” distributors, a “dedicated sales force,” and “shell entities,” along with accusations that the defendants were believed to have made purchases of gold bullion, jewelry, and other luxury items for conversion into cash.

In a curious twist of fate, this sinister effort appeared to have been first revealed not by a pharmacist but by a patient who had returned a bottle of Biktarvy with “foreign medication inside” to the California pharmacy that dispensed it.

“Specifically with HIV medications, there’s no point in which the pharmacy is actually opening the bottle, breaking the seal, and counting out pills to put into a smaller prescription bottle,” Emily Heil, PharmD, BCIDP, AAHIVP, associate professor of infectious diseases in the department of pharmacy practice and science at the University of Maryland School of Pharmacy, Baltimore, told this news organization.

“But that’s also why pharmacies work with these centralized groups of distributors that maintain a chain of command and fidelity with drug manufacturers so that we don’t run into these situations,” she said.

This is the link in the chain where that tightly coordinated and highly regulated process was broken.

Although Gilead and Safe Chain Solutions were informed of the incident as early as August 2020, the distributor repeatedly refused to identify the supplier and the pedigree (the record demonstrating the chain of all sales or transfers of a specific drug, going back to the manufacturer, as required by the FDA’s Drug Supply Chain Security Act in 2013).

Later that year, Janssen Pharmaceutical Companies of Johnson & Johnson issued a media statement saying that they had been alerted to the distribution of counterfeit Symtuza (darunavir/cobicistat/emtricitabine/tenofovir alafenamide) to three pharmacies in the United States.

A spokesperson for the FDA declined to comment on the ongoing investigation when contacted by this news organization and instead wrote in an email that the agency “will continue to use all available tools to ensure consumers and patients have access to a safe and effective medical product supply.”
 

Old dog, new tricks

This is not the first time that HIV drugs have been targeted for criminal benefit. An analysis published in September 2014 in JAMA highlighted a federal investigation that year into a $32 million dollar scheme to defraud Medicare’s Part D program for HIV drugs and divert them for resale on the black market.

What’s more, prior research and news reports highlight the attractiveness of HIV drug diversion both for the buyer and the seller – not only because of the cost of the drugs themselves but also because of institutional or systemic deficiencies that exclude certain individuals from obtaining treatment through federal initiatives such as the Ryan White/AIDS Drug Assistance program.

In its most recent statement, Gilead reinforced that this practice remains alive and well.

On the buyer side, the company stated, many of the counterfeits originated from suppliers who purchased Gilead HIV medication from individuals after it was first dispensed to them. Unfortunately, the exploitation of individuals with low incomes who experience homelessness or substance use/abuse echoes a pattern whereby HIV patients sell medications to cover personal needs or are forced to buy them on the black market to keep up with their treatment regimens.

On the supply side, Gilead explained that individuals’ medications “are unlawfully resold ... on the secondary market by way of counterfeit supply chain documentation, concealing and fraudulently misrepresenting its origin. All of these counterfeits were sold as though they were legitimate Gilead products.”

But counterfeit pedigrees make it impossible to verify where the products came from, how they have been handled and stored, and what pills are in the bottles – all of which can have dire consequences for patients who ingest them.

The ramifications can be devastating.

“With HIV meds specifically, the worst case scenario would be if the medication is not actually the medication they’re supposed to be on,” said Dr. Heil, reinforcing that the increased safety net provided with viral suppression and against transmission is lost.

Dr. Heil pointed to another significant risk: resistance.

“In a situation like this, where maybe it’s not the full strength of the medication, maybe it’s expired and lost potency or was not stored correctly or is not even the accurate medication, changing those drug level exposures potentially puts the patient at risk for developing resistance to their regimen without them knowing.”

Yet another risk was posed by the replacement of HIV drugs with other medications, such as quetiapine, which increased the risk for life-threatening and irreversible side effects. The lawsuit included a story of a patient who unknowingly took quetiapine after receiving a counterfeit bottle of Biktarvy and could not speak or walk afterward.

Where this tale will ultimately end is unclear. There’s no telling what other activities or bad actors the Justice Department investigation will uncover as it works to unravel the counterfeit network’s activities and deal with its aftermath.

Regardless, clinicians are encouraged to inform HIV patients about the risks associated with counterfeit medications, how to determine whether the drugs they’ve been dispensed are authentic, and to report any product they believe to be counterfeit or to have been tampered with to their doctors, pharmacies, and to Gilead or other drug manufacturers.

“It’s okay to ask questions of your pharmacy about where they get their medications from,” noted Dr. Heil. “If patients have access to an independent pharmacy, it’s a great way for them to have a relationship with their pharmacist.

“We went into this profession to be able to have those conversations with patients,” Dr. Heil said.

The FDA recommends that patients receiving these medications who believe that their drugs may be counterfeit or who experience any adverse effects report the event to FDA’s MedWatch Safety Information and Adverse Event Reporting Program (1-800-FDA-1088 or www.fda.gov/medwatch).

Dr. Heil reported having no relevant financial relationships.

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

Since the start of the pandemic, supply-chain problems have permeated just about every industry sector. While most of the media attention has focused on toilet paper and retail shipment delays, a darker, more sinister supply chain disruption has been unfolding, one that entails a sophisticated criminal enterprise that has been operating at scale to distribute and profit from counterfeit HIV drugs.

Recently, news has emerged – most notably in the Wall Street Journal – with reports of a Justice Department investigation into what appears to be a national drug trafficking network comprising more than 70 distributors and marketers.

The details read like a best-selling crime novel.

Since last year, authorities have seized 85,247 bottles of counterfeit HIV drugs, both Biktarvy (bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg tablets) and Descovy (emtricitabine 200 mg and tenofovir alafenamide 25 mg tablets). Law enforcement has conducted raids at 17 locations in eight states. Doctored supply chain papers have provided cover for the fake medicines and the individuals behind them.

But unlike the inconvenience of sparse toilet paper, this crime poses life-threatening risks to millions of patients with HIV who rely on Biktarvy to suppress the virus or Descovy to prevent infection from it. Even worse, some patients have been exposed to over-the-counter painkillers or the antipsychotic drug quetiapine fumarate masquerading as HIV drugs in legitimate but repurposed bottles.

Gilead Sciences (Foster City, Calif.), which manufactures both Biktarvy and Descovy, declined to comment when contacted, instead referring this news organization to previous press statements.
 

Falsified HIV medications, illicit purchases over 2 Years

On Aug. 5, 2021, Gilead first warned the public that it had become aware of tampered and counterfeit Biktarvy and Descovy tablets. In coordination with the Food and Drug Administration, it alerted pharmacies to “investigate the potential for counterfeit or tampered Gilead medication sold by [unauthorized] distributors that may be within their recent supply.”

On Jan. 19, 2022, Gilead issued a second statement outlining ongoing actions in coordination with U.S. marshals and local law enforcement to remove these illegal medications from circulation and prevent further distribution.

The timing of the most recent announcement was not accidental. The day before, a federal judge serving the U.S. District Court for the Eastern District of New York unsealed documents detailing the company’s lawsuit against dozens of individuals and entities who they alleged had engaged in a highly coordinated effort to defraud pharmacies and consumers. The suit followed two prior Gilead filings that ultimately resulted in court-issued ex parte seizure orders (orders that allow a court to seize property without the property owner’s consent) and the recovery of more than 1,000 bottles containing questionable Gilead medications.

The lawsuit centered on Cambridge, Mass.–based wholesale pharmaceutical distributor Safe Chain Solutions and its two cofounders. The document is peppered with terms such as “shifting series of fly-by-night corporate entities,” “gray market” distributors, a “dedicated sales force,” and “shell entities,” along with accusations that the defendants were believed to have made purchases of gold bullion, jewelry, and other luxury items for conversion into cash.

In a curious twist of fate, this sinister effort appeared to have been first revealed not by a pharmacist but by a patient who had returned a bottle of Biktarvy with “foreign medication inside” to the California pharmacy that dispensed it.

“Specifically with HIV medications, there’s no point in which the pharmacy is actually opening the bottle, breaking the seal, and counting out pills to put into a smaller prescription bottle,” Emily Heil, PharmD, BCIDP, AAHIVP, associate professor of infectious diseases in the department of pharmacy practice and science at the University of Maryland School of Pharmacy, Baltimore, told this news organization.

“But that’s also why pharmacies work with these centralized groups of distributors that maintain a chain of command and fidelity with drug manufacturers so that we don’t run into these situations,” she said.

This is the link in the chain where that tightly coordinated and highly regulated process was broken.

Although Gilead and Safe Chain Solutions were informed of the incident as early as August 2020, the distributor repeatedly refused to identify the supplier and the pedigree (the record demonstrating the chain of all sales or transfers of a specific drug, going back to the manufacturer, as required by the FDA’s Drug Supply Chain Security Act in 2013).

Later that year, Janssen Pharmaceutical Companies of Johnson & Johnson issued a media statement saying that they had been alerted to the distribution of counterfeit Symtuza (darunavir/cobicistat/emtricitabine/tenofovir alafenamide) to three pharmacies in the United States.

A spokesperson for the FDA declined to comment on the ongoing investigation when contacted by this news organization and instead wrote in an email that the agency “will continue to use all available tools to ensure consumers and patients have access to a safe and effective medical product supply.”
 

Old dog, new tricks

This is not the first time that HIV drugs have been targeted for criminal benefit. An analysis published in September 2014 in JAMA highlighted a federal investigation that year into a $32 million dollar scheme to defraud Medicare’s Part D program for HIV drugs and divert them for resale on the black market.

What’s more, prior research and news reports highlight the attractiveness of HIV drug diversion both for the buyer and the seller – not only because of the cost of the drugs themselves but also because of institutional or systemic deficiencies that exclude certain individuals from obtaining treatment through federal initiatives such as the Ryan White/AIDS Drug Assistance program.

In its most recent statement, Gilead reinforced that this practice remains alive and well.

On the buyer side, the company stated, many of the counterfeits originated from suppliers who purchased Gilead HIV medication from individuals after it was first dispensed to them. Unfortunately, the exploitation of individuals with low incomes who experience homelessness or substance use/abuse echoes a pattern whereby HIV patients sell medications to cover personal needs or are forced to buy them on the black market to keep up with their treatment regimens.

On the supply side, Gilead explained that individuals’ medications “are unlawfully resold ... on the secondary market by way of counterfeit supply chain documentation, concealing and fraudulently misrepresenting its origin. All of these counterfeits were sold as though they were legitimate Gilead products.”

But counterfeit pedigrees make it impossible to verify where the products came from, how they have been handled and stored, and what pills are in the bottles – all of which can have dire consequences for patients who ingest them.

The ramifications can be devastating.

“With HIV meds specifically, the worst case scenario would be if the medication is not actually the medication they’re supposed to be on,” said Dr. Heil, reinforcing that the increased safety net provided with viral suppression and against transmission is lost.

Dr. Heil pointed to another significant risk: resistance.

“In a situation like this, where maybe it’s not the full strength of the medication, maybe it’s expired and lost potency or was not stored correctly or is not even the accurate medication, changing those drug level exposures potentially puts the patient at risk for developing resistance to their regimen without them knowing.”

Yet another risk was posed by the replacement of HIV drugs with other medications, such as quetiapine, which increased the risk for life-threatening and irreversible side effects. The lawsuit included a story of a patient who unknowingly took quetiapine after receiving a counterfeit bottle of Biktarvy and could not speak or walk afterward.

Where this tale will ultimately end is unclear. There’s no telling what other activities or bad actors the Justice Department investigation will uncover as it works to unravel the counterfeit network’s activities and deal with its aftermath.

Regardless, clinicians are encouraged to inform HIV patients about the risks associated with counterfeit medications, how to determine whether the drugs they’ve been dispensed are authentic, and to report any product they believe to be counterfeit or to have been tampered with to their doctors, pharmacies, and to Gilead or other drug manufacturers.

“It’s okay to ask questions of your pharmacy about where they get their medications from,” noted Dr. Heil. “If patients have access to an independent pharmacy, it’s a great way for them to have a relationship with their pharmacist.

“We went into this profession to be able to have those conversations with patients,” Dr. Heil said.

The FDA recommends that patients receiving these medications who believe that their drugs may be counterfeit or who experience any adverse effects report the event to FDA’s MedWatch Safety Information and Adverse Event Reporting Program (1-800-FDA-1088 or www.fda.gov/medwatch).

Dr. Heil reported having no relevant financial relationships.

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

Since the start of the pandemic, supply-chain problems have permeated just about every industry sector. While most of the media attention has focused on toilet paper and retail shipment delays, a darker, more sinister supply chain disruption has been unfolding, one that entails a sophisticated criminal enterprise that has been operating at scale to distribute and profit from counterfeit HIV drugs.

Recently, news has emerged – most notably in the Wall Street Journal – with reports of a Justice Department investigation into what appears to be a national drug trafficking network comprising more than 70 distributors and marketers.

The details read like a best-selling crime novel.

Since last year, authorities have seized 85,247 bottles of counterfeit HIV drugs, both Biktarvy (bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg tablets) and Descovy (emtricitabine 200 mg and tenofovir alafenamide 25 mg tablets). Law enforcement has conducted raids at 17 locations in eight states. Doctored supply chain papers have provided cover for the fake medicines and the individuals behind them.

But unlike the inconvenience of sparse toilet paper, this crime poses life-threatening risks to millions of patients with HIV who rely on Biktarvy to suppress the virus or Descovy to prevent infection from it. Even worse, some patients have been exposed to over-the-counter painkillers or the antipsychotic drug quetiapine fumarate masquerading as HIV drugs in legitimate but repurposed bottles.

Gilead Sciences (Foster City, Calif.), which manufactures both Biktarvy and Descovy, declined to comment when contacted, instead referring this news organization to previous press statements.
 

Falsified HIV medications, illicit purchases over 2 Years

On Aug. 5, 2021, Gilead first warned the public that it had become aware of tampered and counterfeit Biktarvy and Descovy tablets. In coordination with the Food and Drug Administration, it alerted pharmacies to “investigate the potential for counterfeit or tampered Gilead medication sold by [unauthorized] distributors that may be within their recent supply.”

On Jan. 19, 2022, Gilead issued a second statement outlining ongoing actions in coordination with U.S. marshals and local law enforcement to remove these illegal medications from circulation and prevent further distribution.

The timing of the most recent announcement was not accidental. The day before, a federal judge serving the U.S. District Court for the Eastern District of New York unsealed documents detailing the company’s lawsuit against dozens of individuals and entities who they alleged had engaged in a highly coordinated effort to defraud pharmacies and consumers. The suit followed two prior Gilead filings that ultimately resulted in court-issued ex parte seizure orders (orders that allow a court to seize property without the property owner’s consent) and the recovery of more than 1,000 bottles containing questionable Gilead medications.

The lawsuit centered on Cambridge, Mass.–based wholesale pharmaceutical distributor Safe Chain Solutions and its two cofounders. The document is peppered with terms such as “shifting series of fly-by-night corporate entities,” “gray market” distributors, a “dedicated sales force,” and “shell entities,” along with accusations that the defendants were believed to have made purchases of gold bullion, jewelry, and other luxury items for conversion into cash.

In a curious twist of fate, this sinister effort appeared to have been first revealed not by a pharmacist but by a patient who had returned a bottle of Biktarvy with “foreign medication inside” to the California pharmacy that dispensed it.

“Specifically with HIV medications, there’s no point in which the pharmacy is actually opening the bottle, breaking the seal, and counting out pills to put into a smaller prescription bottle,” Emily Heil, PharmD, BCIDP, AAHIVP, associate professor of infectious diseases in the department of pharmacy practice and science at the University of Maryland School of Pharmacy, Baltimore, told this news organization.

“But that’s also why pharmacies work with these centralized groups of distributors that maintain a chain of command and fidelity with drug manufacturers so that we don’t run into these situations,” she said.

This is the link in the chain where that tightly coordinated and highly regulated process was broken.

Although Gilead and Safe Chain Solutions were informed of the incident as early as August 2020, the distributor repeatedly refused to identify the supplier and the pedigree (the record demonstrating the chain of all sales or transfers of a specific drug, going back to the manufacturer, as required by the FDA’s Drug Supply Chain Security Act in 2013).

Later that year, Janssen Pharmaceutical Companies of Johnson & Johnson issued a media statement saying that they had been alerted to the distribution of counterfeit Symtuza (darunavir/cobicistat/emtricitabine/tenofovir alafenamide) to three pharmacies in the United States.

A spokesperson for the FDA declined to comment on the ongoing investigation when contacted by this news organization and instead wrote in an email that the agency “will continue to use all available tools to ensure consumers and patients have access to a safe and effective medical product supply.”
 

Old dog, new tricks

This is not the first time that HIV drugs have been targeted for criminal benefit. An analysis published in September 2014 in JAMA highlighted a federal investigation that year into a $32 million dollar scheme to defraud Medicare’s Part D program for HIV drugs and divert them for resale on the black market.

What’s more, prior research and news reports highlight the attractiveness of HIV drug diversion both for the buyer and the seller – not only because of the cost of the drugs themselves but also because of institutional or systemic deficiencies that exclude certain individuals from obtaining treatment through federal initiatives such as the Ryan White/AIDS Drug Assistance program.

In its most recent statement, Gilead reinforced that this practice remains alive and well.

On the buyer side, the company stated, many of the counterfeits originated from suppliers who purchased Gilead HIV medication from individuals after it was first dispensed to them. Unfortunately, the exploitation of individuals with low incomes who experience homelessness or substance use/abuse echoes a pattern whereby HIV patients sell medications to cover personal needs or are forced to buy them on the black market to keep up with their treatment regimens.

On the supply side, Gilead explained that individuals’ medications “are unlawfully resold ... on the secondary market by way of counterfeit supply chain documentation, concealing and fraudulently misrepresenting its origin. All of these counterfeits were sold as though they were legitimate Gilead products.”

But counterfeit pedigrees make it impossible to verify where the products came from, how they have been handled and stored, and what pills are in the bottles – all of which can have dire consequences for patients who ingest them.

The ramifications can be devastating.

“With HIV meds specifically, the worst case scenario would be if the medication is not actually the medication they’re supposed to be on,” said Dr. Heil, reinforcing that the increased safety net provided with viral suppression and against transmission is lost.

Dr. Heil pointed to another significant risk: resistance.

“In a situation like this, where maybe it’s not the full strength of the medication, maybe it’s expired and lost potency or was not stored correctly or is not even the accurate medication, changing those drug level exposures potentially puts the patient at risk for developing resistance to their regimen without them knowing.”

Yet another risk was posed by the replacement of HIV drugs with other medications, such as quetiapine, which increased the risk for life-threatening and irreversible side effects. The lawsuit included a story of a patient who unknowingly took quetiapine after receiving a counterfeit bottle of Biktarvy and could not speak or walk afterward.

Where this tale will ultimately end is unclear. There’s no telling what other activities or bad actors the Justice Department investigation will uncover as it works to unravel the counterfeit network’s activities and deal with its aftermath.

Regardless, clinicians are encouraged to inform HIV patients about the risks associated with counterfeit medications, how to determine whether the drugs they’ve been dispensed are authentic, and to report any product they believe to be counterfeit or to have been tampered with to their doctors, pharmacies, and to Gilead or other drug manufacturers.

“It’s okay to ask questions of your pharmacy about where they get their medications from,” noted Dr. Heil. “If patients have access to an independent pharmacy, it’s a great way for them to have a relationship with their pharmacist.

“We went into this profession to be able to have those conversations with patients,” Dr. Heil said.

The FDA recommends that patients receiving these medications who believe that their drugs may be counterfeit or who experience any adverse effects report the event to FDA’s MedWatch Safety Information and Adverse Event Reporting Program (1-800-FDA-1088 or www.fda.gov/medwatch).

Dr. Heil reported having no relevant financial relationships.

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

Similar outcomes in patients with ventilator-associated pneumonia (VAP) suggest that antibiotics selected by Gram staining were noninferior to those based on guidelines and also significantly decreased the use of broad-spectrum antibiotics in this patient population.

The findings were published  in JAMA Network Open. The multicenter, open-label, noninferiority, randomized trial, Gram Stain-Guided Antibiotics Choice for VAP (GRACE-VAP), was conducted for 2 years in intensive care units (ICUs) of a dozen tertiary referral hospitals in Japan, from April 1, 2018, through May 31, 2020.

The authors noted in their paper that the 2016 clinical practice guidelines for VAP published by the Infectious Diseases Society of America (IDSA) and the American Thoracic Society recommend antibiotic agents active against both methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa as an empirical treatment. Adherence to these guidelines may lead to overuse of broad-spectrum antibiotic agents and could be associated with the accelerated emergence of antimicrobial-resistant organisms, the authors postulated.

The study sought to answer the question: Can Gram staining be used as an alternative to established guidelines to direct antibiotic use – thereby curbing the use of broad-spectrum antibiotics – without compromising patient safety and clinical outcomes?

A total of 206 patients, with a mean age of 69, took part in the study. The same number of patients were assigned to each arm. Patients aged 15 years or older with a VAP diagnosis and a modified Clinical Pulmonary Infection Score of 5 or higher were included.

Investigators reported that 79 patients (76.7%) responded to antibiotics in the Gram stain-guided group and 74 (71.8%) responded in the guideline-based group (risk difference, 0.05; 95% confidence interval, –0.07 to 0.17; P < .001, for noninferiority).

There was a decrease in antipseudomonal agent use comparing the Gram stain-guided group with the guideline-based group (30.1%; 95% CI, 21.5% to 39.9%; P < .001). There also was a decrease in anti-MRSA agents in the Gram stain-guided group, compared with the guideline-based group (38.8%; 95% CI, 29.4% to 48.9%; P < .001).

The 28-day cumulative incidence of mortality was 13.6% (n = 14) in the Gram stain-guided group versus 17.5% (n = 18) in the guideline-based group. Escalation of antibiotics according to culture results was performed in seven patients (6.8%) in the Gram stain-guided group and in one patient (1.0%) in the guideline-based group. No significant differences in study arms were observed on other measures, such as ICU-free days, ventilator-free days, and adverse events.

The authors concluded that their findings support the use of Gram staining as a strategy to manage infectious diseases and contain the development of multidrug resistant organisms (MDROs) in the setting of critical care.

“In the GRACE-VAP trial, we used the time-honored Gram stain technique as part of the daily management of infectious diseases. We believe that the trial results are acceptable and have the potential to change the strategy of antibiotic choice worldwide,” the authors wrote.

Benjamin D. Galvan MLS(ASCP), CIC, an infection preventionist with a professional background in clinical microbiology, noted that Gram staining is more accessible and significantly less costly than the rapid polymerase chain reaction testing certain institutions use to rapidly identify MDROs to help tailor therapy.

But one of the pitfalls with relying on Gram stain collection to guide antibiotic use is that it is operator dependent and subject to extrinsic factors, like prior antibiotic use, he pointed out.

“If it is not collected, set up, and read properly, the Gram stain is not going to necessarily be reliable” said Mr. Galvan, also a member of the national communications committee for the Association for Professionals in Infection Control and Epidemiology. He added that the sample in the study was not representative of institutions dealing with elevated rates of multidrug resistance.

“Even from their own results, they were looking at hospitals that have a low rate of multidrug resistance,” he said. “It was not clear if MRSA or just Staphylococcus aureus was identified in significant quantities upon review, and they recognized a lower-than-expected number of isolates of Pseudomonas aeruginosa.”

Establishing antibiotic treatment from the results of Gram-stain collection may not be sufficiently comprehensive, he said.

“Generally speaking, basing it (antibiotic therapy) solely off of a Gram stain is not looking at the whole picture,” said Mr. Galvan, noting that the 2016 IDSA guidelines call for an evaluation of the clinical status, including risk, of the individual patient, as well as locally available antibiotic resistance data.

Moreover, the evidence-based IDSA guidelines are in place to help address the issue of antimicrobial resistance trends, already recommending tailoring empiric antibiotic therapy based upon the levels of resistance in the local population, according to Galvan.

While the study suggests that this Gram-stain-driven tailoring of empiric antibiotic therapy may be noninferior to current guidelines in health care settings with low MDRO rates, its utility may not be suitable in hospitals that are already dealing with high rates of MDROs, such as Pseudomonas aeruginosa and Acinetobacter baumannii, or severe clinical cases of VAP, Mr. Galvan explained.

The researchers and Mr. Galvan disclosed no relevant financial relationships.

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

Similar outcomes in patients with ventilator-associated pneumonia (VAP) suggest that antibiotics selected by Gram staining were noninferior to those based on guidelines and also significantly decreased the use of broad-spectrum antibiotics in this patient population.

The findings were published  in JAMA Network Open. The multicenter, open-label, noninferiority, randomized trial, Gram Stain-Guided Antibiotics Choice for VAP (GRACE-VAP), was conducted for 2 years in intensive care units (ICUs) of a dozen tertiary referral hospitals in Japan, from April 1, 2018, through May 31, 2020.

The authors noted in their paper that the 2016 clinical practice guidelines for VAP published by the Infectious Diseases Society of America (IDSA) and the American Thoracic Society recommend antibiotic agents active against both methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa as an empirical treatment. Adherence to these guidelines may lead to overuse of broad-spectrum antibiotic agents and could be associated with the accelerated emergence of antimicrobial-resistant organisms, the authors postulated.

The study sought to answer the question: Can Gram staining be used as an alternative to established guidelines to direct antibiotic use – thereby curbing the use of broad-spectrum antibiotics – without compromising patient safety and clinical outcomes?

A total of 206 patients, with a mean age of 69, took part in the study. The same number of patients were assigned to each arm. Patients aged 15 years or older with a VAP diagnosis and a modified Clinical Pulmonary Infection Score of 5 or higher were included.

Investigators reported that 79 patients (76.7%) responded to antibiotics in the Gram stain-guided group and 74 (71.8%) responded in the guideline-based group (risk difference, 0.05; 95% confidence interval, –0.07 to 0.17; P < .001, for noninferiority).

There was a decrease in antipseudomonal agent use comparing the Gram stain-guided group with the guideline-based group (30.1%; 95% CI, 21.5% to 39.9%; P < .001). There also was a decrease in anti-MRSA agents in the Gram stain-guided group, compared with the guideline-based group (38.8%; 95% CI, 29.4% to 48.9%; P < .001).

The 28-day cumulative incidence of mortality was 13.6% (n = 14) in the Gram stain-guided group versus 17.5% (n = 18) in the guideline-based group. Escalation of antibiotics according to culture results was performed in seven patients (6.8%) in the Gram stain-guided group and in one patient (1.0%) in the guideline-based group. No significant differences in study arms were observed on other measures, such as ICU-free days, ventilator-free days, and adverse events.

The authors concluded that their findings support the use of Gram staining as a strategy to manage infectious diseases and contain the development of multidrug resistant organisms (MDROs) in the setting of critical care.

“In the GRACE-VAP trial, we used the time-honored Gram stain technique as part of the daily management of infectious diseases. We believe that the trial results are acceptable and have the potential to change the strategy of antibiotic choice worldwide,” the authors wrote.

Benjamin D. Galvan MLS(ASCP), CIC, an infection preventionist with a professional background in clinical microbiology, noted that Gram staining is more accessible and significantly less costly than the rapid polymerase chain reaction testing certain institutions use to rapidly identify MDROs to help tailor therapy.

But one of the pitfalls with relying on Gram stain collection to guide antibiotic use is that it is operator dependent and subject to extrinsic factors, like prior antibiotic use, he pointed out.

“If it is not collected, set up, and read properly, the Gram stain is not going to necessarily be reliable” said Mr. Galvan, also a member of the national communications committee for the Association for Professionals in Infection Control and Epidemiology. He added that the sample in the study was not representative of institutions dealing with elevated rates of multidrug resistance.

“Even from their own results, they were looking at hospitals that have a low rate of multidrug resistance,” he said. “It was not clear if MRSA or just Staphylococcus aureus was identified in significant quantities upon review, and they recognized a lower-than-expected number of isolates of Pseudomonas aeruginosa.”

Establishing antibiotic treatment from the results of Gram-stain collection may not be sufficiently comprehensive, he said.

“Generally speaking, basing it (antibiotic therapy) solely off of a Gram stain is not looking at the whole picture,” said Mr. Galvan, noting that the 2016 IDSA guidelines call for an evaluation of the clinical status, including risk, of the individual patient, as well as locally available antibiotic resistance data.

Moreover, the evidence-based IDSA guidelines are in place to help address the issue of antimicrobial resistance trends, already recommending tailoring empiric antibiotic therapy based upon the levels of resistance in the local population, according to Galvan.

While the study suggests that this Gram-stain-driven tailoring of empiric antibiotic therapy may be noninferior to current guidelines in health care settings with low MDRO rates, its utility may not be suitable in hospitals that are already dealing with high rates of MDROs, such as Pseudomonas aeruginosa and Acinetobacter baumannii, or severe clinical cases of VAP, Mr. Galvan explained.

The researchers and Mr. Galvan disclosed no relevant financial relationships.

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

Similar outcomes in patients with ventilator-associated pneumonia (VAP) suggest that antibiotics selected by Gram staining were noninferior to those based on guidelines and also significantly decreased the use of broad-spectrum antibiotics in this patient population.

The findings were published  in JAMA Network Open. The multicenter, open-label, noninferiority, randomized trial, Gram Stain-Guided Antibiotics Choice for VAP (GRACE-VAP), was conducted for 2 years in intensive care units (ICUs) of a dozen tertiary referral hospitals in Japan, from April 1, 2018, through May 31, 2020.

The authors noted in their paper that the 2016 clinical practice guidelines for VAP published by the Infectious Diseases Society of America (IDSA) and the American Thoracic Society recommend antibiotic agents active against both methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa as an empirical treatment. Adherence to these guidelines may lead to overuse of broad-spectrum antibiotic agents and could be associated with the accelerated emergence of antimicrobial-resistant organisms, the authors postulated.

The study sought to answer the question: Can Gram staining be used as an alternative to established guidelines to direct antibiotic use – thereby curbing the use of broad-spectrum antibiotics – without compromising patient safety and clinical outcomes?

A total of 206 patients, with a mean age of 69, took part in the study. The same number of patients were assigned to each arm. Patients aged 15 years or older with a VAP diagnosis and a modified Clinical Pulmonary Infection Score of 5 or higher were included.

Investigators reported that 79 patients (76.7%) responded to antibiotics in the Gram stain-guided group and 74 (71.8%) responded in the guideline-based group (risk difference, 0.05; 95% confidence interval, –0.07 to 0.17; P < .001, for noninferiority).

There was a decrease in antipseudomonal agent use comparing the Gram stain-guided group with the guideline-based group (30.1%; 95% CI, 21.5% to 39.9%; P < .001). There also was a decrease in anti-MRSA agents in the Gram stain-guided group, compared with the guideline-based group (38.8%; 95% CI, 29.4% to 48.9%; P < .001).

The 28-day cumulative incidence of mortality was 13.6% (n = 14) in the Gram stain-guided group versus 17.5% (n = 18) in the guideline-based group. Escalation of antibiotics according to culture results was performed in seven patients (6.8%) in the Gram stain-guided group and in one patient (1.0%) in the guideline-based group. No significant differences in study arms were observed on other measures, such as ICU-free days, ventilator-free days, and adverse events.

The authors concluded that their findings support the use of Gram staining as a strategy to manage infectious diseases and contain the development of multidrug resistant organisms (MDROs) in the setting of critical care.

“In the GRACE-VAP trial, we used the time-honored Gram stain technique as part of the daily management of infectious diseases. We believe that the trial results are acceptable and have the potential to change the strategy of antibiotic choice worldwide,” the authors wrote.

Benjamin D. Galvan MLS(ASCP), CIC, an infection preventionist with a professional background in clinical microbiology, noted that Gram staining is more accessible and significantly less costly than the rapid polymerase chain reaction testing certain institutions use to rapidly identify MDROs to help tailor therapy.

But one of the pitfalls with relying on Gram stain collection to guide antibiotic use is that it is operator dependent and subject to extrinsic factors, like prior antibiotic use, he pointed out.

“If it is not collected, set up, and read properly, the Gram stain is not going to necessarily be reliable” said Mr. Galvan, also a member of the national communications committee for the Association for Professionals in Infection Control and Epidemiology. He added that the sample in the study was not representative of institutions dealing with elevated rates of multidrug resistance.

“Even from their own results, they were looking at hospitals that have a low rate of multidrug resistance,” he said. “It was not clear if MRSA or just Staphylococcus aureus was identified in significant quantities upon review, and they recognized a lower-than-expected number of isolates of Pseudomonas aeruginosa.”

Establishing antibiotic treatment from the results of Gram-stain collection may not be sufficiently comprehensive, he said.

“Generally speaking, basing it (antibiotic therapy) solely off of a Gram stain is not looking at the whole picture,” said Mr. Galvan, noting that the 2016 IDSA guidelines call for an evaluation of the clinical status, including risk, of the individual patient, as well as locally available antibiotic resistance data.

Moreover, the evidence-based IDSA guidelines are in place to help address the issue of antimicrobial resistance trends, already recommending tailoring empiric antibiotic therapy based upon the levels of resistance in the local population, according to Galvan.

While the study suggests that this Gram-stain-driven tailoring of empiric antibiotic therapy may be noninferior to current guidelines in health care settings with low MDRO rates, its utility may not be suitable in hospitals that are already dealing with high rates of MDROs, such as Pseudomonas aeruginosa and Acinetobacter baumannii, or severe clinical cases of VAP, Mr. Galvan explained.

The researchers and Mr. Galvan disclosed no relevant financial relationships.

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

Structural aortic valve deterioration (SVD) at 5 years is lower following repair with a contemporary transcatheter implantation (TAVI) device than with surgery, according to a pooled analysis of major trials.

For healthier patients with a relatively long life expectancy, this is important information for deciding whether to undergo TAVI or surgical aortic valve repair (SAVR), Michael J. Reardon, MD, said at the annual scientific sessions of the American College of Cardiology.

“Every week I get this question about which repair is more durable,” said Dr. Reardon, whose study was not only designed to compare device deterioration but to evaluate the effect of SVD on major outcomes.

In this analysis, the rates of SVD were compared for the self-expanding supra-annular CoreValve Evolut device and SAVR. The SVD curves separated within the first year. At 5 years, the differences were highly significant favoring TAVI (2.57% vs. 4.38%; P = .0095).

As part of this analysis, the impact of SVD was also assessed independent of type of repair. At 5 years, those with SVD relative to those without had an approximately twofold increase in all-cause mortality, cardiovascular mortality, and hospitalization of aortic valve worsening. These risks were elevated regardless of type of valve repair.

The data presented by Dr. Reardon can be considered device specific. The earlier PARTNER 2A study comparing older- and newer-generation TAVI devices with SAVR produced a different result. When a second-generation balloon-expandable SAPIEN XT device and a third-generation SAPIEN 3 device were compared with surgery, neither device achieved lower SVD rates relative to SAVR.

In PARTNER 2A, the SVD rate for the older device was nearly three times greater than SAVR (1.61 vs. 0.58 per 100 patient-years). The numerically higher SVD rates for the newer device (0.68 vs. 0.58 per 100 patient-years) was not statistically different, but the TAVI device was not superior.

More than 4,000 patients evaluated at 5 years

In the analysis presented by Dr. Reardon, data were pooled from the randomized CoreValve U.S. High-Risk Pivotal Trial and the SURTAVI Intermediate Risk Trial. Together, these studies randomized 971 patients to surgery and 1,128 patients to TAVI. Data on an additional 2,663 patients treated with the Evolut valve in two registries were added to the randomized trial data, providing data on 4,762 total patients with 5-year follow-up.

SVD was defined by two criteria. The first was a mean gradient increase of at least 10 mm Hg plus a mean overall gradient of at least 20 mm Hg as measured with echocardiography and assessed, when possible, by an independent core laboratory. The second was new-onset or increased intraprosthetic aortic regurgitation of at least moderate severity.

When graphed over time, the SVD curves separated in favor of TAVI after about 6 months of follow-up. The shape of the curves also differed. Unlike the steady rise in SVD observed in the surgery group, the SVD rate in the TAVI group remained below 1% for almost 4 years before beginning to climb.

There was greater relative benefit for the TAVI device in patients with annular diameters of 23 mm or less. Unlike the rise in SVD rates that began about 6 months after SAVR, the SVD rates in the TAVI patients remained at 0% for more than 2 years. At 5 years, the differences remained significant favoring TAVI (1.39% vs. 5.86%; P = .049).

In those with larger annular diameters, there was still a consistently lower SVD rate over time for TAVI relative to SAVR, but the trend for an advantage at 5 years fell just short of significance (2.48% vs. 3.96%; P = .067).
 

SVD linked to doubling of mortality

SVD worsened outcomes. When all data surgery and TAVI data were pooled, the hazard ratios corresponded with about a doubling of risk for major adverse outcomes, including all-cause mortality (HR, 1.98; P < .001), cardiovascular mortality (HR, 1.82; P = .008), and hospitalization for aortic valve disease or worsening heart failure (HR, 2.11; P = .01). The relative risks were similar in the two treatment groups, including the risk of all-cause mortality (HR, 2.24; P < .001 for TAVI vs. HR, 2.45; P = .002 for SAVR).

The predictors for SVD on multivariate analysis included female sex, increased body surface area, prior percutaneous coronary intervention, and a prior diagnosis of atrial fibrillation.

Design improvements in TAVI devices are likely to explain these results, said Dr. Reardon, chair of cardiovascular research at Houston Methodist Hospital.

“The CoreValve/Evolut supra-annular, self-expanding bioprosthesis is the first and only transcatheter bioprosthesis to demonstrate lower rates of SVD, compared with surgery,” Dr. Reardon said.

This analysis validated the risks posed by the definition of SVD applied in this study, which appears to be a practical tool for tracking valve function and patient risk. Dr. Reardon also said that the study confirms the value of serial Doppler transthoracic echocardiography as a tool for monitoring SVD.

Several experts agreed that this is important new information.

“This is a remarkable series of findings,” said James McClurken, MD, who is a cardiovascular surgeon affiliated with Temple University, Philadelphia, and practices in Doylestown, Penn. By both demonstrating the prognostic importance of SVD and showing differences between the study device and SAVR, this trial will yield practical data to inform patients about relative risks and benefits.

Athena Poppas, MD, the new president of the ACC and a professor of medicine at Brown University, Providence, R.I., called this study “practice changing” for the same reasons. She also thinks it has valuable data for guiding choice of intervention.

Overall, the data are likely to change thinking about the role of TAVI and surgery in younger, fit patients, according to Megan Coylewright, MD, chief of cardiology at Erlanger Cardiology, Chattanooga, Tenn.

“There are patients [in need of aortic valve repair] with a long life expectancy who have been told you have to have a surgical repair because we know they last longer,” she said. Although she said that relative outcomes after longer follow-up remain unknown, “I think this does throw that comment into question.”

Dr. Reardon has financial relationships with Abbott, Boston Scientific, Medtronic, and Gore Medical. Dr. Poppas and McClurken reported no potential financial conflicts of interest. Dr. Coylewright reported financial relationships with Abbott, Alleviant, Boston Scientific, Cardiosmart, Edwards Lifesciences, Medtronic, and Occlutech. The study received financial support from Medtronic.

Structural aortic valve deterioration (SVD) at 5 years is lower following repair with a contemporary transcatheter implantation (TAVI) device than with surgery, according to a pooled analysis of major trials.

For healthier patients with a relatively long life expectancy, this is important information for deciding whether to undergo TAVI or surgical aortic valve repair (SAVR), Michael J. Reardon, MD, said at the annual scientific sessions of the American College of Cardiology.

“Every week I get this question about which repair is more durable,” said Dr. Reardon, whose study was not only designed to compare device deterioration but to evaluate the effect of SVD on major outcomes.

In this analysis, the rates of SVD were compared for the self-expanding supra-annular CoreValve Evolut device and SAVR. The SVD curves separated within the first year. At 5 years, the differences were highly significant favoring TAVI (2.57% vs. 4.38%; P = .0095).

As part of this analysis, the impact of SVD was also assessed independent of type of repair. At 5 years, those with SVD relative to those without had an approximately twofold increase in all-cause mortality, cardiovascular mortality, and hospitalization of aortic valve worsening. These risks were elevated regardless of type of valve repair.

The data presented by Dr. Reardon can be considered device specific. The earlier PARTNER 2A study comparing older- and newer-generation TAVI devices with SAVR produced a different result. When a second-generation balloon-expandable SAPIEN XT device and a third-generation SAPIEN 3 device were compared with surgery, neither device achieved lower SVD rates relative to SAVR.

In PARTNER 2A, the SVD rate for the older device was nearly three times greater than SAVR (1.61 vs. 0.58 per 100 patient-years). The numerically higher SVD rates for the newer device (0.68 vs. 0.58 per 100 patient-years) was not statistically different, but the TAVI device was not superior.

More than 4,000 patients evaluated at 5 years

In the analysis presented by Dr. Reardon, data were pooled from the randomized CoreValve U.S. High-Risk Pivotal Trial and the SURTAVI Intermediate Risk Trial. Together, these studies randomized 971 patients to surgery and 1,128 patients to TAVI. Data on an additional 2,663 patients treated with the Evolut valve in two registries were added to the randomized trial data, providing data on 4,762 total patients with 5-year follow-up.

SVD was defined by two criteria. The first was a mean gradient increase of at least 10 mm Hg plus a mean overall gradient of at least 20 mm Hg as measured with echocardiography and assessed, when possible, by an independent core laboratory. The second was new-onset or increased intraprosthetic aortic regurgitation of at least moderate severity.

When graphed over time, the SVD curves separated in favor of TAVI after about 6 months of follow-up. The shape of the curves also differed. Unlike the steady rise in SVD observed in the surgery group, the SVD rate in the TAVI group remained below 1% for almost 4 years before beginning to climb.

There was greater relative benefit for the TAVI device in patients with annular diameters of 23 mm or less. Unlike the rise in SVD rates that began about 6 months after SAVR, the SVD rates in the TAVI patients remained at 0% for more than 2 years. At 5 years, the differences remained significant favoring TAVI (1.39% vs. 5.86%; P = .049).

In those with larger annular diameters, there was still a consistently lower SVD rate over time for TAVI relative to SAVR, but the trend for an advantage at 5 years fell just short of significance (2.48% vs. 3.96%; P = .067).
 

SVD linked to doubling of mortality

SVD worsened outcomes. When all data surgery and TAVI data were pooled, the hazard ratios corresponded with about a doubling of risk for major adverse outcomes, including all-cause mortality (HR, 1.98; P < .001), cardiovascular mortality (HR, 1.82; P = .008), and hospitalization for aortic valve disease or worsening heart failure (HR, 2.11; P = .01). The relative risks were similar in the two treatment groups, including the risk of all-cause mortality (HR, 2.24; P < .001 for TAVI vs. HR, 2.45; P = .002 for SAVR).

The predictors for SVD on multivariate analysis included female sex, increased body surface area, prior percutaneous coronary intervention, and a prior diagnosis of atrial fibrillation.

Design improvements in TAVI devices are likely to explain these results, said Dr. Reardon, chair of cardiovascular research at Houston Methodist Hospital.

“The CoreValve/Evolut supra-annular, self-expanding bioprosthesis is the first and only transcatheter bioprosthesis to demonstrate lower rates of SVD, compared with surgery,” Dr. Reardon said.

This analysis validated the risks posed by the definition of SVD applied in this study, which appears to be a practical tool for tracking valve function and patient risk. Dr. Reardon also said that the study confirms the value of serial Doppler transthoracic echocardiography as a tool for monitoring SVD.

Several experts agreed that this is important new information.

“This is a remarkable series of findings,” said James McClurken, MD, who is a cardiovascular surgeon affiliated with Temple University, Philadelphia, and practices in Doylestown, Penn. By both demonstrating the prognostic importance of SVD and showing differences between the study device and SAVR, this trial will yield practical data to inform patients about relative risks and benefits.

Athena Poppas, MD, the new president of the ACC and a professor of medicine at Brown University, Providence, R.I., called this study “practice changing” for the same reasons. She also thinks it has valuable data for guiding choice of intervention.

Overall, the data are likely to change thinking about the role of TAVI and surgery in younger, fit patients, according to Megan Coylewright, MD, chief of cardiology at Erlanger Cardiology, Chattanooga, Tenn.

“There are patients [in need of aortic valve repair] with a long life expectancy who have been told you have to have a surgical repair because we know they last longer,” she said. Although she said that relative outcomes after longer follow-up remain unknown, “I think this does throw that comment into question.”

Dr. Reardon has financial relationships with Abbott, Boston Scientific, Medtronic, and Gore Medical. Dr. Poppas and McClurken reported no potential financial conflicts of interest. Dr. Coylewright reported financial relationships with Abbott, Alleviant, Boston Scientific, Cardiosmart, Edwards Lifesciences, Medtronic, and Occlutech. The study received financial support from Medtronic.

Structural aortic valve deterioration (SVD) at 5 years is lower following repair with a contemporary transcatheter implantation (TAVI) device than with surgery, according to a pooled analysis of major trials.

For healthier patients with a relatively long life expectancy, this is important information for deciding whether to undergo TAVI or surgical aortic valve repair (SAVR), Michael J. Reardon, MD, said at the annual scientific sessions of the American College of Cardiology.

“Every week I get this question about which repair is more durable,” said Dr. Reardon, whose study was not only designed to compare device deterioration but to evaluate the effect of SVD on major outcomes.

In this analysis, the rates of SVD were compared for the self-expanding supra-annular CoreValve Evolut device and SAVR. The SVD curves separated within the first year. At 5 years, the differences were highly significant favoring TAVI (2.57% vs. 4.38%; P = .0095).

As part of this analysis, the impact of SVD was also assessed independent of type of repair. At 5 years, those with SVD relative to those without had an approximately twofold increase in all-cause mortality, cardiovascular mortality, and hospitalization of aortic valve worsening. These risks were elevated regardless of type of valve repair.

The data presented by Dr. Reardon can be considered device specific. The earlier PARTNER 2A study comparing older- and newer-generation TAVI devices with SAVR produced a different result. When a second-generation balloon-expandable SAPIEN XT device and a third-generation SAPIEN 3 device were compared with surgery, neither device achieved lower SVD rates relative to SAVR.

In PARTNER 2A, the SVD rate for the older device was nearly three times greater than SAVR (1.61 vs. 0.58 per 100 patient-years). The numerically higher SVD rates for the newer device (0.68 vs. 0.58 per 100 patient-years) was not statistically different, but the TAVI device was not superior.

More than 4,000 patients evaluated at 5 years

In the analysis presented by Dr. Reardon, data were pooled from the randomized CoreValve U.S. High-Risk Pivotal Trial and the SURTAVI Intermediate Risk Trial. Together, these studies randomized 971 patients to surgery and 1,128 patients to TAVI. Data on an additional 2,663 patients treated with the Evolut valve in two registries were added to the randomized trial data, providing data on 4,762 total patients with 5-year follow-up.

SVD was defined by two criteria. The first was a mean gradient increase of at least 10 mm Hg plus a mean overall gradient of at least 20 mm Hg as measured with echocardiography and assessed, when possible, by an independent core laboratory. The second was new-onset or increased intraprosthetic aortic regurgitation of at least moderate severity.

When graphed over time, the SVD curves separated in favor of TAVI after about 6 months of follow-up. The shape of the curves also differed. Unlike the steady rise in SVD observed in the surgery group, the SVD rate in the TAVI group remained below 1% for almost 4 years before beginning to climb.

There was greater relative benefit for the TAVI device in patients with annular diameters of 23 mm or less. Unlike the rise in SVD rates that began about 6 months after SAVR, the SVD rates in the TAVI patients remained at 0% for more than 2 years. At 5 years, the differences remained significant favoring TAVI (1.39% vs. 5.86%; P = .049).

In those with larger annular diameters, there was still a consistently lower SVD rate over time for TAVI relative to SAVR, but the trend for an advantage at 5 years fell just short of significance (2.48% vs. 3.96%; P = .067).
 

SVD linked to doubling of mortality

SVD worsened outcomes. When all data surgery and TAVI data were pooled, the hazard ratios corresponded with about a doubling of risk for major adverse outcomes, including all-cause mortality (HR, 1.98; P < .001), cardiovascular mortality (HR, 1.82; P = .008), and hospitalization for aortic valve disease or worsening heart failure (HR, 2.11; P = .01). The relative risks were similar in the two treatment groups, including the risk of all-cause mortality (HR, 2.24; P < .001 for TAVI vs. HR, 2.45; P = .002 for SAVR).

The predictors for SVD on multivariate analysis included female sex, increased body surface area, prior percutaneous coronary intervention, and a prior diagnosis of atrial fibrillation.

Design improvements in TAVI devices are likely to explain these results, said Dr. Reardon, chair of cardiovascular research at Houston Methodist Hospital.

“The CoreValve/Evolut supra-annular, self-expanding bioprosthesis is the first and only transcatheter bioprosthesis to demonstrate lower rates of SVD, compared with surgery,” Dr. Reardon said.

This analysis validated the risks posed by the definition of SVD applied in this study, which appears to be a practical tool for tracking valve function and patient risk. Dr. Reardon also said that the study confirms the value of serial Doppler transthoracic echocardiography as a tool for monitoring SVD.

Several experts agreed that this is important new information.

“This is a remarkable series of findings,” said James McClurken, MD, who is a cardiovascular surgeon affiliated with Temple University, Philadelphia, and practices in Doylestown, Penn. By both demonstrating the prognostic importance of SVD and showing differences between the study device and SAVR, this trial will yield practical data to inform patients about relative risks and benefits.

Athena Poppas, MD, the new president of the ACC and a professor of medicine at Brown University, Providence, R.I., called this study “practice changing” for the same reasons. She also thinks it has valuable data for guiding choice of intervention.

Overall, the data are likely to change thinking about the role of TAVI and surgery in younger, fit patients, according to Megan Coylewright, MD, chief of cardiology at Erlanger Cardiology, Chattanooga, Tenn.

“There are patients [in need of aortic valve repair] with a long life expectancy who have been told you have to have a surgical repair because we know they last longer,” she said. Although she said that relative outcomes after longer follow-up remain unknown, “I think this does throw that comment into question.”

Dr. Reardon has financial relationships with Abbott, Boston Scientific, Medtronic, and Gore Medical. Dr. Poppas and McClurken reported no potential financial conflicts of interest. Dr. Coylewright reported financial relationships with Abbott, Alleviant, Boston Scientific, Cardiosmart, Edwards Lifesciences, Medtronic, and Occlutech. The study received financial support from Medtronic.

Bone strength and microarchitecture remained stronger at 24 months after treatment with denosumab compared to risedronate, in a study of 110 adults using glucocorticoids.

Patients using glucocorticoids are at increased risk for vertebral and nonvertebral fractures at both the start of treatment or as treatment continues, wrote Piet Geusens, MD, of Maastricht University, the Netherlands, and colleagues.

Imaging data collected via high-resolution peripheral quantitative computed tomography (HR-pQCT) allow for the assessment of bone microarchitecture and strength, but specific data comparing the impact of bone treatment in patients using glucocorticoids are lacking, they said.

In a study published in the Journal of Bone and Mineral Research, the researchers identified a subset of 56 patients randomized to denosumab and 54 to risedronate patients out of a total of 590 patients who were enrolled in a phase 3 randomized, controlled trial of denosumab vs. risedronate for bone mineral density. The main results of the larger trial – presented at EULAR 2018 – showed greater increases in bone strength with denosumab over risedronate in patients receiving glucocorticoids.

In the current study, the researchers reviewed HR-pQCT scans of the distal radius and tibia at baseline, 12 months, and 24 months. Bone strength and microarchitecture were defined in terms of failure load (FL) as a primary outcome. Patients also were divided into subpopulations of those initiating glucocorticoid treatment (GC-I) and continuing treatment (GC-C).

Baseline characteristics were mainly balanced among the treatment groups within the GC-I and GC-C categories.

Among the GC-I patients, in the denosumab group, FL increased significantly from baseline to 12 months at the radius at tibia (1.8% and 1.7%, respectively) but did not change significantly in the risedronate group, which translated to a significant treatment difference between the drugs of 3.3% for radius and 2.5% for tibia.

At 24 months, the radius measure of FL was unchanged from baseline in denosumab patients but significantly decreased in risedronate patients, with a difference of –4.1%, which translated to a significant between-treatment difference at the radius of 5.6% (P < .001). Changes at the tibia were not significantly different between the groups at 24 months.

Among the GC-C patients, FL was unchanged from baseline to 12 months for both the denosumab and risedronate groups. However, FL significantly increased with denosumab (4.3%) and remained unchanged in the risedronate group.

The researchers also found significant differences between denosumab and risedronate in percentage changes in cortical bone mineral density, and less prominent changes and differences in trabecular bone mineral density.

The study findings were limited by several factors including the use of the HR-pQCT scanner, which limits the measurement of trabecular microarchitecture, and the use of only standard HR-pQCT parameters, which do not allow insight into endosteal changes, and the inability to correct for multiplicity of data, the researchers noted.

However, the results support the superiority of denosumab over risedronate for preventing FL and total bone mineral density loss at the radius and tibia in new glucocorticoid users, and for increasing FL and total bone mineral density at the radius in long-term glucocorticoid users, they said.

Denosumab therefore could be a useful therapeutic option and could inform decision-making in patients initiating GC-therapy or on long-term GC-therapy, they concluded.

The study was supported by Amgen. Dr. Geusens disclosed grants from Amgen, Celgene, Lilly, Merck, Pfizer, Roche, UCB, Fresenius, Mylan, and Sandoz, and grants and other funding from AbbVie, outside the current study.

Bone strength and microarchitecture remained stronger at 24 months after treatment with denosumab compared to risedronate, in a study of 110 adults using glucocorticoids.

Patients using glucocorticoids are at increased risk for vertebral and nonvertebral fractures at both the start of treatment or as treatment continues, wrote Piet Geusens, MD, of Maastricht University, the Netherlands, and colleagues.

Imaging data collected via high-resolution peripheral quantitative computed tomography (HR-pQCT) allow for the assessment of bone microarchitecture and strength, but specific data comparing the impact of bone treatment in patients using glucocorticoids are lacking, they said.

In a study published in the Journal of Bone and Mineral Research, the researchers identified a subset of 56 patients randomized to denosumab and 54 to risedronate patients out of a total of 590 patients who were enrolled in a phase 3 randomized, controlled trial of denosumab vs. risedronate for bone mineral density. The main results of the larger trial – presented at EULAR 2018 – showed greater increases in bone strength with denosumab over risedronate in patients receiving glucocorticoids.

In the current study, the researchers reviewed HR-pQCT scans of the distal radius and tibia at baseline, 12 months, and 24 months. Bone strength and microarchitecture were defined in terms of failure load (FL) as a primary outcome. Patients also were divided into subpopulations of those initiating glucocorticoid treatment (GC-I) and continuing treatment (GC-C).

Baseline characteristics were mainly balanced among the treatment groups within the GC-I and GC-C categories.

Among the GC-I patients, in the denosumab group, FL increased significantly from baseline to 12 months at the radius at tibia (1.8% and 1.7%, respectively) but did not change significantly in the risedronate group, which translated to a significant treatment difference between the drugs of 3.3% for radius and 2.5% for tibia.

At 24 months, the radius measure of FL was unchanged from baseline in denosumab patients but significantly decreased in risedronate patients, with a difference of –4.1%, which translated to a significant between-treatment difference at the radius of 5.6% (P < .001). Changes at the tibia were not significantly different between the groups at 24 months.

Among the GC-C patients, FL was unchanged from baseline to 12 months for both the denosumab and risedronate groups. However, FL significantly increased with denosumab (4.3%) and remained unchanged in the risedronate group.

The researchers also found significant differences between denosumab and risedronate in percentage changes in cortical bone mineral density, and less prominent changes and differences in trabecular bone mineral density.

The study findings were limited by several factors including the use of the HR-pQCT scanner, which limits the measurement of trabecular microarchitecture, and the use of only standard HR-pQCT parameters, which do not allow insight into endosteal changes, and the inability to correct for multiplicity of data, the researchers noted.

However, the results support the superiority of denosumab over risedronate for preventing FL and total bone mineral density loss at the radius and tibia in new glucocorticoid users, and for increasing FL and total bone mineral density at the radius in long-term glucocorticoid users, they said.

Denosumab therefore could be a useful therapeutic option and could inform decision-making in patients initiating GC-therapy or on long-term GC-therapy, they concluded.

The study was supported by Amgen. Dr. Geusens disclosed grants from Amgen, Celgene, Lilly, Merck, Pfizer, Roche, UCB, Fresenius, Mylan, and Sandoz, and grants and other funding from AbbVie, outside the current study.

Bone strength and microarchitecture remained stronger at 24 months after treatment with denosumab compared to risedronate, in a study of 110 adults using glucocorticoids.

Patients using glucocorticoids are at increased risk for vertebral and nonvertebral fractures at both the start of treatment or as treatment continues, wrote Piet Geusens, MD, of Maastricht University, the Netherlands, and colleagues.

Imaging data collected via high-resolution peripheral quantitative computed tomography (HR-pQCT) allow for the assessment of bone microarchitecture and strength, but specific data comparing the impact of bone treatment in patients using glucocorticoids are lacking, they said.

In a study published in the Journal of Bone and Mineral Research, the researchers identified a subset of 56 patients randomized to denosumab and 54 to risedronate patients out of a total of 590 patients who were enrolled in a phase 3 randomized, controlled trial of denosumab vs. risedronate for bone mineral density. The main results of the larger trial – presented at EULAR 2018 – showed greater increases in bone strength with denosumab over risedronate in patients receiving glucocorticoids.

In the current study, the researchers reviewed HR-pQCT scans of the distal radius and tibia at baseline, 12 months, and 24 months. Bone strength and microarchitecture were defined in terms of failure load (FL) as a primary outcome. Patients also were divided into subpopulations of those initiating glucocorticoid treatment (GC-I) and continuing treatment (GC-C).

Baseline characteristics were mainly balanced among the treatment groups within the GC-I and GC-C categories.

Among the GC-I patients, in the denosumab group, FL increased significantly from baseline to 12 months at the radius at tibia (1.8% and 1.7%, respectively) but did not change significantly in the risedronate group, which translated to a significant treatment difference between the drugs of 3.3% for radius and 2.5% for tibia.

At 24 months, the radius measure of FL was unchanged from baseline in denosumab patients but significantly decreased in risedronate patients, with a difference of –4.1%, which translated to a significant between-treatment difference at the radius of 5.6% (P < .001). Changes at the tibia were not significantly different between the groups at 24 months.

Among the GC-C patients, FL was unchanged from baseline to 12 months for both the denosumab and risedronate groups. However, FL significantly increased with denosumab (4.3%) and remained unchanged in the risedronate group.

The researchers also found significant differences between denosumab and risedronate in percentage changes in cortical bone mineral density, and less prominent changes and differences in trabecular bone mineral density.

The study findings were limited by several factors including the use of the HR-pQCT scanner, which limits the measurement of trabecular microarchitecture, and the use of only standard HR-pQCT parameters, which do not allow insight into endosteal changes, and the inability to correct for multiplicity of data, the researchers noted.

However, the results support the superiority of denosumab over risedronate for preventing FL and total bone mineral density loss at the radius and tibia in new glucocorticoid users, and for increasing FL and total bone mineral density at the radius in long-term glucocorticoid users, they said.

Denosumab therefore could be a useful therapeutic option and could inform decision-making in patients initiating GC-therapy or on long-term GC-therapy, they concluded.

The study was supported by Amgen. Dr. Geusens disclosed grants from Amgen, Celgene, Lilly, Merck, Pfizer, Roche, UCB, Fresenius, Mylan, and Sandoz, and grants and other funding from AbbVie, outside the current study.

BOSTON – Although skin biopsy remains the gold standard for diagnosing early-stage melanoma, advances in genetic expression profiling are helping dermatologists provide a nuanced approach to managing suspicious lesions.

One such test, the Pigmented Lesional Assay (PLA) uses adhesive patches applied to lesions of concern at the bedside to extract RNA from the stratum corneum to help determine the risk for melanoma.

At the annual meeting of the American Academy of Dermatology, Caroline C. Kim, MD, director of melanoma and pigmented lesion clinics at Newton Wellesley Dermatology, Wellesley Hills, Mass., and Tufts Medical Center, Boston, spoke about the PLA, which uses genetic expression profiling to measure the expression level of specific genes that are associated with melanoma: PRAME (preferentially expressed antigen in melanoma) and LINC00518 (LINC). There are four possible results of the test: Aberrant expression of both LINC and PRAME (high risk); aberrant expression of a single gene (moderate risk); aberrant expression of neither gene (low risk); or inconclusive.

Validation data have shown a sensitivity of 91% and a specificity of 69% for the PLA, with a 99% negative predictive value; so a lesion that tested negative by PLA has a less than 1% chance of being melanoma. In addition, a study published in 2020 found that the addition of TERT (telomerase reverse transcriptase) mutation analyses increased the sensitivity of the PLA to 97%.

While the high negative predictive value is helpful to consider in clinical scenarios to rule-out melanoma for borderline lesions, one must consider the positive predictive value as well and how this may impact clinical care, Dr. Kim said. In a study examining outcomes of 381 lesions, 51 were PLA positive (single or double) and were biopsied, of which 19 (37%) revealed a melanoma diagnosis. In a large U.S. registry study of 3,418 lesions, 324 lesions that were PLA double positive were biopsied, with 18.7% revealing a melanoma diagnosis.

“No test is perfect, and this applies to PLA, even if you get a double-positive or double-negative test result,” Dr. Kim said. “You want to make sure that patients are aware of false positives and negatives. However, PLA could be an additional piece of data to inform your decision to proceed with biopsy on select borderline suspicious pigmented lesions. More studies are needed to better understand the approach to single- and double-positive PLA results.”

The PLA kit contains adhesive patches and supplies and a FedEx envelope for return to DermTech, the test’s manufacturer, for processing. The patches can be applied to lesions at least 4 mm in diameter; multiple kits are recommended for those greater than 16 mm in diameter. The test is not validated for lesions located on mucous membranes, palms, soles, nails, or on ulcerated or bleeding lesions, nor for those that have been previously biopsied. It is also not validated for use in pediatric patients or in those with skin types IV or higher. Results are returned in 2-3 days. If insurance does not cover the test, the cost to the patient is approximately $50 per lesion or a maximum of $150, according to Dr. Kim.
 

Use in clinical practice

In Dr. Kim’s clinical experience, the PLA can be considered for suspicious pigmented lesions on cosmetically sensitive areas and for suspicious lesions in areas difficult to biopsy or excise. For example, she discussed the case of a 72-year-old woman with a family history of melanoma, who presented to her clinic with a longstanding pigmented lesion on her right upper and lower eyelids that had previously been treated with laser. She had undergone multiple prior biopsies over 12 years, which caused mild to moderate atypical melanocytic proliferation. The PLA result was double negative for PRAME and LINC in her upper and lower eyelid, “which provided reassurance to the patient,” Dr. Kim said. The patient continues to be followed closely for any clinical changes.

Another patient, a 67-year-old woman, was referred to Dr. Kim from out of state for a teledermatology visit early in the COVID-19 pandemic. The patient had a lesion on her right calf that was hard, raised, and pink, did not resemble other lesions on her body, and had been present for a few weeks. “Her husband had recently passed away from brain cancer and she was very concerned about melanoma,” Dr. Kim recalled. “She lived alone, and the adult son was with her during the teledermatology call to assist. The patient asked about the PLA test, and given her difficulty going to a medical office at the time, we agreed to help her with this test.” The patient and her son arranged another teledermatology visit with Dr. Kim after receiving the kit in the mail from DermTech, and Dr. Kim coached them on how to properly administer the test. The results came back as PRAME negative and LINC positive. A biopsy with a local provider was recommended and the pathology results showed an inflamed seborrheic keratosis.

“This case exemplifies a false-positive result. We should be sure to make patients aware of this possibility,” Dr. Kim said.

Incorporating PLA into clinical practice requires certain workflow considerations, with paperwork to fill out in addition to performing the adhesive test, collection of insurance information, mailing the kit via FedEx, retrieving the results, and following up with the patient, said Dr. Kim. “For select borderline pigmented lesions, I discuss the rationale of the test with patients, the possibility of false-positive and false-negative results and the need to return for a biopsy when there is positive result. Clinical follow-up is recommended for negative results. There is also the possibility of charge to the patient if the test is not covered by their insurance.”
 

Skin biopsy still the gold standard

Despite the availability of the PLA as an assessment tool, Dr. Kim emphasized that skin biopsy remains the gold standard for diagnosing melanoma. “Future prospective randomized clinical trials are needed to examine the role of genetic expression profiling in staging and managing patients,” she said.

In 2019, she and her colleagues surveyed 42 pigmented lesion experts in the United States about why they ordered one of three molecular tests on the market or not and how results affected patient treatment. The proportion of clinicians who ordered the tests ranged from 21% to 29%. The top 2 reasons respondents chose for not ordering the PLA test specifically were: “Feel that further validation studies are necessary” (20%) and “do not feel it would be useful in my practice” (18%).

Results of a larger follow-up survey on usage patterns of PLA of both pigmented lesion experts and general clinicians on this topic are expected to be published shortly.

Dr. Kim reported having no disclosures related to her presentation.

BOSTON – Although skin biopsy remains the gold standard for diagnosing early-stage melanoma, advances in genetic expression profiling are helping dermatologists provide a nuanced approach to managing suspicious lesions.

One such test, the Pigmented Lesional Assay (PLA) uses adhesive patches applied to lesions of concern at the bedside to extract RNA from the stratum corneum to help determine the risk for melanoma.

At the annual meeting of the American Academy of Dermatology, Caroline C. Kim, MD, director of melanoma and pigmented lesion clinics at Newton Wellesley Dermatology, Wellesley Hills, Mass., and Tufts Medical Center, Boston, spoke about the PLA, which uses genetic expression profiling to measure the expression level of specific genes that are associated with melanoma: PRAME (preferentially expressed antigen in melanoma) and LINC00518 (LINC). There are four possible results of the test: Aberrant expression of both LINC and PRAME (high risk); aberrant expression of a single gene (moderate risk); aberrant expression of neither gene (low risk); or inconclusive.

Validation data have shown a sensitivity of 91% and a specificity of 69% for the PLA, with a 99% negative predictive value; so a lesion that tested negative by PLA has a less than 1% chance of being melanoma. In addition, a study published in 2020 found that the addition of TERT (telomerase reverse transcriptase) mutation analyses increased the sensitivity of the PLA to 97%.

While the high negative predictive value is helpful to consider in clinical scenarios to rule-out melanoma for borderline lesions, one must consider the positive predictive value as well and how this may impact clinical care, Dr. Kim said. In a study examining outcomes of 381 lesions, 51 were PLA positive (single or double) and were biopsied, of which 19 (37%) revealed a melanoma diagnosis. In a large U.S. registry study of 3,418 lesions, 324 lesions that were PLA double positive were biopsied, with 18.7% revealing a melanoma diagnosis.

“No test is perfect, and this applies to PLA, even if you get a double-positive or double-negative test result,” Dr. Kim said. “You want to make sure that patients are aware of false positives and negatives. However, PLA could be an additional piece of data to inform your decision to proceed with biopsy on select borderline suspicious pigmented lesions. More studies are needed to better understand the approach to single- and double-positive PLA results.”

The PLA kit contains adhesive patches and supplies and a FedEx envelope for return to DermTech, the test’s manufacturer, for processing. The patches can be applied to lesions at least 4 mm in diameter; multiple kits are recommended for those greater than 16 mm in diameter. The test is not validated for lesions located on mucous membranes, palms, soles, nails, or on ulcerated or bleeding lesions, nor for those that have been previously biopsied. It is also not validated for use in pediatric patients or in those with skin types IV or higher. Results are returned in 2-3 days. If insurance does not cover the test, the cost to the patient is approximately $50 per lesion or a maximum of $150, according to Dr. Kim.
 

Use in clinical practice

In Dr. Kim’s clinical experience, the PLA can be considered for suspicious pigmented lesions on cosmetically sensitive areas and for suspicious lesions in areas difficult to biopsy or excise. For example, she discussed the case of a 72-year-old woman with a family history of melanoma, who presented to her clinic with a longstanding pigmented lesion on her right upper and lower eyelids that had previously been treated with laser. She had undergone multiple prior biopsies over 12 years, which caused mild to moderate atypical melanocytic proliferation. The PLA result was double negative for PRAME and LINC in her upper and lower eyelid, “which provided reassurance to the patient,” Dr. Kim said. The patient continues to be followed closely for any clinical changes.

Another patient, a 67-year-old woman, was referred to Dr. Kim from out of state for a teledermatology visit early in the COVID-19 pandemic. The patient had a lesion on her right calf that was hard, raised, and pink, did not resemble other lesions on her body, and had been present for a few weeks. “Her husband had recently passed away from brain cancer and she was very concerned about melanoma,” Dr. Kim recalled. “She lived alone, and the adult son was with her during the teledermatology call to assist. The patient asked about the PLA test, and given her difficulty going to a medical office at the time, we agreed to help her with this test.” The patient and her son arranged another teledermatology visit with Dr. Kim after receiving the kit in the mail from DermTech, and Dr. Kim coached them on how to properly administer the test. The results came back as PRAME negative and LINC positive. A biopsy with a local provider was recommended and the pathology results showed an inflamed seborrheic keratosis.

“This case exemplifies a false-positive result. We should be sure to make patients aware of this possibility,” Dr. Kim said.

Incorporating PLA into clinical practice requires certain workflow considerations, with paperwork to fill out in addition to performing the adhesive test, collection of insurance information, mailing the kit via FedEx, retrieving the results, and following up with the patient, said Dr. Kim. “For select borderline pigmented lesions, I discuss the rationale of the test with patients, the possibility of false-positive and false-negative results and the need to return for a biopsy when there is positive result. Clinical follow-up is recommended for negative results. There is also the possibility of charge to the patient if the test is not covered by their insurance.”
 

Skin biopsy still the gold standard

Despite the availability of the PLA as an assessment tool, Dr. Kim emphasized that skin biopsy remains the gold standard for diagnosing melanoma. “Future prospective randomized clinical trials are needed to examine the role of genetic expression profiling in staging and managing patients,” she said.

In 2019, she and her colleagues surveyed 42 pigmented lesion experts in the United States about why they ordered one of three molecular tests on the market or not and how results affected patient treatment. The proportion of clinicians who ordered the tests ranged from 21% to 29%. The top 2 reasons respondents chose for not ordering the PLA test specifically were: “Feel that further validation studies are necessary” (20%) and “do not feel it would be useful in my practice” (18%).

Results of a larger follow-up survey on usage patterns of PLA of both pigmented lesion experts and general clinicians on this topic are expected to be published shortly.

Dr. Kim reported having no disclosures related to her presentation.

BOSTON – Although skin biopsy remains the gold standard for diagnosing early-stage melanoma, advances in genetic expression profiling are helping dermatologists provide a nuanced approach to managing suspicious lesions.

One such test, the Pigmented Lesional Assay (PLA) uses adhesive patches applied to lesions of concern at the bedside to extract RNA from the stratum corneum to help determine the risk for melanoma.

At the annual meeting of the American Academy of Dermatology, Caroline C. Kim, MD, director of melanoma and pigmented lesion clinics at Newton Wellesley Dermatology, Wellesley Hills, Mass., and Tufts Medical Center, Boston, spoke about the PLA, which uses genetic expression profiling to measure the expression level of specific genes that are associated with melanoma: PRAME (preferentially expressed antigen in melanoma) and LINC00518 (LINC). There are four possible results of the test: Aberrant expression of both LINC and PRAME (high risk); aberrant expression of a single gene (moderate risk); aberrant expression of neither gene (low risk); or inconclusive.

Validation data have shown a sensitivity of 91% and a specificity of 69% for the PLA, with a 99% negative predictive value; so a lesion that tested negative by PLA has a less than 1% chance of being melanoma. In addition, a study published in 2020 found that the addition of TERT (telomerase reverse transcriptase) mutation analyses increased the sensitivity of the PLA to 97%.

While the high negative predictive value is helpful to consider in clinical scenarios to rule-out melanoma for borderline lesions, one must consider the positive predictive value as well and how this may impact clinical care, Dr. Kim said. In a study examining outcomes of 381 lesions, 51 were PLA positive (single or double) and were biopsied, of which 19 (37%) revealed a melanoma diagnosis. In a large U.S. registry study of 3,418 lesions, 324 lesions that were PLA double positive were biopsied, with 18.7% revealing a melanoma diagnosis.

“No test is perfect, and this applies to PLA, even if you get a double-positive or double-negative test result,” Dr. Kim said. “You want to make sure that patients are aware of false positives and negatives. However, PLA could be an additional piece of data to inform your decision to proceed with biopsy on select borderline suspicious pigmented lesions. More studies are needed to better understand the approach to single- and double-positive PLA results.”

The PLA kit contains adhesive patches and supplies and a FedEx envelope for return to DermTech, the test’s manufacturer, for processing. The patches can be applied to lesions at least 4 mm in diameter; multiple kits are recommended for those greater than 16 mm in diameter. The test is not validated for lesions located on mucous membranes, palms, soles, nails, or on ulcerated or bleeding lesions, nor for those that have been previously biopsied. It is also not validated for use in pediatric patients or in those with skin types IV or higher. Results are returned in 2-3 days. If insurance does not cover the test, the cost to the patient is approximately $50 per lesion or a maximum of $150, according to Dr. Kim.