Telehealth is increasingly being viewed as a key way to help fight the COVID-19 outbreak in the United States. Recognizing the potential of this technology to slow the spread of the disease, the House of Representatives included a provision in an $8.3 billion emergency response bill it approved today that would temporarily lift restrictions on Medicare telehealth coverage to assist in the efforts to contain the virus.

Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases at the Centers for Disease Control and Prevention (CDC), said that hospitals should be prepared to use telehealth as one of their tools in fighting the outbreak, according to a recent news release from the American Hospital Association (AHA).

Congress is responding to that need by including the service in the new coronavirus legislation now headed to the Senate, after the funding bill was approved in a 415-2 vote by the House.

The bill empowers the Secretary of Health and Human Services (HHS) to “waive or modify application of certain Medicare requirements with respect to telehealth services furnished during certain emergency periods.”

While the measure adds telehealth to the waiver authority that the HHS secretary currently has during national emergencies, it’s only for the coronavirus crisis in this case, Krista Drobac, executive director of the Alliance for Connected Care, told Medscape Medical News.

The waiver would apply to originating sites of telehealth visits, she noted. Thus Medicare coverage of telemedicine would be expanded beyond rural areas.

In addition, the waiver would allow coverage of virtual visits conducted on smartphones with audio and video capabilities. A “qualified provider,” as defined by the legislation, would be a practitioner who has an established relationship with the patient or who is in the same practice as the provider who has that relationship.

An advantage of telehealth, proponents say, is that it can enable people who believe they have COVID-19 to be seen at home rather than visit offices or emergency departments (EDs) where they might spread the disease or be in proximity to others who have it.

In an editorial published March 2 in Modern Healthcare, medical directors from Stanford Medicine, MedStar Health, and Intermountain Healthcare also noted that telehealth can give patients 24/7 access to care, allow surveillance of patients at risk while keeping them at home, ensure that treatment in hospitals is reserved for high-need patients, and enable providers to triage and screen more patients than can be handled in brick-and-mortar care settings.

However, telehealth screening would allow physicians only to judge whether a patient’s symptoms might be indicative of COVID-19, the Alliance for Connected Care, a telehealth advocacy group, noted in a letter to Congressional leaders. Patients would still have to be seen in person to be tested for the disease.

The group, which represents technology companies, health insurers, pharmacies, and other healthcare players, has been lobbying Congress to include telehealth in federal funds to combat the outbreak.

The American Telemedicine Association (ATA) also supports this goal, ATA President Joseph Kvedar, MD, told Medscape Medical News. And the authors of the Modern Healthcare editorial also advocated for this legislative solution. Because the fatality rate for COVID-19 is significantly higher for older people than for other age groups, they noted, telehealth should be an economically viable option for all seniors.

The Centers for Medicare and Medicaid Services (CMS) long covered telemedicine only in rural areas and only when initiated in healthcare settings. Recently, however, CMS loosened its approach to some extent. Virtual “check-in visits” can now be initiated from any location, including home, to determine whether a Medicare patient needs to be seen in the office. In addition, CMS allows Medicare Advantage plans to offer telemedicine as a core benefit.

Are healthcare systems prepared?

Some large healthcare systems such as Stanford, MedStar, and Intermountain are already using telehealth to diagnose and treat patients who have traditional influenza. Telehealth providers at Stanford estimate that almost 50% of these patients are being prescribed the antiviral drug Tamiflu.

It’s unclear whether other healthcare systems are this well prepared to offer telehealth on a large scale. But, according to an AHA survey, Kvedar noted, three quarters of AHA members are engaged in some form of telehealth.

Drobac said “it wouldn’t require too much effort” to ramp up a wide-scale telehealth program that could help reduce the impact of the outbreak. “The technology is there,” she noted. “You need a HIPAA-compliant telehealth platform, but there are so many out there.”

Kvedar agreed. To begin with, he said, hospitals might sequester patients who visit the ED with COVID-19 symptoms in a video-equipped “isolation room.” Staff members could then do the patient intake from a different location in the hospital.

He admitted that this approach would be infeasible if a lot of patients arrived in EDs with coronavirus symptoms. However, Kvedar noted, “All the tools are in place to go well beyond that. American Well, Teladoc, and others are all offering ways to get out in front of this. There are plenty of vendors out there, and most people have a connected cell phone that you can do a video call on.”

Hospital leaders would have to decide whether to embrace telehealth, which would mean less use of services in their institutions, he said. “But it would be for the greater good of the public.”

Kvedar recalled that there was some use of telehealth in the New York area after 9/11. Telehealth was also used in the aftermath of Hurricane Katrina in 2005. But the ATA president, who is also vice president of connected health at Partners HealthCare in Boston, noted that the COVID-19 outbreak is the first public health emergency to occur in the era of Skype and smartphones.

If Congress does ultimately authorize CMS to cover telehealth across the board during this emergency, might that lead to a permanent change in Medicare coverage policy? Kvedar wouldn’t venture an opinion. “However, the current CMS leadership has been incredibly telehealth friendly,” he said. “So it’s possible they would [embrace a lifting of restrictions]. As patients get a sense of this modality of care and how convenient it is for them, they’ll start asking for more.”

Meanwhile, he said, the telehealth opportunity goes beyond video visits with doctors to mitigate the outbreak. Telehealth data could also be used to track disease spread, similar to how researchers have studied Google searches to predict the spread of the flu, he noted.

Teladoc, a major telehealth vendor, recently told stock analysts it’s already working with the CDC on disease surveillance, according to a report in FierceHealthcare.

This article first appeared on Medscape.com.

Telehealth is increasingly being viewed as a key way to help fight the COVID-19 outbreak in the United States. Recognizing the potential of this technology to slow the spread of the disease, the House of Representatives included a provision in an $8.3 billion emergency response bill it approved today that would temporarily lift restrictions on Medicare telehealth coverage to assist in the efforts to contain the virus.

Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases at the Centers for Disease Control and Prevention (CDC), said that hospitals should be prepared to use telehealth as one of their tools in fighting the outbreak, according to a recent news release from the American Hospital Association (AHA).

Congress is responding to that need by including the service in the new coronavirus legislation now headed to the Senate, after the funding bill was approved in a 415-2 vote by the House.

The bill empowers the Secretary of Health and Human Services (HHS) to “waive or modify application of certain Medicare requirements with respect to telehealth services furnished during certain emergency periods.”

While the measure adds telehealth to the waiver authority that the HHS secretary currently has during national emergencies, it’s only for the coronavirus crisis in this case, Krista Drobac, executive director of the Alliance for Connected Care, told Medscape Medical News.

The waiver would apply to originating sites of telehealth visits, she noted. Thus Medicare coverage of telemedicine would be expanded beyond rural areas.

In addition, the waiver would allow coverage of virtual visits conducted on smartphones with audio and video capabilities. A “qualified provider,” as defined by the legislation, would be a practitioner who has an established relationship with the patient or who is in the same practice as the provider who has that relationship.

An advantage of telehealth, proponents say, is that it can enable people who believe they have COVID-19 to be seen at home rather than visit offices or emergency departments (EDs) where they might spread the disease or be in proximity to others who have it.

In an editorial published March 2 in Modern Healthcare, medical directors from Stanford Medicine, MedStar Health, and Intermountain Healthcare also noted that telehealth can give patients 24/7 access to care, allow surveillance of patients at risk while keeping them at home, ensure that treatment in hospitals is reserved for high-need patients, and enable providers to triage and screen more patients than can be handled in brick-and-mortar care settings.

However, telehealth screening would allow physicians only to judge whether a patient’s symptoms might be indicative of COVID-19, the Alliance for Connected Care, a telehealth advocacy group, noted in a letter to Congressional leaders. Patients would still have to be seen in person to be tested for the disease.

The group, which represents technology companies, health insurers, pharmacies, and other healthcare players, has been lobbying Congress to include telehealth in federal funds to combat the outbreak.

The American Telemedicine Association (ATA) also supports this goal, ATA President Joseph Kvedar, MD, told Medscape Medical News. And the authors of the Modern Healthcare editorial also advocated for this legislative solution. Because the fatality rate for COVID-19 is significantly higher for older people than for other age groups, they noted, telehealth should be an economically viable option for all seniors.

The Centers for Medicare and Medicaid Services (CMS) long covered telemedicine only in rural areas and only when initiated in healthcare settings. Recently, however, CMS loosened its approach to some extent. Virtual “check-in visits” can now be initiated from any location, including home, to determine whether a Medicare patient needs to be seen in the office. In addition, CMS allows Medicare Advantage plans to offer telemedicine as a core benefit.

Are healthcare systems prepared?

Some large healthcare systems such as Stanford, MedStar, and Intermountain are already using telehealth to diagnose and treat patients who have traditional influenza. Telehealth providers at Stanford estimate that almost 50% of these patients are being prescribed the antiviral drug Tamiflu.

It’s unclear whether other healthcare systems are this well prepared to offer telehealth on a large scale. But, according to an AHA survey, Kvedar noted, three quarters of AHA members are engaged in some form of telehealth.

Drobac said “it wouldn’t require too much effort” to ramp up a wide-scale telehealth program that could help reduce the impact of the outbreak. “The technology is there,” she noted. “You need a HIPAA-compliant telehealth platform, but there are so many out there.”

Kvedar agreed. To begin with, he said, hospitals might sequester patients who visit the ED with COVID-19 symptoms in a video-equipped “isolation room.” Staff members could then do the patient intake from a different location in the hospital.

He admitted that this approach would be infeasible if a lot of patients arrived in EDs with coronavirus symptoms. However, Kvedar noted, “All the tools are in place to go well beyond that. American Well, Teladoc, and others are all offering ways to get out in front of this. There are plenty of vendors out there, and most people have a connected cell phone that you can do a video call on.”

Hospital leaders would have to decide whether to embrace telehealth, which would mean less use of services in their institutions, he said. “But it would be for the greater good of the public.”

Kvedar recalled that there was some use of telehealth in the New York area after 9/11. Telehealth was also used in the aftermath of Hurricane Katrina in 2005. But the ATA president, who is also vice president of connected health at Partners HealthCare in Boston, noted that the COVID-19 outbreak is the first public health emergency to occur in the era of Skype and smartphones.

If Congress does ultimately authorize CMS to cover telehealth across the board during this emergency, might that lead to a permanent change in Medicare coverage policy? Kvedar wouldn’t venture an opinion. “However, the current CMS leadership has been incredibly telehealth friendly,” he said. “So it’s possible they would [embrace a lifting of restrictions]. As patients get a sense of this modality of care and how convenient it is for them, they’ll start asking for more.”

Meanwhile, he said, the telehealth opportunity goes beyond video visits with doctors to mitigate the outbreak. Telehealth data could also be used to track disease spread, similar to how researchers have studied Google searches to predict the spread of the flu, he noted.

Teladoc, a major telehealth vendor, recently told stock analysts it’s already working with the CDC on disease surveillance, according to a report in FierceHealthcare.

This article first appeared on Medscape.com.

Telehealth is increasingly being viewed as a key way to help fight the COVID-19 outbreak in the United States. Recognizing the potential of this technology to slow the spread of the disease, the House of Representatives included a provision in an $8.3 billion emergency response bill it approved today that would temporarily lift restrictions on Medicare telehealth coverage to assist in the efforts to contain the virus.

Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases at the Centers for Disease Control and Prevention (CDC), said that hospitals should be prepared to use telehealth as one of their tools in fighting the outbreak, according to a recent news release from the American Hospital Association (AHA).

Congress is responding to that need by including the service in the new coronavirus legislation now headed to the Senate, after the funding bill was approved in a 415-2 vote by the House.

The bill empowers the Secretary of Health and Human Services (HHS) to “waive or modify application of certain Medicare requirements with respect to telehealth services furnished during certain emergency periods.”

While the measure adds telehealth to the waiver authority that the HHS secretary currently has during national emergencies, it’s only for the coronavirus crisis in this case, Krista Drobac, executive director of the Alliance for Connected Care, told Medscape Medical News.

The waiver would apply to originating sites of telehealth visits, she noted. Thus Medicare coverage of telemedicine would be expanded beyond rural areas.

In addition, the waiver would allow coverage of virtual visits conducted on smartphones with audio and video capabilities. A “qualified provider,” as defined by the legislation, would be a practitioner who has an established relationship with the patient or who is in the same practice as the provider who has that relationship.

An advantage of telehealth, proponents say, is that it can enable people who believe they have COVID-19 to be seen at home rather than visit offices or emergency departments (EDs) where they might spread the disease or be in proximity to others who have it.

In an editorial published March 2 in Modern Healthcare, medical directors from Stanford Medicine, MedStar Health, and Intermountain Healthcare also noted that telehealth can give patients 24/7 access to care, allow surveillance of patients at risk while keeping them at home, ensure that treatment in hospitals is reserved for high-need patients, and enable providers to triage and screen more patients than can be handled in brick-and-mortar care settings.

However, telehealth screening would allow physicians only to judge whether a patient’s symptoms might be indicative of COVID-19, the Alliance for Connected Care, a telehealth advocacy group, noted in a letter to Congressional leaders. Patients would still have to be seen in person to be tested for the disease.

The group, which represents technology companies, health insurers, pharmacies, and other healthcare players, has been lobbying Congress to include telehealth in federal funds to combat the outbreak.

The American Telemedicine Association (ATA) also supports this goal, ATA President Joseph Kvedar, MD, told Medscape Medical News. And the authors of the Modern Healthcare editorial also advocated for this legislative solution. Because the fatality rate for COVID-19 is significantly higher for older people than for other age groups, they noted, telehealth should be an economically viable option for all seniors.

The Centers for Medicare and Medicaid Services (CMS) long covered telemedicine only in rural areas and only when initiated in healthcare settings. Recently, however, CMS loosened its approach to some extent. Virtual “check-in visits” can now be initiated from any location, including home, to determine whether a Medicare patient needs to be seen in the office. In addition, CMS allows Medicare Advantage plans to offer telemedicine as a core benefit.

Are healthcare systems prepared?

Some large healthcare systems such as Stanford, MedStar, and Intermountain are already using telehealth to diagnose and treat patients who have traditional influenza. Telehealth providers at Stanford estimate that almost 50% of these patients are being prescribed the antiviral drug Tamiflu.

It’s unclear whether other healthcare systems are this well prepared to offer telehealth on a large scale. But, according to an AHA survey, Kvedar noted, three quarters of AHA members are engaged in some form of telehealth.

Drobac said “it wouldn’t require too much effort” to ramp up a wide-scale telehealth program that could help reduce the impact of the outbreak. “The technology is there,” she noted. “You need a HIPAA-compliant telehealth platform, but there are so many out there.”

Kvedar agreed. To begin with, he said, hospitals might sequester patients who visit the ED with COVID-19 symptoms in a video-equipped “isolation room.” Staff members could then do the patient intake from a different location in the hospital.

He admitted that this approach would be infeasible if a lot of patients arrived in EDs with coronavirus symptoms. However, Kvedar noted, “All the tools are in place to go well beyond that. American Well, Teladoc, and others are all offering ways to get out in front of this. There are plenty of vendors out there, and most people have a connected cell phone that you can do a video call on.”

Hospital leaders would have to decide whether to embrace telehealth, which would mean less use of services in their institutions, he said. “But it would be for the greater good of the public.”

Kvedar recalled that there was some use of telehealth in the New York area after 9/11. Telehealth was also used in the aftermath of Hurricane Katrina in 2005. But the ATA president, who is also vice president of connected health at Partners HealthCare in Boston, noted that the COVID-19 outbreak is the first public health emergency to occur in the era of Skype and smartphones.

If Congress does ultimately authorize CMS to cover telehealth across the board during this emergency, might that lead to a permanent change in Medicare coverage policy? Kvedar wouldn’t venture an opinion. “However, the current CMS leadership has been incredibly telehealth friendly,” he said. “So it’s possible they would [embrace a lifting of restrictions]. As patients get a sense of this modality of care and how convenient it is for them, they’ll start asking for more.”

Meanwhile, he said, the telehealth opportunity goes beyond video visits with doctors to mitigate the outbreak. Telehealth data could also be used to track disease spread, similar to how researchers have studied Google searches to predict the spread of the flu, he noted.

Teladoc, a major telehealth vendor, recently told stock analysts it’s already working with the CDC on disease surveillance, according to a report in FierceHealthcare.

This article first appeared on Medscape.com.

In this edition of “Applying research to practice,” I highlight I-SPY2 and other studies of pembrolizumab plus chemotherapy in breast cancer patients.

Pathologic complete response (pCR) rates up to 60% were reported for patients with high-risk, stage II/III breast cancer who received pembrolizumab plus standard neoadjuvant chemotherapy (NAC) in I-SPY2, an ongoing platform trial designed to screen multiple agents and pinpoint those with a high probability of success (JAMA Oncol. 2020 Feb 13. doi: 10.1001/jamaoncol.2019.6650).

The addition of pembrolizumab to NAC doubled pCR rates in all three biomarker signatures studied, including ERBB2 (HER2)-negative, hormone receptor (HR)-positive/ERBB2-negative, and triple-negative breast cancer (TNBC).

As a result, pembrolizumab “graduated” from I-SPY2, with a more than 99% predictive probability that the pembrolizumab-plus-NAC approach would be superior to NAC alone in a phase 3 trial. In the HR-positive/ERBB2-negative signature, pembrolizumab is the first agent to graduate among the 10 agents studied since I-SPY2 opened in 2010.

The control arm in I-SPY2 had 181 patients randomized to standard NAC (paclitaxel followed by doxorubicin plus cyclophosphamide). The pembrolizumab arm included 69 patients who received the same NAC regimen plus pembrolizumab, given concurrently with paclitaxel.

The estimated pCR rates in all ERBB2-negative patients were 44% in the pembrolizumab arm and 17% in the control arm. Among the 40 HR-positive/ERBB2-negative patients, the estimated pCR rates were 30% and 13%, respectively. In the 29 TNBC patients, the estimated pCR rates were 60% and 22%, respectively.

Extensive residual cancer burden was less often seen in the pembrolizumab-treated patients than in the comparison group. At a median follow-up of 2.8 years in the pembrolizumab arm and 3.5 years in the NAC arm, 3-year event-free survival was similar between the arms. However, the investigators cautioned against drawing conclusions from this exploratory analysis in a small number of patients. Testifying to the importance of the primary endpoint of pCR rate, patients who achieved pCR had excellent outcomes regardless of their assigned study arms.

Immune-related adverse events in the pembrolizumab-treated patients were generally grade 1 or 2 and were managed with dose interruption or corticosteroid therapy. Most commonly seen was thyroid dysfunction in 13% of patients, as in previously published reports. Adrenal insufficiency occurred more often than expected (8.7%), for unclear reasons, with five of the six reported cases occurring more than 30 days after the last dose of pembrolizumab.

The bigger picture: Putting I-SPY2 results into context

It is well known that responses to pembrolizumab monotherapy in patients with advanced, refractory breast cancer are infrequent. In contrast, in previously untreated patients with PD-L1 positive TNBC, pembrolizumab monotherapy produced a response rate of 21% in KEYNOTE-086 (Ann Oncol. 2019 Mar 1;30(3):405-11). This response rate is similar to that observed with standard chemotherapy, but responses with pembrolizumab were more durable.

In the phase 3 KEYNOTE-355 trial (NCT02819518), researchers are comparing pembrolizumab plus chemotherapy to placebo plus chemotherapy in patients with previously untreated, stage IV TNBC with high PD-L1 expression. Researchers saw a significant and clinically meaningful improvement in progression-free survival in the pembrolizumab arm, according to a recent announcement from Merck. These results lend credence to the I-SPY2 authors’ hypothesis that immune-targeted agents would show their greatest benefit in early-stage breast cancer patients.

In fact, results from I-SPY2 have been confirmed by results from the phase 3 KEYNOTE-522 trial, which were recently published (N Engl J Med 2020;382:810-21) and presented at the San Antonio Breast Cancer Symposium. I-SPY2 predicted that pembrolizumab would be superior to standard NAC in TNBC patients in a phase 3 trial, and it was.

In KEYNOTE-522, the pCR rate was significantly higher in early-stage TNBC patients who received pembrolizumab plus NAC than in early-stage TNBC patients who received placebo plus NAC. The pCR rate was 64.8% in the pembrolizumab-NAC arm and 51.2% in the placebo–NAC arm (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P less than .001).

These results are exciting. Results from I-SPY2 and KEYNOTE-522 whet the appetite for results of KEYNOTE-756, an ongoing trial of pembrolizumab plus NAC in HR-positive/ERBB2-negative patients (NCT03725059). Hopefully, the efficacy and toxicity results of KEYNOTE-756 will be as exciting as the I-SPY2 results predict they will be. Among patients with early stage breast cancer whose tumor characteristics are adverse enough to require NAC, better regimens are needed to attain pCR, a validated surrogate for long-term freedom from recurrence.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations.

In this edition of “Applying research to practice,” I highlight I-SPY2 and other studies of pembrolizumab plus chemotherapy in breast cancer patients.

Pathologic complete response (pCR) rates up to 60% were reported for patients with high-risk, stage II/III breast cancer who received pembrolizumab plus standard neoadjuvant chemotherapy (NAC) in I-SPY2, an ongoing platform trial designed to screen multiple agents and pinpoint those with a high probability of success (JAMA Oncol. 2020 Feb 13. doi: 10.1001/jamaoncol.2019.6650).

The addition of pembrolizumab to NAC doubled pCR rates in all three biomarker signatures studied, including ERBB2 (HER2)-negative, hormone receptor (HR)-positive/ERBB2-negative, and triple-negative breast cancer (TNBC).

As a result, pembrolizumab “graduated” from I-SPY2, with a more than 99% predictive probability that the pembrolizumab-plus-NAC approach would be superior to NAC alone in a phase 3 trial. In the HR-positive/ERBB2-negative signature, pembrolizumab is the first agent to graduate among the 10 agents studied since I-SPY2 opened in 2010.

The control arm in I-SPY2 had 181 patients randomized to standard NAC (paclitaxel followed by doxorubicin plus cyclophosphamide). The pembrolizumab arm included 69 patients who received the same NAC regimen plus pembrolizumab, given concurrently with paclitaxel.

The estimated pCR rates in all ERBB2-negative patients were 44% in the pembrolizumab arm and 17% in the control arm. Among the 40 HR-positive/ERBB2-negative patients, the estimated pCR rates were 30% and 13%, respectively. In the 29 TNBC patients, the estimated pCR rates were 60% and 22%, respectively.

Extensive residual cancer burden was less often seen in the pembrolizumab-treated patients than in the comparison group. At a median follow-up of 2.8 years in the pembrolizumab arm and 3.5 years in the NAC arm, 3-year event-free survival was similar between the arms. However, the investigators cautioned against drawing conclusions from this exploratory analysis in a small number of patients. Testifying to the importance of the primary endpoint of pCR rate, patients who achieved pCR had excellent outcomes regardless of their assigned study arms.

Immune-related adverse events in the pembrolizumab-treated patients were generally grade 1 or 2 and were managed with dose interruption or corticosteroid therapy. Most commonly seen was thyroid dysfunction in 13% of patients, as in previously published reports. Adrenal insufficiency occurred more often than expected (8.7%), for unclear reasons, with five of the six reported cases occurring more than 30 days after the last dose of pembrolizumab.

The bigger picture: Putting I-SPY2 results into context

It is well known that responses to pembrolizumab monotherapy in patients with advanced, refractory breast cancer are infrequent. In contrast, in previously untreated patients with PD-L1 positive TNBC, pembrolizumab monotherapy produced a response rate of 21% in KEYNOTE-086 (Ann Oncol. 2019 Mar 1;30(3):405-11). This response rate is similar to that observed with standard chemotherapy, but responses with pembrolizumab were more durable.

In the phase 3 KEYNOTE-355 trial (NCT02819518), researchers are comparing pembrolizumab plus chemotherapy to placebo plus chemotherapy in patients with previously untreated, stage IV TNBC with high PD-L1 expression. Researchers saw a significant and clinically meaningful improvement in progression-free survival in the pembrolizumab arm, according to a recent announcement from Merck. These results lend credence to the I-SPY2 authors’ hypothesis that immune-targeted agents would show their greatest benefit in early-stage breast cancer patients.

In fact, results from I-SPY2 have been confirmed by results from the phase 3 KEYNOTE-522 trial, which were recently published (N Engl J Med 2020;382:810-21) and presented at the San Antonio Breast Cancer Symposium. I-SPY2 predicted that pembrolizumab would be superior to standard NAC in TNBC patients in a phase 3 trial, and it was.

In KEYNOTE-522, the pCR rate was significantly higher in early-stage TNBC patients who received pembrolizumab plus NAC than in early-stage TNBC patients who received placebo plus NAC. The pCR rate was 64.8% in the pembrolizumab-NAC arm and 51.2% in the placebo–NAC arm (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P less than .001).

These results are exciting. Results from I-SPY2 and KEYNOTE-522 whet the appetite for results of KEYNOTE-756, an ongoing trial of pembrolizumab plus NAC in HR-positive/ERBB2-negative patients (NCT03725059). Hopefully, the efficacy and toxicity results of KEYNOTE-756 will be as exciting as the I-SPY2 results predict they will be. Among patients with early stage breast cancer whose tumor characteristics are adverse enough to require NAC, better regimens are needed to attain pCR, a validated surrogate for long-term freedom from recurrence.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations.

In this edition of “Applying research to practice,” I highlight I-SPY2 and other studies of pembrolizumab plus chemotherapy in breast cancer patients.

Pathologic complete response (pCR) rates up to 60% were reported for patients with high-risk, stage II/III breast cancer who received pembrolizumab plus standard neoadjuvant chemotherapy (NAC) in I-SPY2, an ongoing platform trial designed to screen multiple agents and pinpoint those with a high probability of success (JAMA Oncol. 2020 Feb 13. doi: 10.1001/jamaoncol.2019.6650).

The addition of pembrolizumab to NAC doubled pCR rates in all three biomarker signatures studied, including ERBB2 (HER2)-negative, hormone receptor (HR)-positive/ERBB2-negative, and triple-negative breast cancer (TNBC).

As a result, pembrolizumab “graduated” from I-SPY2, with a more than 99% predictive probability that the pembrolizumab-plus-NAC approach would be superior to NAC alone in a phase 3 trial. In the HR-positive/ERBB2-negative signature, pembrolizumab is the first agent to graduate among the 10 agents studied since I-SPY2 opened in 2010.

The control arm in I-SPY2 had 181 patients randomized to standard NAC (paclitaxel followed by doxorubicin plus cyclophosphamide). The pembrolizumab arm included 69 patients who received the same NAC regimen plus pembrolizumab, given concurrently with paclitaxel.

The estimated pCR rates in all ERBB2-negative patients were 44% in the pembrolizumab arm and 17% in the control arm. Among the 40 HR-positive/ERBB2-negative patients, the estimated pCR rates were 30% and 13%, respectively. In the 29 TNBC patients, the estimated pCR rates were 60% and 22%, respectively.

Extensive residual cancer burden was less often seen in the pembrolizumab-treated patients than in the comparison group. At a median follow-up of 2.8 years in the pembrolizumab arm and 3.5 years in the NAC arm, 3-year event-free survival was similar between the arms. However, the investigators cautioned against drawing conclusions from this exploratory analysis in a small number of patients. Testifying to the importance of the primary endpoint of pCR rate, patients who achieved pCR had excellent outcomes regardless of their assigned study arms.

Immune-related adverse events in the pembrolizumab-treated patients were generally grade 1 or 2 and were managed with dose interruption or corticosteroid therapy. Most commonly seen was thyroid dysfunction in 13% of patients, as in previously published reports. Adrenal insufficiency occurred more often than expected (8.7%), for unclear reasons, with five of the six reported cases occurring more than 30 days after the last dose of pembrolizumab.

The bigger picture: Putting I-SPY2 results into context

It is well known that responses to pembrolizumab monotherapy in patients with advanced, refractory breast cancer are infrequent. In contrast, in previously untreated patients with PD-L1 positive TNBC, pembrolizumab monotherapy produced a response rate of 21% in KEYNOTE-086 (Ann Oncol. 2019 Mar 1;30(3):405-11). This response rate is similar to that observed with standard chemotherapy, but responses with pembrolizumab were more durable.

In the phase 3 KEYNOTE-355 trial (NCT02819518), researchers are comparing pembrolizumab plus chemotherapy to placebo plus chemotherapy in patients with previously untreated, stage IV TNBC with high PD-L1 expression. Researchers saw a significant and clinically meaningful improvement in progression-free survival in the pembrolizumab arm, according to a recent announcement from Merck. These results lend credence to the I-SPY2 authors’ hypothesis that immune-targeted agents would show their greatest benefit in early-stage breast cancer patients.

In fact, results from I-SPY2 have been confirmed by results from the phase 3 KEYNOTE-522 trial, which were recently published (N Engl J Med 2020;382:810-21) and presented at the San Antonio Breast Cancer Symposium. I-SPY2 predicted that pembrolizumab would be superior to standard NAC in TNBC patients in a phase 3 trial, and it was.

In KEYNOTE-522, the pCR rate was significantly higher in early-stage TNBC patients who received pembrolizumab plus NAC than in early-stage TNBC patients who received placebo plus NAC. The pCR rate was 64.8% in the pembrolizumab-NAC arm and 51.2% in the placebo–NAC arm (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P less than .001).

These results are exciting. Results from I-SPY2 and KEYNOTE-522 whet the appetite for results of KEYNOTE-756, an ongoing trial of pembrolizumab plus NAC in HR-positive/ERBB2-negative patients (NCT03725059). Hopefully, the efficacy and toxicity results of KEYNOTE-756 will be as exciting as the I-SPY2 results predict they will be. Among patients with early stage breast cancer whose tumor characteristics are adverse enough to require NAC, better regimens are needed to attain pCR, a validated surrogate for long-term freedom from recurrence.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations.

Background

On Dec. 31, 2019, the Chinese city of Wuhan reported an outbreak of pneumonia from an unknown cause. The outbreak was found to be linked to the Hunan seafood market because of a shared history of exposure by many patients. After a full-scale investigation, China’s Center for Disease Control activated a level 2 emergency response on Jan. 4, 2020. A novel coronavirus was officially identified as a causative pathogen for the outbreak.¹

Coronavirus, first discovered in the 1960s, is a respiratory RNA virus, most commonly associated with the “common cold.” However, we have had two highly pathogenic forms of coronavirus that originated from animal reservoirs, leading to global epidemics. This includes SARS-CoV in 2002-2004 and MERS-CoV in 2012 with more than 10,000 combined cases. The primary host has been bats, but mammals like camels, cattle, cats, and palm civets have been intermediate hosts in previous epidemics.²

The International Committee on Taxonomy of Viruses named the 2019-nCoV officially as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease, COVID-19, on Feb. 11, 2020.³ Currently, the presentation includes fever, cough, trouble breathing, fatigue, and, rarely, watery diarrhea. More severe presentations include respiratory failure and death. Based on the incubation period of illness for Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) coronaviruses, as well as observational data from reports of travel-related COVID-19, CDC estimates that symptoms of COVID-19 occur within 2-14 days after exposure. Asymptomatic transmission is also documented in some cases.⁴

On Jan. 13, the first case of COVID-19 outside of China was identified in Thailand. On Jan. 21, the first case of COVID-19 was identified in the United States. On Jan. 23, Chinese authorities suspended travel in and out of Wuhan, followed by other cities in the Hubei Province, leading to a quarantine of 50 million people. By Jan. 30, the World Health Organization had identified COVID-19 as the highest level of an epidemic alert referred to as a PHEIC: Public Health Emergency of International Concern. On Feb. 2, the first death outside China from coronavirus was reported in the Philippines. As of March 4 there have been 95,000 confirmed cases and 3,246 deaths globally. Within China, there have been 80,200 cases with 2,981 deaths.⁵

Cases have now been diagnosed in increasing numbers in Italy, Japan, South Korea, Iran, and 76 countries. Of note, the fatalities were of patients already in critical condition, who were typically older (more than 60 years old, especially more than 80) and immunocompromised with comorbid conditions (cardiovascular disease, diabetes, chronic respiratory disease, cancer).⁶ To put this in perspective, since 2010, CDC reports 140,000-810,000 hospitalizations and 12,000-61,000 deaths from the influenza virus annually in the US.⁷
 

The current situation in the United States

In the United States, as of March 4, 2020, there are currently 152 confirmed cases in 16 states. The first U.S. case of coronavirus without any of the travel-related and exposure risk factors was identified on Feb. 27 in California, indicating the first instance of community spread.⁸ The first death was reported in Washington state on Feb. 28, after which the state’s governor declared a state of emergency.⁹ On March 1, Washington state health officials investigated an outbreak of coronavirus at a long-term nursing facility in which two people tested positive for the disease, heralding the probable first nosocomial transmission of the virus in the United States. Since then, there have been 10 deaths in Washington state related to the coronavirus.

Current interventions in the United States

The U.S. Centers for Disease Control and Prevention is leading a multiagency effort to combat the COVID-19 potential pandemic. A Feb. 24 report in Morbidity and Mortality Weekly Report revealed that 1,336 CDC staff members have been involved in the COVID-19 response.¹⁰ CDC staff members have been deployed to 39 locations in the United States and internationally. CDC staff members are working with state and local health departments and other public health authorities to assist with case identification, contact tracing, evaluation of persons under investigation (PUI) for COVID-19, and medical management of cases, as well as with research and academic institutions to understand the virulence, risk for transmission, and other characteristics of this novel virus. The CDC is also working with other agencies of the U.S. government including the U.S. Department of Defense, Department of Health & Human Services and the U.S. Department of State to safely evacuate U.S. citizens, residents, and their families from international locations with high incidence and transmission of COVID-19.

Specific real-time updated guidance has been developed and posted online for health care settings for patient management, infection control and prevention, laboratory testing, environmental cleaning, worker safety, and international travel. The CDC has developed communications materials in English and Spanish for communities and guidance for health care settings, public health, laboratories, schools, and businesses to prepare for a potential pandemic. Travel advisories to countries affected by the epidemic are regularly updated to inform travelers and clinicians about current health issues that need to be considered before travel.¹¹ A level 3 travel notice (avoid all nonessential travel) for China has been in effect since Jan. 27, and on Feb. 29 this was upgraded to a level 4 travel notice.¹² Airport screening has been implemented in the 11 U.S. international airports to which flights from China have been diverted, and a total of 46,016 air travelers had been screened by Feb. 23. Incoming passengers are screened for fever, cough, and shortness of breath.

Currently, the CDC has a comprehensive algorithm for further investigation of a PUI – fever, cough, shortness of breath, and a history of travel to areas with increased coronavirus circulation within 14 days of onset of symptoms, OR a close household contact of a confirmed case. When there is a PUI, the current protocol indicates health care providers should alert a local or state health department official. After the health department completes a case investigation, the CDC will help transport specimens (upper respiratory and lower respiratory specimens, and sometimes stool or urine) as soon as possible to the centralized lab for polymerase chain reaction (PCR) testing.¹³ CDC laboratories are currently using real-time reverse transcription–PCR (RT-PCR). The CDC is also developing a serologic test to assist with surveillance for SARS-CoV-2 circulation in the U.S. population. There is also a safe repository of viral isolates set up to help with sharing of isolates with academic institutions for research purposes.¹⁴

At hospitals and outpatient offices in the United States, we are preparing for potential cases by reminding frontline health care workers to routinely ask about travel history in addition to relevant symptoms. By eliciting the history early, they should be able to identify and isolate PUIs, appropriately minimizing exposure. Some facilities are displaying signage in waiting rooms to alert patients to provide relevant history, helping to improve triage. COVID-19 symptoms are like those of influenza (e.g., fever, cough, and shortness of breath), and the current outbreak is occurring during a time of year when respiratory illnesses from influenza and other viruses are highly prevalent. To prevent influenza and possible unnecessary evaluation for COVID-19, all persons aged 6 months and older are strongly encouraged to receive an annual influenza vaccine.

To decrease the risk for respiratory disease, persons can practice recommended preventive measures. Persons ill with symptoms of COVID-19 who have had contact with a person with COVID-19, or recent travel to countries with apparent community spread, should proactively communicate with their health care provider before showing up at the health care facility to help make arrangements to prevent possible transmission in the health care setting. In a medical emergency, they should inform emergency medical personnel about possible COVID-19 exposure. If found positive, the current recommendation is to place patients on airborne isolation. N95 masks are being recommended for health care professionals. Hospitals are reinforcing effective infection control procedures, updating pandemic preparedness protocols, and ensuring adequate supplies in the case of an enormous influx of patients.¹⁵

Challenges and opportunities

Many challenges present in the process of getting prepared for a potential outbreak. Personal protective equipment such as N-95 masks are in short supply, as they are in high demand in the general public.¹⁶ The CDC currently does not recommend that members of the general public use face masks, given low levels of circulation of SARS-CoV-2 currently in the United States. The CDC has developed several documents regarding infection control, hospital preparedness assessments, personal protective equipment (PPE) supply planning, clinical evaluation and management, and respirator conservation strategies.

The RT-PCR test developed by the CDC has had some setbacks, with recent testing kits showing “inconclusive results.” The testing was initially available only through the CDC lab in Atlanta, with a 48-hour turnaround. This led to potential delays in diagnosis and the timely isolation and treatment of infected patients. On March 3, the CDC broadened the guidelines for coronavirus testing, allowing clinicians to order a test for any patients who have symptoms of COVID-19 infection. The greatest need is for decentralized testing in local and state labs, as well as validated testing in local hospitals and commercial labs. The ability to develop and scale-up diagnostic abilities is critically important.

There is also concern about overwhelming hospitals with a strain on the availability of beds, ventilators, and airborne isolation rooms. The CDC is recommending leveraging telehealth tools to direct people to the right level of health care for their medical needs. Hospitalization should only be for the sickest patients.¹⁷

Funding for a pandemic response is of paramount importance. Proposed 2021 federal budget cuts include $2.9 billion in cuts to the National Institutes of Health, and $708 million in cuts to the CDC, which makes the situation look especially worrisome as we face a potentially severe pandemic. The Infectious Diseases Society of America identifies antimicrobial resistance, NIH research, global health security, global HIV epidemic, and CDC vaccine programs as five “deeply underfunded” areas in the federal budget.¹⁸

The NIH has recently begun the first randomized clinical trial, treating patients at the University of Nebraska with laboratory-confirmed SARS-CoV-2 with a broad-spectrum antiviral drug called remdesivir. Patients from the Diamond Princess Cruise ship are also participating in this clinical trial. This study will hopefully shed light on potential treatments for coronavirus to stop or alleviate the consequences in real time. Similar clinical trials are also occurring in China.¹⁹

Vaccine development is underway in many public and private research facilities, but it will take approximately 6-18 months before they will be available for use. In the absence of a vaccine or therapeutic, community mitigation measures are the primary method to respond to the widespread transmission, and supportive care is the current medical treatment. In the case of a pandemic, the mitigation measures might include school dismissals and social distancing in other settings, like suspension of mass gatherings, telework and remote-meeting options in workplaces.

Many respected medical journals in the United States have made access to SARS-CoV-2 articles and literature readily and freely available, which is a remarkable step. Multiple societies and journals have made information available in real time and have used media effectively (e.g., podcasts, e-learning) to disseminate information to the general public. Articles have been made available in other languages, including Chinese.
 

Conclusions

In summary, there have been 3,280 total deaths attributable to SARS-CoV-2 to date globally, mostly among geriatric patients with comorbidities. To provide some perspective on the statistics, influenza has killed almost 14,000 patients this season alone (much more than coronavirus). COVID-19 is undoubtedly a global public health threat. We in the U.S. health care system are taking swift public health actions, including isolation of patients and contacts to prevent secondary spread, but it is unclear if this is enough to stop an outbreak from becoming a pandemic.

The CDC is warning of significant social and economic disruption in the coming weeks, with more expected community spread and confirmed cases. It is challenging to prepare for a pandemic when the transmission dynamics are not clearly known, the duration of infectiousness is not well defined, and asymptomatic transmission is a possibility. It is time for the public to be informed from trusted sources and avoid unverified information, especially on social media which can lead to confusion and panic. The spread of COVID-19 infection in the United States is inevitable, and there must be sufficient, well-coordinated planning that can curtail the spread and reduce the impact.
 

Dr. Tirupathi is the medical director of Keystone Infectious Diseases/HIV in Chambersburg, Pa., and currently chair of infection prevention at Wellspan Chambersburg and Waynesboro (Pa.) Hospitals. He also is the lead physician for antibiotic stewardship at these hospitals. Dr. Palabindala is hospital medicine division chief at the University of Mississippi Medical Center, Jackson. Ms. Sathya Areti is a 3rd-year medical student at the Virginia Commonwealth University School of Medicine (class of 2021), planning to apply into Internal Medicine-Pediatrics. Dr. Swetha Areti is currently working as a hospitalist at Wellspan Chambersburg Hospital and is also a member of the Wellspan Pharmacy and Therapeutics committee.

References

1. Phelan AL et al. The novel coronavirus originating in Wuhan, China: Challenges for global health governance. JAMA. 2020;323(8):709-10. doi: 10.1001/jama.2020.1097.

2. del Rio C, Malani PN. 2019 Novel coronavirus – Important information for clinicians. JAMA. Published online Feb. 5, 2020. doi: 10.1001/jama.2020.1490.

3. Gorbalenya AE et al. Severe acute respiratory syndrome-related coronavirus: The species and its viruses – a statement of the Coronavirus Study Group. bioRxiv. Published Jan. 1, 2020. doi: 10.1101/2020.02.07.937862.

4. Jernigan DB. CDC COVID-19 response team. Update: Public health response to the coronavirus disease 2019 outbreak – United States, Feb 24, 2020. MMWR Morbidity and Mortality Weekly Report 2020;69:216-19. doi: 10.15585/mmwr.mm6908e1.

5. Coronavirus disease 2019 (COVID-19). Situation Report – 40. Published Feb. 29, 2020.

6. Kaiyuan Sun, et al. Early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a population level observational study, Feb. 20, 2020. Lancet Digital Health 2020. doi: 10.1016/S2589-7500(20)30026-1.

7. Rolfes MA et al. Annual estimates of the burden of seasonal influenza in the United States: A tool for strengthening influenza surveillance and preparedness. Influenza Other Respir Viruses. 2018;12(1):132-7. doi: 10.1111/irv.12486.

8. Jernigan DB. CDC COVID-19 response team. Update: Public health response to the coronavirus disease 2019 outbreak – United States, Feb. 24, 2020. MMWR Morbidity and Mortality Weekly Report 2020;69:216-19. doi: 10.15585/mmwr.mm6908e1.

9. Jablon R, Baumann L. Washington governor declares state of emergency over virus. AP News. Published Feb. 29, 2020.

10. Jernigan DB, CDC COVID-19 response team. Update: Public health response to the coronavirus disease 2019 outbreak – United States, Feb. 24, 2020. MMWR Morbidity and Mortality Weekly Report 2020; 69:216-219. doi: 10.15585/mmwr.mm6908e1.

11. Information for health departments on reporting a person under investigation (PUI) or laboratory-confirmed case for COVID-19. Centers for Disease Control and Prevention. Published Feb 24, 2020.

12. Hines M. Coronavirus: Travel advisory for Italy, South Korea raised to level 4, ‘Do Not Travel’. USA Today. Published Feb. 29, 2020.

13. Information for health departments on reporting a person under investigation (PUI) or laboratory-confirmed case for COVID-19. Centers for Disease Control and Prevention. Published Feb. 24, 2020.

14. CDC Tests for COVID-19. Centers for Disease Control and Prevention. Published Feb. 25, 2020.

15. Jernigan DB. CDC COVID-19 response team. Update: Public health response to the coronavirus disease 2019 outbreak – United States, Feb. 24, 2020. MMWR Morbidity and Mortality Weekly Report 2020; 69:216-19. doi: 10.15585/mmwr.mm6908e1.

16. Gunia A. The global shortage of medical masks won’t be easing soon. Time. Published Feb. 27, 2020.

17. CDC in action: Preparing communities for potential spread of COVID-19. Centers for Disease Control and Prevention. Published Feb. 23, 2020.

18. Kadets L. White House budget cuts vital domestic and global public health programs. IDSA Home. Published 2020.

19. NIH clinical trial of remdesivir to treat COVID-19 begins. National Institutes of Health. Feb. 25, 2020.

Background

On Dec. 31, 2019, the Chinese city of Wuhan reported an outbreak of pneumonia from an unknown cause. The outbreak was found to be linked to the Hunan seafood market because of a shared history of exposure by many patients. After a full-scale investigation, China’s Center for Disease Control activated a level 2 emergency response on Jan. 4, 2020. A novel coronavirus was officially identified as a causative pathogen for the outbreak.¹

Coronavirus, first discovered in the 1960s, is a respiratory RNA virus, most commonly associated with the “common cold.” However, we have had two highly pathogenic forms of coronavirus that originated from animal reservoirs, leading to global epidemics. This includes SARS-CoV in 2002-2004 and MERS-CoV in 2012 with more than 10,000 combined cases. The primary host has been bats, but mammals like camels, cattle, cats, and palm civets have been intermediate hosts in previous epidemics.²

The International Committee on Taxonomy of Viruses named the 2019-nCoV officially as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease, COVID-19, on Feb. 11, 2020.³ Currently, the presentation includes fever, cough, trouble breathing, fatigue, and, rarely, watery diarrhea. More severe presentations include respiratory failure and death. Based on the incubation period of illness for Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) coronaviruses, as well as observational data from reports of travel-related COVID-19, CDC estimates that symptoms of COVID-19 occur within 2-14 days after exposure. Asymptomatic transmission is also documented in some cases.⁴

On Jan. 13, the first case of COVID-19 outside of China was identified in Thailand. On Jan. 21, the first case of COVID-19 was identified in the United States. On Jan. 23, Chinese authorities suspended travel in and out of Wuhan, followed by other cities in the Hubei Province, leading to a quarantine of 50 million people. By Jan. 30, the World Health Organization had identified COVID-19 as the highest level of an epidemic alert referred to as a PHEIC: Public Health Emergency of International Concern. On Feb. 2, the first death outside China from coronavirus was reported in the Philippines. As of March 4 there have been 95,000 confirmed cases and 3,246 deaths globally. Within China, there have been 80,200 cases with 2,981 deaths.⁵

Cases have now been diagnosed in increasing numbers in Italy, Japan, South Korea, Iran, and 76 countries. Of note, the fatalities were of patients already in critical condition, who were typically older (more than 60 years old, especially more than 80) and immunocompromised with comorbid conditions (cardiovascular disease, diabetes, chronic respiratory disease, cancer).⁶ To put this in perspective, since 2010, CDC reports 140,000-810,000 hospitalizations and 12,000-61,000 deaths from the influenza virus annually in the US.⁷
 

The current situation in the United States

In the United States, as of March 4, 2020, there are currently 152 confirmed cases in 16 states. The first U.S. case of coronavirus without any of the travel-related and exposure risk factors was identified on Feb. 27 in California, indicating the first instance of community spread.⁸ The first death was reported in Washington state on Feb. 28, after which the state’s governor declared a state of emergency.⁹ On March 1, Washington state health officials investigated an outbreak of coronavirus at a long-term nursing facility in which two people tested positive for the disease, heralding the probable first nosocomial transmission of the virus in the United States. Since then, there have been 10 deaths in Washington state related to the coronavirus.

Current interventions in the United States

The U.S. Centers for Disease Control and Prevention is leading a multiagency effort to combat the COVID-19 potential pandemic. A Feb. 24 report in Morbidity and Mortality Weekly Report revealed that 1,336 CDC staff members have been involved in the COVID-19 response.¹⁰ CDC staff members have been deployed to 39 locations in the United States and internationally. CDC staff members are working with state and local health departments and other public health authorities to assist with case identification, contact tracing, evaluation of persons under investigation (PUI) for COVID-19, and medical management of cases, as well as with research and academic institutions to understand the virulence, risk for transmission, and other characteristics of this novel virus. The CDC is also working with other agencies of the U.S. government including the U.S. Department of Defense, Department of Health & Human Services and the U.S. Department of State to safely evacuate U.S. citizens, residents, and their families from international locations with high incidence and transmission of COVID-19.

Specific real-time updated guidance has been developed and posted online for health care settings for patient management, infection control and prevention, laboratory testing, environmental cleaning, worker safety, and international travel. The CDC has developed communications materials in English and Spanish for communities and guidance for health care settings, public health, laboratories, schools, and businesses to prepare for a potential pandemic. Travel advisories to countries affected by the epidemic are regularly updated to inform travelers and clinicians about current health issues that need to be considered before travel.¹¹ A level 3 travel notice (avoid all nonessential travel) for China has been in effect since Jan. 27, and on Feb. 29 this was upgraded to a level 4 travel notice.¹² Airport screening has been implemented in the 11 U.S. international airports to which flights from China have been diverted, and a total of 46,016 air travelers had been screened by Feb. 23. Incoming passengers are screened for fever, cough, and shortness of breath.

Currently, the CDC has a comprehensive algorithm for further investigation of a PUI – fever, cough, shortness of breath, and a history of travel to areas with increased coronavirus circulation within 14 days of onset of symptoms, OR a close household contact of a confirmed case. When there is a PUI, the current protocol indicates health care providers should alert a local or state health department official. After the health department completes a case investigation, the CDC will help transport specimens (upper respiratory and lower respiratory specimens, and sometimes stool or urine) as soon as possible to the centralized lab for polymerase chain reaction (PCR) testing.¹³ CDC laboratories are currently using real-time reverse transcription–PCR (RT-PCR). The CDC is also developing a serologic test to assist with surveillance for SARS-CoV-2 circulation in the U.S. population. There is also a safe repository of viral isolates set up to help with sharing of isolates with academic institutions for research purposes.¹⁴

At hospitals and outpatient offices in the United States, we are preparing for potential cases by reminding frontline health care workers to routinely ask about travel history in addition to relevant symptoms. By eliciting the history early, they should be able to identify and isolate PUIs, appropriately minimizing exposure. Some facilities are displaying signage in waiting rooms to alert patients to provide relevant history, helping to improve triage. COVID-19 symptoms are like those of influenza (e.g., fever, cough, and shortness of breath), and the current outbreak is occurring during a time of year when respiratory illnesses from influenza and other viruses are highly prevalent. To prevent influenza and possible unnecessary evaluation for COVID-19, all persons aged 6 months and older are strongly encouraged to receive an annual influenza vaccine.

To decrease the risk for respiratory disease, persons can practice recommended preventive measures. Persons ill with symptoms of COVID-19 who have had contact with a person with COVID-19, or recent travel to countries with apparent community spread, should proactively communicate with their health care provider before showing up at the health care facility to help make arrangements to prevent possible transmission in the health care setting. In a medical emergency, they should inform emergency medical personnel about possible COVID-19 exposure. If found positive, the current recommendation is to place patients on airborne isolation. N95 masks are being recommended for health care professionals. Hospitals are reinforcing effective infection control procedures, updating pandemic preparedness protocols, and ensuring adequate supplies in the case of an enormous influx of patients.¹⁵

Challenges and opportunities

Many challenges present in the process of getting prepared for a potential outbreak. Personal protective equipment such as N-95 masks are in short supply, as they are in high demand in the general public.¹⁶ The CDC currently does not recommend that members of the general public use face masks, given low levels of circulation of SARS-CoV-2 currently in the United States. The CDC has developed several documents regarding infection control, hospital preparedness assessments, personal protective equipment (PPE) supply planning, clinical evaluation and management, and respirator conservation strategies.

The RT-PCR test developed by the CDC has had some setbacks, with recent testing kits showing “inconclusive results.” The testing was initially available only through the CDC lab in Atlanta, with a 48-hour turnaround. This led to potential delays in diagnosis and the timely isolation and treatment of infected patients. On March 3, the CDC broadened the guidelines for coronavirus testing, allowing clinicians to order a test for any patients who have symptoms of COVID-19 infection. The greatest need is for decentralized testing in local and state labs, as well as validated testing in local hospitals and commercial labs. The ability to develop and scale-up diagnostic abilities is critically important.

There is also concern about overwhelming hospitals with a strain on the availability of beds, ventilators, and airborne isolation rooms. The CDC is recommending leveraging telehealth tools to direct people to the right level of health care for their medical needs. Hospitalization should only be for the sickest patients.¹⁷

Funding for a pandemic response is of paramount importance. Proposed 2021 federal budget cuts include $2.9 billion in cuts to the National Institutes of Health, and $708 million in cuts to the CDC, which makes the situation look especially worrisome as we face a potentially severe pandemic. The Infectious Diseases Society of America identifies antimicrobial resistance, NIH research, global health security, global HIV epidemic, and CDC vaccine programs as five “deeply underfunded” areas in the federal budget.¹⁸

The NIH has recently begun the first randomized clinical trial, treating patients at the University of Nebraska with laboratory-confirmed SARS-CoV-2 with a broad-spectrum antiviral drug called remdesivir. Patients from the Diamond Princess Cruise ship are also participating in this clinical trial. This study will hopefully shed light on potential treatments for coronavirus to stop or alleviate the consequences in real time. Similar clinical trials are also occurring in China.¹⁹

Vaccine development is underway in many public and private research facilities, but it will take approximately 6-18 months before they will be available for use. In the absence of a vaccine or therapeutic, community mitigation measures are the primary method to respond to the widespread transmission, and supportive care is the current medical treatment. In the case of a pandemic, the mitigation measures might include school dismissals and social distancing in other settings, like suspension of mass gatherings, telework and remote-meeting options in workplaces.

Many respected medical journals in the United States have made access to SARS-CoV-2 articles and literature readily and freely available, which is a remarkable step. Multiple societies and journals have made information available in real time and have used media effectively (e.g., podcasts, e-learning) to disseminate information to the general public. Articles have been made available in other languages, including Chinese.
 

Conclusions

In summary, there have been 3,280 total deaths attributable to SARS-CoV-2 to date globally, mostly among geriatric patients with comorbidities. To provide some perspective on the statistics, influenza has killed almost 14,000 patients this season alone (much more than coronavirus). COVID-19 is undoubtedly a global public health threat. We in the U.S. health care system are taking swift public health actions, including isolation of patients and contacts to prevent secondary spread, but it is unclear if this is enough to stop an outbreak from becoming a pandemic.

The CDC is warning of significant social and economic disruption in the coming weeks, with more expected community spread and confirmed cases. It is challenging to prepare for a pandemic when the transmission dynamics are not clearly known, the duration of infectiousness is not well defined, and asymptomatic transmission is a possibility. It is time for the public to be informed from trusted sources and avoid unverified information, especially on social media which can lead to confusion and panic. The spread of COVID-19 infection in the United States is inevitable, and there must be sufficient, well-coordinated planning that can curtail the spread and reduce the impact.
 

Dr. Tirupathi is the medical director of Keystone Infectious Diseases/HIV in Chambersburg, Pa., and currently chair of infection prevention at Wellspan Chambersburg and Waynesboro (Pa.) Hospitals. He also is the lead physician for antibiotic stewardship at these hospitals. Dr. Palabindala is hospital medicine division chief at the University of Mississippi Medical Center, Jackson. Ms. Sathya Areti is a 3rd-year medical student at the Virginia Commonwealth University School of Medicine (class of 2021), planning to apply into Internal Medicine-Pediatrics. Dr. Swetha Areti is currently working as a hospitalist at Wellspan Chambersburg Hospital and is also a member of the Wellspan Pharmacy and Therapeutics committee.

References

1. Phelan AL et al. The novel coronavirus originating in Wuhan, China: Challenges for global health governance. JAMA. 2020;323(8):709-10. doi: 10.1001/jama.2020.1097.

2. del Rio C, Malani PN. 2019 Novel coronavirus – Important information for clinicians. JAMA. Published online Feb. 5, 2020. doi: 10.1001/jama.2020.1490.

3. Gorbalenya AE et al. Severe acute respiratory syndrome-related coronavirus: The species and its viruses – a statement of the Coronavirus Study Group. bioRxiv. Published Jan. 1, 2020. doi: 10.1101/2020.02.07.937862.

4. Jernigan DB. CDC COVID-19 response team. Update: Public health response to the coronavirus disease 2019 outbreak – United States, Feb 24, 2020. MMWR Morbidity and Mortality Weekly Report 2020;69:216-19. doi: 10.15585/mmwr.mm6908e1.

5. Coronavirus disease 2019 (COVID-19). Situation Report – 40. Published Feb. 29, 2020.

6. Kaiyuan Sun, et al. Early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a population level observational study, Feb. 20, 2020. Lancet Digital Health 2020. doi: 10.1016/S2589-7500(20)30026-1.

7. Rolfes MA et al. Annual estimates of the burden of seasonal influenza in the United States: A tool for strengthening influenza surveillance and preparedness. Influenza Other Respir Viruses. 2018;12(1):132-7. doi: 10.1111/irv.12486.

8. Jernigan DB. CDC COVID-19 response team. Update: Public health response to the coronavirus disease 2019 outbreak – United States, Feb. 24, 2020. MMWR Morbidity and Mortality Weekly Report 2020;69:216-19. doi: 10.15585/mmwr.mm6908e1.

9. Jablon R, Baumann L. Washington governor declares state of emergency over virus. AP News. Published Feb. 29, 2020.

10. Jernigan DB, CDC COVID-19 response team. Update: Public health response to the coronavirus disease 2019 outbreak – United States, Feb. 24, 2020. MMWR Morbidity and Mortality Weekly Report 2020; 69:216-219. doi: 10.15585/mmwr.mm6908e1.

11. Information for health departments on reporting a person under investigation (PUI) or laboratory-confirmed case for COVID-19. Centers for Disease Control and Prevention. Published Feb 24, 2020.

12. Hines M. Coronavirus: Travel advisory for Italy, South Korea raised to level 4, ‘Do Not Travel’. USA Today. Published Feb. 29, 2020.

13. Information for health departments on reporting a person under investigation (PUI) or laboratory-confirmed case for COVID-19. Centers for Disease Control and Prevention. Published Feb. 24, 2020.

14. CDC Tests for COVID-19. Centers for Disease Control and Prevention. Published Feb. 25, 2020.

15. Jernigan DB. CDC COVID-19 response team. Update: Public health response to the coronavirus disease 2019 outbreak – United States, Feb. 24, 2020. MMWR Morbidity and Mortality Weekly Report 2020; 69:216-19. doi: 10.15585/mmwr.mm6908e1.

16. Gunia A. The global shortage of medical masks won’t be easing soon. Time. Published Feb. 27, 2020.

17. CDC in action: Preparing communities for potential spread of COVID-19. Centers for Disease Control and Prevention. Published Feb. 23, 2020.

18. Kadets L. White House budget cuts vital domestic and global public health programs. IDSA Home. Published 2020.

19. NIH clinical trial of remdesivir to treat COVID-19 begins. National Institutes of Health. Feb. 25, 2020.

Background

On Dec. 31, 2019, the Chinese city of Wuhan reported an outbreak of pneumonia from an unknown cause. The outbreak was found to be linked to the Hunan seafood market because of a shared history of exposure by many patients. After a full-scale investigation, China’s Center for Disease Control activated a level 2 emergency response on Jan. 4, 2020. A novel coronavirus was officially identified as a causative pathogen for the outbreak.¹

Coronavirus, first discovered in the 1960s, is a respiratory RNA virus, most commonly associated with the “common cold.” However, we have had two highly pathogenic forms of coronavirus that originated from animal reservoirs, leading to global epidemics. This includes SARS-CoV in 2002-2004 and MERS-CoV in 2012 with more than 10,000 combined cases. The primary host has been bats, but mammals like camels, cattle, cats, and palm civets have been intermediate hosts in previous epidemics.²

The International Committee on Taxonomy of Viruses named the 2019-nCoV officially as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease, COVID-19, on Feb. 11, 2020.³ Currently, the presentation includes fever, cough, trouble breathing, fatigue, and, rarely, watery diarrhea. More severe presentations include respiratory failure and death. Based on the incubation period of illness for Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) coronaviruses, as well as observational data from reports of travel-related COVID-19, CDC estimates that symptoms of COVID-19 occur within 2-14 days after exposure. Asymptomatic transmission is also documented in some cases.⁴

On Jan. 13, the first case of COVID-19 outside of China was identified in Thailand. On Jan. 21, the first case of COVID-19 was identified in the United States. On Jan. 23, Chinese authorities suspended travel in and out of Wuhan, followed by other cities in the Hubei Province, leading to a quarantine of 50 million people. By Jan. 30, the World Health Organization had identified COVID-19 as the highest level of an epidemic alert referred to as a PHEIC: Public Health Emergency of International Concern. On Feb. 2, the first death outside China from coronavirus was reported in the Philippines. As of March 4 there have been 95,000 confirmed cases and 3,246 deaths globally. Within China, there have been 80,200 cases with 2,981 deaths.⁵

Cases have now been diagnosed in increasing numbers in Italy, Japan, South Korea, Iran, and 76 countries. Of note, the fatalities were of patients already in critical condition, who were typically older (more than 60 years old, especially more than 80) and immunocompromised with comorbid conditions (cardiovascular disease, diabetes, chronic respiratory disease, cancer).⁶ To put this in perspective, since 2010, CDC reports 140,000-810,000 hospitalizations and 12,000-61,000 deaths from the influenza virus annually in the US.⁷
 

The current situation in the United States

In the United States, as of March 4, 2020, there are currently 152 confirmed cases in 16 states. The first U.S. case of coronavirus without any of the travel-related and exposure risk factors was identified on Feb. 27 in California, indicating the first instance of community spread.⁸ The first death was reported in Washington state on Feb. 28, after which the state’s governor declared a state of emergency.⁹ On March 1, Washington state health officials investigated an outbreak of coronavirus at a long-term nursing facility in which two people tested positive for the disease, heralding the probable first nosocomial transmission of the virus in the United States. Since then, there have been 10 deaths in Washington state related to the coronavirus.

Current interventions in the United States

The U.S. Centers for Disease Control and Prevention is leading a multiagency effort to combat the COVID-19 potential pandemic. A Feb. 24 report in Morbidity and Mortality Weekly Report revealed that 1,336 CDC staff members have been involved in the COVID-19 response.¹⁰ CDC staff members have been deployed to 39 locations in the United States and internationally. CDC staff members are working with state and local health departments and other public health authorities to assist with case identification, contact tracing, evaluation of persons under investigation (PUI) for COVID-19, and medical management of cases, as well as with research and academic institutions to understand the virulence, risk for transmission, and other characteristics of this novel virus. The CDC is also working with other agencies of the U.S. government including the U.S. Department of Defense, Department of Health & Human Services and the U.S. Department of State to safely evacuate U.S. citizens, residents, and their families from international locations with high incidence and transmission of COVID-19.

Specific real-time updated guidance has been developed and posted online for health care settings for patient management, infection control and prevention, laboratory testing, environmental cleaning, worker safety, and international travel. The CDC has developed communications materials in English and Spanish for communities and guidance for health care settings, public health, laboratories, schools, and businesses to prepare for a potential pandemic. Travel advisories to countries affected by the epidemic are regularly updated to inform travelers and clinicians about current health issues that need to be considered before travel.¹¹ A level 3 travel notice (avoid all nonessential travel) for China has been in effect since Jan. 27, and on Feb. 29 this was upgraded to a level 4 travel notice.¹² Airport screening has been implemented in the 11 U.S. international airports to which flights from China have been diverted, and a total of 46,016 air travelers had been screened by Feb. 23. Incoming passengers are screened for fever, cough, and shortness of breath.

Currently, the CDC has a comprehensive algorithm for further investigation of a PUI – fever, cough, shortness of breath, and a history of travel to areas with increased coronavirus circulation within 14 days of onset of symptoms, OR a close household contact of a confirmed case. When there is a PUI, the current protocol indicates health care providers should alert a local or state health department official. After the health department completes a case investigation, the CDC will help transport specimens (upper respiratory and lower respiratory specimens, and sometimes stool or urine) as soon as possible to the centralized lab for polymerase chain reaction (PCR) testing.¹³ CDC laboratories are currently using real-time reverse transcription–PCR (RT-PCR). The CDC is also developing a serologic test to assist with surveillance for SARS-CoV-2 circulation in the U.S. population. There is also a safe repository of viral isolates set up to help with sharing of isolates with academic institutions for research purposes.¹⁴

At hospitals and outpatient offices in the United States, we are preparing for potential cases by reminding frontline health care workers to routinely ask about travel history in addition to relevant symptoms. By eliciting the history early, they should be able to identify and isolate PUIs, appropriately minimizing exposure. Some facilities are displaying signage in waiting rooms to alert patients to provide relevant history, helping to improve triage. COVID-19 symptoms are like those of influenza (e.g., fever, cough, and shortness of breath), and the current outbreak is occurring during a time of year when respiratory illnesses from influenza and other viruses are highly prevalent. To prevent influenza and possible unnecessary evaluation for COVID-19, all persons aged 6 months and older are strongly encouraged to receive an annual influenza vaccine.

To decrease the risk for respiratory disease, persons can practice recommended preventive measures. Persons ill with symptoms of COVID-19 who have had contact with a person with COVID-19, or recent travel to countries with apparent community spread, should proactively communicate with their health care provider before showing up at the health care facility to help make arrangements to prevent possible transmission in the health care setting. In a medical emergency, they should inform emergency medical personnel about possible COVID-19 exposure. If found positive, the current recommendation is to place patients on airborne isolation. N95 masks are being recommended for health care professionals. Hospitals are reinforcing effective infection control procedures, updating pandemic preparedness protocols, and ensuring adequate supplies in the case of an enormous influx of patients.¹⁵

Challenges and opportunities

Many challenges present in the process of getting prepared for a potential outbreak. Personal protective equipment such as N-95 masks are in short supply, as they are in high demand in the general public.¹⁶ The CDC currently does not recommend that members of the general public use face masks, given low levels of circulation of SARS-CoV-2 currently in the United States. The CDC has developed several documents regarding infection control, hospital preparedness assessments, personal protective equipment (PPE) supply planning, clinical evaluation and management, and respirator conservation strategies.

The RT-PCR test developed by the CDC has had some setbacks, with recent testing kits showing “inconclusive results.” The testing was initially available only through the CDC lab in Atlanta, with a 48-hour turnaround. This led to potential delays in diagnosis and the timely isolation and treatment of infected patients. On March 3, the CDC broadened the guidelines for coronavirus testing, allowing clinicians to order a test for any patients who have symptoms of COVID-19 infection. The greatest need is for decentralized testing in local and state labs, as well as validated testing in local hospitals and commercial labs. The ability to develop and scale-up diagnostic abilities is critically important.

There is also concern about overwhelming hospitals with a strain on the availability of beds, ventilators, and airborne isolation rooms. The CDC is recommending leveraging telehealth tools to direct people to the right level of health care for their medical needs. Hospitalization should only be for the sickest patients.¹⁷

Funding for a pandemic response is of paramount importance. Proposed 2021 federal budget cuts include $2.9 billion in cuts to the National Institutes of Health, and $708 million in cuts to the CDC, which makes the situation look especially worrisome as we face a potentially severe pandemic. The Infectious Diseases Society of America identifies antimicrobial resistance, NIH research, global health security, global HIV epidemic, and CDC vaccine programs as five “deeply underfunded” areas in the federal budget.¹⁸

The NIH has recently begun the first randomized clinical trial, treating patients at the University of Nebraska with laboratory-confirmed SARS-CoV-2 with a broad-spectrum antiviral drug called remdesivir. Patients from the Diamond Princess Cruise ship are also participating in this clinical trial. This study will hopefully shed light on potential treatments for coronavirus to stop or alleviate the consequences in real time. Similar clinical trials are also occurring in China.¹⁹

Vaccine development is underway in many public and private research facilities, but it will take approximately 6-18 months before they will be available for use. In the absence of a vaccine or therapeutic, community mitigation measures are the primary method to respond to the widespread transmission, and supportive care is the current medical treatment. In the case of a pandemic, the mitigation measures might include school dismissals and social distancing in other settings, like suspension of mass gatherings, telework and remote-meeting options in workplaces.

Many respected medical journals in the United States have made access to SARS-CoV-2 articles and literature readily and freely available, which is a remarkable step. Multiple societies and journals have made information available in real time and have used media effectively (e.g., podcasts, e-learning) to disseminate information to the general public. Articles have been made available in other languages, including Chinese.
 

Conclusions

In summary, there have been 3,280 total deaths attributable to SARS-CoV-2 to date globally, mostly among geriatric patients with comorbidities. To provide some perspective on the statistics, influenza has killed almost 14,000 patients this season alone (much more than coronavirus). COVID-19 is undoubtedly a global public health threat. We in the U.S. health care system are taking swift public health actions, including isolation of patients and contacts to prevent secondary spread, but it is unclear if this is enough to stop an outbreak from becoming a pandemic.

The CDC is warning of significant social and economic disruption in the coming weeks, with more expected community spread and confirmed cases. It is challenging to prepare for a pandemic when the transmission dynamics are not clearly known, the duration of infectiousness is not well defined, and asymptomatic transmission is a possibility. It is time for the public to be informed from trusted sources and avoid unverified information, especially on social media which can lead to confusion and panic. The spread of COVID-19 infection in the United States is inevitable, and there must be sufficient, well-coordinated planning that can curtail the spread and reduce the impact.
 

Dr. Tirupathi is the medical director of Keystone Infectious Diseases/HIV in Chambersburg, Pa., and currently chair of infection prevention at Wellspan Chambersburg and Waynesboro (Pa.) Hospitals. He also is the lead physician for antibiotic stewardship at these hospitals. Dr. Palabindala is hospital medicine division chief at the University of Mississippi Medical Center, Jackson. Ms. Sathya Areti is a 3rd-year medical student at the Virginia Commonwealth University School of Medicine (class of 2021), planning to apply into Internal Medicine-Pediatrics. Dr. Swetha Areti is currently working as a hospitalist at Wellspan Chambersburg Hospital and is also a member of the Wellspan Pharmacy and Therapeutics committee.

References

1. Phelan AL et al. The novel coronavirus originating in Wuhan, China: Challenges for global health governance. JAMA. 2020;323(8):709-10. doi: 10.1001/jama.2020.1097.

2. del Rio C, Malani PN. 2019 Novel coronavirus – Important information for clinicians. JAMA. Published online Feb. 5, 2020. doi: 10.1001/jama.2020.1490.

3. Gorbalenya AE et al. Severe acute respiratory syndrome-related coronavirus: The species and its viruses – a statement of the Coronavirus Study Group. bioRxiv. Published Jan. 1, 2020. doi: 10.1101/2020.02.07.937862.

4. Jernigan DB. CDC COVID-19 response team. Update: Public health response to the coronavirus disease 2019 outbreak – United States, Feb 24, 2020. MMWR Morbidity and Mortality Weekly Report 2020;69:216-19. doi: 10.15585/mmwr.mm6908e1.

5. Coronavirus disease 2019 (COVID-19). Situation Report – 40. Published Feb. 29, 2020.

6. Kaiyuan Sun, et al. Early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a population level observational study, Feb. 20, 2020. Lancet Digital Health 2020. doi: 10.1016/S2589-7500(20)30026-1.

7. Rolfes MA et al. Annual estimates of the burden of seasonal influenza in the United States: A tool for strengthening influenza surveillance and preparedness. Influenza Other Respir Viruses. 2018;12(1):132-7. doi: 10.1111/irv.12486.

8. Jernigan DB. CDC COVID-19 response team. Update: Public health response to the coronavirus disease 2019 outbreak – United States, Feb. 24, 2020. MMWR Morbidity and Mortality Weekly Report 2020;69:216-19. doi: 10.15585/mmwr.mm6908e1.

9. Jablon R, Baumann L. Washington governor declares state of emergency over virus. AP News. Published Feb. 29, 2020.

10. Jernigan DB, CDC COVID-19 response team. Update: Public health response to the coronavirus disease 2019 outbreak – United States, Feb. 24, 2020. MMWR Morbidity and Mortality Weekly Report 2020; 69:216-219. doi: 10.15585/mmwr.mm6908e1.

11. Information for health departments on reporting a person under investigation (PUI) or laboratory-confirmed case for COVID-19. Centers for Disease Control and Prevention. Published Feb 24, 2020.

12. Hines M. Coronavirus: Travel advisory for Italy, South Korea raised to level 4, ‘Do Not Travel’. USA Today. Published Feb. 29, 2020.

13. Information for health departments on reporting a person under investigation (PUI) or laboratory-confirmed case for COVID-19. Centers for Disease Control and Prevention. Published Feb. 24, 2020.

14. CDC Tests for COVID-19. Centers for Disease Control and Prevention. Published Feb. 25, 2020.

15. Jernigan DB. CDC COVID-19 response team. Update: Public health response to the coronavirus disease 2019 outbreak – United States, Feb. 24, 2020. MMWR Morbidity and Mortality Weekly Report 2020; 69:216-19. doi: 10.15585/mmwr.mm6908e1.

16. Gunia A. The global shortage of medical masks won’t be easing soon. Time. Published Feb. 27, 2020.

17. CDC in action: Preparing communities for potential spread of COVID-19. Centers for Disease Control and Prevention. Published Feb. 23, 2020.

18. Kadets L. White House budget cuts vital domestic and global public health programs. IDSA Home. Published 2020.

19. NIH clinical trial of remdesivir to treat COVID-19 begins. National Institutes of Health. Feb. 25, 2020.

MAUI, HAWAII – Osteoarthritis therapy remains a barren landscape where conventional medicine has so little to offer that many affected patients eagerly embrace unproven Internet claims for costly out-of-pocket intra-articular injections of platelet-rich plasma, oxygen ozone, and mesenchymal stem cells, Eric M. Ruderman, MD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

He presented a whirlwind review of the evidence – or lack thereof – for a wide range of contemporary OA therapies, ranging from acupuncture to cupping, lateral wedge insoles, various substances for intra-articular injection, radiofrequency therapy, medical leeches, and several widely ballyhooed medications that are well along in the developmental pipeline but whose placebo-subtracted efficacy is actually quite modest.

“I’ve shown you the evidence, such as it is – it’s not very much. The question is, have we really moved the needle in this disease in the last 30 years? The answer is I’m not so sure we have,” concluded Dr. Ruderman, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University, Chicago.

Several audience members were less restrained in their assessments.

“You have not moved the needle in osteoarthritis,” stated orthopedic surgeon William Bugbee, MD, chief of joint reconstruction at the Scripps Clinic in La Jolla, Calif., adding that he’s not much impressed by the long-term impact of intra-articular injections, be they of glucocorticoid, hyaluronic acid, or anything else being put into osteoarthritic joints.

Bruce Jancin/MDedge News

“To me, and to most orthopedic surgeons, an injection is a handshake. It’s like: ‘How do you do? Let’s get to know each other.’ But you know where this interaction is going – it’s going to end up in surgery. But that’s okay. Surgery is great. Let’s face it: It’s the only disease-modifying treatment for OA,” Dr. Bugbee declared.

Roy Fleischmann, MD, rose from the audience to assert that “the biggest need in rheumatology right now is a medication for OA that actually works and is actually disease modifying.”

That’s not going to happen until clinical trialists and the pharmaceutical industry learn how to subgroup OA and separate inflammatory OA from noninflammatory OA. Lumping the two together tends to wash out any strong efficacy signal an investigational agent might have, added Dr. Fleischmann, a rheumatologist at the University of Texas and medical director of the Metroplex Clinical Research Center, both in Dallas.

Dr. Ruderman noted that his own analysis of the contemporary evidence base for OA pharmacotherapies reached conclusions generally similar to those contained in the new American College of Rheumatology/Arthritis Foundation “Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee”. The list of pharmacotherapies that were strongly recommended in the guidelines was slim and rather tired: oral NSAIDs, intra-articular glucocorticoid injections, and – for knee OA only – topical NSAIDs. The strength of those favorable recommendations was based more upon solid evidence of safety rather than impressive efficacy, in his view. And the guidelines’ list of therapies whose use was strongly discouraged was much longer.

A factor in the flimsy evidence base for OA treatment is the strikingly large across-the-board placebo effect. This was nicely captured in a meta-analysis of 215 randomized, controlled trials of various therapies totaling more than 41,000 participants. Drilling down into the data, the British and Chinese investigators concluded that on average 75% of the overall treatment effect seen in the trials was caused by the placebo effect and only 25% represented a treatment-specific effect. The “winner” was intra-articular glucocorticoid, where the placebo effect was a mere 47%.
 

In the OA pipeline

“There’s a lot of interest in DMOADs – disease-modifying osteoarthritis drugs – but not a lot of success so far,” Dr. Ruderman observed.

Case in point: intra-articular sprifermin, a recombinant human fibroblast growth factor 18. In a 549-patient, multicenter, dose-ranging study, the two highest doses achieved a modest yet statistically significant advantage over placebo in total femorotibial joint cartilage thickness on MRI at 2 years. However, the investigators added that the result was of “uncertain clinical importance,” given the lack of a difference from baseline in total Western Ontario and McMaster Universities OA Index score.

“I’m not sure this is going anywhere,” Dr. Ruderman commented.

Tanezumab, a novel subcutaneously injected monoclonal antibody directed against nerve growth factor, has drawn a lot of attention. In an initial multicenter, phase 3, randomized trial it showed what Dr. Ruderman termed “some modest benefit” on pain and function.

“Very much like everything else in OA, you see a huge placebo effect buried in there,” according to the rheumatologist.

This modest clinical benefit was accompanied by a safety signal at the higher 5-mg dose of tanezumab. Moreover, a second phase 3 trial, this one conducted in nearly 3,000 OA patients and presented at the 2019 annual meeting of the American College of Rheumatology, also raised significant safety concerns at the higher dose. And while the 2.5-mg dose was safer, it was disappointingly no more effective in terms of improvement in pain and function scores than diclofenac at 75 mg twice daily, Dr. Ruderman noted.

Dr. Fleischmann predicted that, given the enormous unmet need for new OA treatments, tanezumab at 2.5 mg will win regulatory approval, but it will be a costly niche drug reserved for the challenging subset of patients who can’t take an NSAID and are poor surgical candidates. (On March 2, 2020, Eli Lilly announced that the Food and Drug Administration had accepted its Biologics License Application for tanezumab for the treatment of chronic pain caused by moderate to severe OA.)

Intra-articular FX006, a microsphere-based, extended-release formulation of triamcinolone, outperformed conventional triamcinolone in a phase 3 clinical trial. However, the placebo-subtracted improvement in pain was modest.

“There’s some marginal benefit here, but over time I’m not sure this adds much to just straight-up triamcinolone,” Dr. Ruderman opined.

Welcome to the wild, wild West

Patients with knee OA ask Dr. Ruderman all the time about the intra-articular injections of platelet-rich plasma (PRP) or mesenchymal stem cells they’ve seen touted on the Internet. As an evidence-based physician, he’s not a fan. A meta-analysis of 14 controlled trials of PRP, none double blind, showed some benefit in terms of pain and function at 3, 6, and 12 months, with little risk of adverse events. However, PRP is being marketed with a hype and claimed efficacy out of all proportion to the actual evidence.

“It’s the wild, wild West out there,” the rheumatologist warned.

He cited a study involving a scripted survey of 179 U.S. clinics offering PRP. The mean price quoted for a unilateral knee injection in a hypothetical 52-year-old man with knee OA was $714, and it’s a cash business, since insurance companies won’t cover PRP. Out of 84 centers that were willing to share their claimed efficacy, 10 quoted 90%-100% rates of good results or symptomatic improvement, 27 claimed 80%-90% efficacy, and 29 quoted figures of 70%-80%, all of which are well above the success rates achieved in the flawed clinical trials.

As for mesenchymal stem cells, “if PRP is the wild, wild West, this is the surface of Mars,” Dr. Ruderman quipped.

These stem cell injections are neither FDA regulated nor approved. There are no barriers to setting up a mesenchymal stem cell injection center, and the number of such centers is skyrocketing. Anybody can set up a center, and there’s essentially no oversight.

“The evidence in this area is really terrible,” the rheumatologist said. He pointed to a meta-analysis of five trials, only two of which were rated by the researchers as having a low risk of bias. The conclusion: There was limited evidence of short-term benefit in pain and function, but no evidence of cartilage repair, which is the chief claimed benefit.

The same group of investigators who queried the PRP clinics also successfully contacted 273 of the proliferating U.S. centers offering direct-to-consumer mesenchymal stem cell therapy. The mean price quoted for a unilateral knee injection was a whopping $5,156, which – like PRP – isn’t covered by insurance. At the 36 clinics responding to a request for their efficacy rates, the mean claim was good results or symptomatic improvement in 82% of treated patients.

Dr. Bugbee didn’t endorse this intervention, which is increasingly popular among his fellow orthopedic surgeons.

“The regulatory pathway drives this. Mesenchymal stem cells are categorized as a minimally manipulated tissue, so the regulatory pathway is easy,” explained Dr. Bugbee. “I talk 9 out of 10 patients out of it because there’s no evidence of disease modification.”


 

On a brighter note

Radiofrequency ablation and neuromodulation procedures for treatment of symptomatic knee OA make no pretense of being disease modifying, but a new systematic review of 33 published studies deemed of moderate or high methodological quality totaling 1,512 patients documented improved pain, function, and disease-specific quality of life for 3-12 months with minimal complications.

Most of these procedures target the genicular nerve, the sensory nerve that innervates the knee.

“There’s some value here to this,” Dr. Ruderman said. “Our pain folks are actually pretty interested in this. At our center, they’re using this for patients with persistent knee pain after knee replacement, with some success. It’s not an unreasonable approach.”

As part of his examination of the evidence base for OA treatment, Dr. Ruderman looked into an intervention he wasn’t familiar with: acupuncture. He was pleasantly surprised.

“There’s quite a bit of data. There is decent evidence that acupuncture has significant benefit, at least for pain, and is certainly without significant side effects,” according to the rheumatologist.

He cited a review of a dozen systematic reviews of randomized, controlled trials of acupuncture for OA. The Chinese investigators rated the overall quality of the evidence as moderate to low, but with some studies being rated high quality. “That’s not as bad as some of the other stuff I looked at,” Dr. Ruderman said.

Acupuncture was found to be 2.4 times more effective than Western medicine for short-term pain relief, and 4.1 times better in terms of total efficacy, with a lower risk of adverse events than with Western medicine.

Dr. Ruderman reported serving as a consultant for and/or receiving research grants from more than a half-dozen pharmaceutical companies.

[email protected]

MAUI, HAWAII – Osteoarthritis therapy remains a barren landscape where conventional medicine has so little to offer that many affected patients eagerly embrace unproven Internet claims for costly out-of-pocket intra-articular injections of platelet-rich plasma, oxygen ozone, and mesenchymal stem cells, Eric M. Ruderman, MD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

He presented a whirlwind review of the evidence – or lack thereof – for a wide range of contemporary OA therapies, ranging from acupuncture to cupping, lateral wedge insoles, various substances for intra-articular injection, radiofrequency therapy, medical leeches, and several widely ballyhooed medications that are well along in the developmental pipeline but whose placebo-subtracted efficacy is actually quite modest.

“I’ve shown you the evidence, such as it is – it’s not very much. The question is, have we really moved the needle in this disease in the last 30 years? The answer is I’m not so sure we have,” concluded Dr. Ruderman, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University, Chicago.

Several audience members were less restrained in their assessments.

“You have not moved the needle in osteoarthritis,” stated orthopedic surgeon William Bugbee, MD, chief of joint reconstruction at the Scripps Clinic in La Jolla, Calif., adding that he’s not much impressed by the long-term impact of intra-articular injections, be they of glucocorticoid, hyaluronic acid, or anything else being put into osteoarthritic joints.

Bruce Jancin/MDedge News

“To me, and to most orthopedic surgeons, an injection is a handshake. It’s like: ‘How do you do? Let’s get to know each other.’ But you know where this interaction is going – it’s going to end up in surgery. But that’s okay. Surgery is great. Let’s face it: It’s the only disease-modifying treatment for OA,” Dr. Bugbee declared.

Roy Fleischmann, MD, rose from the audience to assert that “the biggest need in rheumatology right now is a medication for OA that actually works and is actually disease modifying.”

That’s not going to happen until clinical trialists and the pharmaceutical industry learn how to subgroup OA and separate inflammatory OA from noninflammatory OA. Lumping the two together tends to wash out any strong efficacy signal an investigational agent might have, added Dr. Fleischmann, a rheumatologist at the University of Texas and medical director of the Metroplex Clinical Research Center, both in Dallas.

Dr. Ruderman noted that his own analysis of the contemporary evidence base for OA pharmacotherapies reached conclusions generally similar to those contained in the new American College of Rheumatology/Arthritis Foundation “Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee”. The list of pharmacotherapies that were strongly recommended in the guidelines was slim and rather tired: oral NSAIDs, intra-articular glucocorticoid injections, and – for knee OA only – topical NSAIDs. The strength of those favorable recommendations was based more upon solid evidence of safety rather than impressive efficacy, in his view. And the guidelines’ list of therapies whose use was strongly discouraged was much longer.

A factor in the flimsy evidence base for OA treatment is the strikingly large across-the-board placebo effect. This was nicely captured in a meta-analysis of 215 randomized, controlled trials of various therapies totaling more than 41,000 participants. Drilling down into the data, the British and Chinese investigators concluded that on average 75% of the overall treatment effect seen in the trials was caused by the placebo effect and only 25% represented a treatment-specific effect. The “winner” was intra-articular glucocorticoid, where the placebo effect was a mere 47%.
 

In the OA pipeline

“There’s a lot of interest in DMOADs – disease-modifying osteoarthritis drugs – but not a lot of success so far,” Dr. Ruderman observed.

Case in point: intra-articular sprifermin, a recombinant human fibroblast growth factor 18. In a 549-patient, multicenter, dose-ranging study, the two highest doses achieved a modest yet statistically significant advantage over placebo in total femorotibial joint cartilage thickness on MRI at 2 years. However, the investigators added that the result was of “uncertain clinical importance,” given the lack of a difference from baseline in total Western Ontario and McMaster Universities OA Index score.

“I’m not sure this is going anywhere,” Dr. Ruderman commented.

Tanezumab, a novel subcutaneously injected monoclonal antibody directed against nerve growth factor, has drawn a lot of attention. In an initial multicenter, phase 3, randomized trial it showed what Dr. Ruderman termed “some modest benefit” on pain and function.

“Very much like everything else in OA, you see a huge placebo effect buried in there,” according to the rheumatologist.

This modest clinical benefit was accompanied by a safety signal at the higher 5-mg dose of tanezumab. Moreover, a second phase 3 trial, this one conducted in nearly 3,000 OA patients and presented at the 2019 annual meeting of the American College of Rheumatology, also raised significant safety concerns at the higher dose. And while the 2.5-mg dose was safer, it was disappointingly no more effective in terms of improvement in pain and function scores than diclofenac at 75 mg twice daily, Dr. Ruderman noted.

Dr. Fleischmann predicted that, given the enormous unmet need for new OA treatments, tanezumab at 2.5 mg will win regulatory approval, but it will be a costly niche drug reserved for the challenging subset of patients who can’t take an NSAID and are poor surgical candidates. (On March 2, 2020, Eli Lilly announced that the Food and Drug Administration had accepted its Biologics License Application for tanezumab for the treatment of chronic pain caused by moderate to severe OA.)

Intra-articular FX006, a microsphere-based, extended-release formulation of triamcinolone, outperformed conventional triamcinolone in a phase 3 clinical trial. However, the placebo-subtracted improvement in pain was modest.

“There’s some marginal benefit here, but over time I’m not sure this adds much to just straight-up triamcinolone,” Dr. Ruderman opined.

Welcome to the wild, wild West

Patients with knee OA ask Dr. Ruderman all the time about the intra-articular injections of platelet-rich plasma (PRP) or mesenchymal stem cells they’ve seen touted on the Internet. As an evidence-based physician, he’s not a fan. A meta-analysis of 14 controlled trials of PRP, none double blind, showed some benefit in terms of pain and function at 3, 6, and 12 months, with little risk of adverse events. However, PRP is being marketed with a hype and claimed efficacy out of all proportion to the actual evidence.

“It’s the wild, wild West out there,” the rheumatologist warned.

He cited a study involving a scripted survey of 179 U.S. clinics offering PRP. The mean price quoted for a unilateral knee injection in a hypothetical 52-year-old man with knee OA was $714, and it’s a cash business, since insurance companies won’t cover PRP. Out of 84 centers that were willing to share their claimed efficacy, 10 quoted 90%-100% rates of good results or symptomatic improvement, 27 claimed 80%-90% efficacy, and 29 quoted figures of 70%-80%, all of which are well above the success rates achieved in the flawed clinical trials.

As for mesenchymal stem cells, “if PRP is the wild, wild West, this is the surface of Mars,” Dr. Ruderman quipped.

These stem cell injections are neither FDA regulated nor approved. There are no barriers to setting up a mesenchymal stem cell injection center, and the number of such centers is skyrocketing. Anybody can set up a center, and there’s essentially no oversight.

“The evidence in this area is really terrible,” the rheumatologist said. He pointed to a meta-analysis of five trials, only two of which were rated by the researchers as having a low risk of bias. The conclusion: There was limited evidence of short-term benefit in pain and function, but no evidence of cartilage repair, which is the chief claimed benefit.

The same group of investigators who queried the PRP clinics also successfully contacted 273 of the proliferating U.S. centers offering direct-to-consumer mesenchymal stem cell therapy. The mean price quoted for a unilateral knee injection was a whopping $5,156, which – like PRP – isn’t covered by insurance. At the 36 clinics responding to a request for their efficacy rates, the mean claim was good results or symptomatic improvement in 82% of treated patients.

Dr. Bugbee didn’t endorse this intervention, which is increasingly popular among his fellow orthopedic surgeons.

“The regulatory pathway drives this. Mesenchymal stem cells are categorized as a minimally manipulated tissue, so the regulatory pathway is easy,” explained Dr. Bugbee. “I talk 9 out of 10 patients out of it because there’s no evidence of disease modification.”


 

On a brighter note

Radiofrequency ablation and neuromodulation procedures for treatment of symptomatic knee OA make no pretense of being disease modifying, but a new systematic review of 33 published studies deemed of moderate or high methodological quality totaling 1,512 patients documented improved pain, function, and disease-specific quality of life for 3-12 months with minimal complications.

Most of these procedures target the genicular nerve, the sensory nerve that innervates the knee.

“There’s some value here to this,” Dr. Ruderman said. “Our pain folks are actually pretty interested in this. At our center, they’re using this for patients with persistent knee pain after knee replacement, with some success. It’s not an unreasonable approach.”

As part of his examination of the evidence base for OA treatment, Dr. Ruderman looked into an intervention he wasn’t familiar with: acupuncture. He was pleasantly surprised.

“There’s quite a bit of data. There is decent evidence that acupuncture has significant benefit, at least for pain, and is certainly without significant side effects,” according to the rheumatologist.

He cited a review of a dozen systematic reviews of randomized, controlled trials of acupuncture for OA. The Chinese investigators rated the overall quality of the evidence as moderate to low, but with some studies being rated high quality. “That’s not as bad as some of the other stuff I looked at,” Dr. Ruderman said.

Acupuncture was found to be 2.4 times more effective than Western medicine for short-term pain relief, and 4.1 times better in terms of total efficacy, with a lower risk of adverse events than with Western medicine.

Dr. Ruderman reported serving as a consultant for and/or receiving research grants from more than a half-dozen pharmaceutical companies.

[email protected]

MAUI, HAWAII – Osteoarthritis therapy remains a barren landscape where conventional medicine has so little to offer that many affected patients eagerly embrace unproven Internet claims for costly out-of-pocket intra-articular injections of platelet-rich plasma, oxygen ozone, and mesenchymal stem cells, Eric M. Ruderman, MD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

He presented a whirlwind review of the evidence – or lack thereof – for a wide range of contemporary OA therapies, ranging from acupuncture to cupping, lateral wedge insoles, various substances for intra-articular injection, radiofrequency therapy, medical leeches, and several widely ballyhooed medications that are well along in the developmental pipeline but whose placebo-subtracted efficacy is actually quite modest.

“I’ve shown you the evidence, such as it is – it’s not very much. The question is, have we really moved the needle in this disease in the last 30 years? The answer is I’m not so sure we have,” concluded Dr. Ruderman, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University, Chicago.

Several audience members were less restrained in their assessments.

“You have not moved the needle in osteoarthritis,” stated orthopedic surgeon William Bugbee, MD, chief of joint reconstruction at the Scripps Clinic in La Jolla, Calif., adding that he’s not much impressed by the long-term impact of intra-articular injections, be they of glucocorticoid, hyaluronic acid, or anything else being put into osteoarthritic joints.

Bruce Jancin/MDedge News

“To me, and to most orthopedic surgeons, an injection is a handshake. It’s like: ‘How do you do? Let’s get to know each other.’ But you know where this interaction is going – it’s going to end up in surgery. But that’s okay. Surgery is great. Let’s face it: It’s the only disease-modifying treatment for OA,” Dr. Bugbee declared.

Roy Fleischmann, MD, rose from the audience to assert that “the biggest need in rheumatology right now is a medication for OA that actually works and is actually disease modifying.”

That’s not going to happen until clinical trialists and the pharmaceutical industry learn how to subgroup OA and separate inflammatory OA from noninflammatory OA. Lumping the two together tends to wash out any strong efficacy signal an investigational agent might have, added Dr. Fleischmann, a rheumatologist at the University of Texas and medical director of the Metroplex Clinical Research Center, both in Dallas.

Dr. Ruderman noted that his own analysis of the contemporary evidence base for OA pharmacotherapies reached conclusions generally similar to those contained in the new American College of Rheumatology/Arthritis Foundation “Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee”. The list of pharmacotherapies that were strongly recommended in the guidelines was slim and rather tired: oral NSAIDs, intra-articular glucocorticoid injections, and – for knee OA only – topical NSAIDs. The strength of those favorable recommendations was based more upon solid evidence of safety rather than impressive efficacy, in his view. And the guidelines’ list of therapies whose use was strongly discouraged was much longer.

A factor in the flimsy evidence base for OA treatment is the strikingly large across-the-board placebo effect. This was nicely captured in a meta-analysis of 215 randomized, controlled trials of various therapies totaling more than 41,000 participants. Drilling down into the data, the British and Chinese investigators concluded that on average 75% of the overall treatment effect seen in the trials was caused by the placebo effect and only 25% represented a treatment-specific effect. The “winner” was intra-articular glucocorticoid, where the placebo effect was a mere 47%.
 

In the OA pipeline

“There’s a lot of interest in DMOADs – disease-modifying osteoarthritis drugs – but not a lot of success so far,” Dr. Ruderman observed.

Case in point: intra-articular sprifermin, a recombinant human fibroblast growth factor 18. In a 549-patient, multicenter, dose-ranging study, the two highest doses achieved a modest yet statistically significant advantage over placebo in total femorotibial joint cartilage thickness on MRI at 2 years. However, the investigators added that the result was of “uncertain clinical importance,” given the lack of a difference from baseline in total Western Ontario and McMaster Universities OA Index score.

“I’m not sure this is going anywhere,” Dr. Ruderman commented.

Tanezumab, a novel subcutaneously injected monoclonal antibody directed against nerve growth factor, has drawn a lot of attention. In an initial multicenter, phase 3, randomized trial it showed what Dr. Ruderman termed “some modest benefit” on pain and function.

“Very much like everything else in OA, you see a huge placebo effect buried in there,” according to the rheumatologist.

This modest clinical benefit was accompanied by a safety signal at the higher 5-mg dose of tanezumab. Moreover, a second phase 3 trial, this one conducted in nearly 3,000 OA patients and presented at the 2019 annual meeting of the American College of Rheumatology, also raised significant safety concerns at the higher dose. And while the 2.5-mg dose was safer, it was disappointingly no more effective in terms of improvement in pain and function scores than diclofenac at 75 mg twice daily, Dr. Ruderman noted.

Dr. Fleischmann predicted that, given the enormous unmet need for new OA treatments, tanezumab at 2.5 mg will win regulatory approval, but it will be a costly niche drug reserved for the challenging subset of patients who can’t take an NSAID and are poor surgical candidates. (On March 2, 2020, Eli Lilly announced that the Food and Drug Administration had accepted its Biologics License Application for tanezumab for the treatment of chronic pain caused by moderate to severe OA.)

Intra-articular FX006, a microsphere-based, extended-release formulation of triamcinolone, outperformed conventional triamcinolone in a phase 3 clinical trial. However, the placebo-subtracted improvement in pain was modest.

“There’s some marginal benefit here, but over time I’m not sure this adds much to just straight-up triamcinolone,” Dr. Ruderman opined.

Welcome to the wild, wild West

Patients with knee OA ask Dr. Ruderman all the time about the intra-articular injections of platelet-rich plasma (PRP) or mesenchymal stem cells they’ve seen touted on the Internet. As an evidence-based physician, he’s not a fan. A meta-analysis of 14 controlled trials of PRP, none double blind, showed some benefit in terms of pain and function at 3, 6, and 12 months, with little risk of adverse events. However, PRP is being marketed with a hype and claimed efficacy out of all proportion to the actual evidence.

“It’s the wild, wild West out there,” the rheumatologist warned.

He cited a study involving a scripted survey of 179 U.S. clinics offering PRP. The mean price quoted for a unilateral knee injection in a hypothetical 52-year-old man with knee OA was $714, and it’s a cash business, since insurance companies won’t cover PRP. Out of 84 centers that were willing to share their claimed efficacy, 10 quoted 90%-100% rates of good results or symptomatic improvement, 27 claimed 80%-90% efficacy, and 29 quoted figures of 70%-80%, all of which are well above the success rates achieved in the flawed clinical trials.

As for mesenchymal stem cells, “if PRP is the wild, wild West, this is the surface of Mars,” Dr. Ruderman quipped.

These stem cell injections are neither FDA regulated nor approved. There are no barriers to setting up a mesenchymal stem cell injection center, and the number of such centers is skyrocketing. Anybody can set up a center, and there’s essentially no oversight.

“The evidence in this area is really terrible,” the rheumatologist said. He pointed to a meta-analysis of five trials, only two of which were rated by the researchers as having a low risk of bias. The conclusion: There was limited evidence of short-term benefit in pain and function, but no evidence of cartilage repair, which is the chief claimed benefit.

The same group of investigators who queried the PRP clinics also successfully contacted 273 of the proliferating U.S. centers offering direct-to-consumer mesenchymal stem cell therapy. The mean price quoted for a unilateral knee injection was a whopping $5,156, which – like PRP – isn’t covered by insurance. At the 36 clinics responding to a request for their efficacy rates, the mean claim was good results or symptomatic improvement in 82% of treated patients.

Dr. Bugbee didn’t endorse this intervention, which is increasingly popular among his fellow orthopedic surgeons.

“The regulatory pathway drives this. Mesenchymal stem cells are categorized as a minimally manipulated tissue, so the regulatory pathway is easy,” explained Dr. Bugbee. “I talk 9 out of 10 patients out of it because there’s no evidence of disease modification.”


 

On a brighter note

Radiofrequency ablation and neuromodulation procedures for treatment of symptomatic knee OA make no pretense of being disease modifying, but a new systematic review of 33 published studies deemed of moderate or high methodological quality totaling 1,512 patients documented improved pain, function, and disease-specific quality of life for 3-12 months with minimal complications.

Most of these procedures target the genicular nerve, the sensory nerve that innervates the knee.

“There’s some value here to this,” Dr. Ruderman said. “Our pain folks are actually pretty interested in this. At our center, they’re using this for patients with persistent knee pain after knee replacement, with some success. It’s not an unreasonable approach.”

As part of his examination of the evidence base for OA treatment, Dr. Ruderman looked into an intervention he wasn’t familiar with: acupuncture. He was pleasantly surprised.

“There’s quite a bit of data. There is decent evidence that acupuncture has significant benefit, at least for pain, and is certainly without significant side effects,” according to the rheumatologist.

He cited a review of a dozen systematic reviews of randomized, controlled trials of acupuncture for OA. The Chinese investigators rated the overall quality of the evidence as moderate to low, but with some studies being rated high quality. “That’s not as bad as some of the other stuff I looked at,” Dr. Ruderman said.

Acupuncture was found to be 2.4 times more effective than Western medicine for short-term pain relief, and 4.1 times better in terms of total efficacy, with a lower risk of adverse events than with Western medicine.

Dr. Ruderman reported serving as a consultant for and/or receiving research grants from more than a half-dozen pharmaceutical companies.

[email protected]

LAHAINA, HAWAII – The most intriguing recent development in the treatment of actinic keratosis is a study in which a short-course of topical field therapy with calcipotriol plus 5-fluorouracil was shown to create a population of persistent epidermal memory T cells directed against actinic keratoses, with a resultant markedly reduced risk of developing squamous cell carcinoma within the next 3 years, Kishwer S. Nehal, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/MDedge News

The annual cost of treating actinic keratoses (AKs) exceeds $1 billion in the United States, so the billion-dollar question in dermatology is, does AK reduction lead to long-term protection against cancer? And this 3-year study by investigators at Washington University in St. Louis and Massachusetts General Hospital in Boston suggests the answer may be yes – when topical immunotherapy is utilized to induce robust T cell immunity, said Dr. Nehal, director of Mohs micrographic and dermatologic surgery, and codirector of the multidisciplinary skin cancer management program at Memorial Sloan Kettering Cancer Center in New York.

The investigators previously conducted a randomized, double-blind clinical trial in which 130 participants with a substantial AK burden received a 4-day course of 0.005% calcipotriol ointment plus 5% 5-FU cream or Vaseline plus 5-FU. The combination therapy proved more effective than the comparator in eliminating AKs at 8 weeks of follow-up. Moreover, tissue analysis pointed to the mechanism of benefit: The combination treatment induced keratinocyte expression of thymic stromal lymphopoietin (TSLP) cytokine, which led to a powerful CD4+ T cell response against AKs.

The researchers’ follow-up study addressed two key questions: Whether this epidermal T cell immunity persists long term, and if it actually achieves a reduced risk of squamous cell carcinoma (SCC) over time. The answers were yes and yes.

Seventy of the original 130 patients were prospectively followed for 3 years. Only 2 of 30 (7%) in the short-course combination therapy group developed SCC in treated areas of the face and scalp, compared with 11 of 40 controls (28%), a statistically significant difference, which constitutes a 79% relative risk reduction. This chemopreventive effect was long lasting at the cellular level, as the combination therapy group still retained measurable T cell immunity in the skin at the 3-year mark. As expected, the topical therapy had no impact on the development of basal cell carcinoma. The question now becomes how long the chemopreventive effect extends beyond 3 years.

“These remarkable findings substantiate the use of immunotherapeutic agents with minimal side effects and high efficacy against precancerous lesions in order to reduce the risk of cancer development and recurrence, which may be broadly applicable to skin and internal malignancies,” the investigators wrote in the study (JCI Insight. 2019 Mar 21;4(6). pii: 125476. doi: 10.1172/jci.insight.125476). Dr. Nehal said that this study requires confirmation in light of its post hoc design and the relatively small numbers of patients and SCCs. But the potential public health implications are profound, since roughly 40 million Americans have AKs, subclinical AKs are 10 times more common than visible ones, AKs are known precursors for SCC, and high-risk SCC is the cause of roughly 10,000 deaths per year, an underappreciated mortality burden that’s actually comparable to that of melanoma.

While awaiting further studies, this short-course combination therapy also offers the ready appeal of a field therapy without much downtime due to treatment-induced inflammation. In the study, 4 days of combo therapy resulted in moderate inflammation which quickly resolved.

“Does treatment duration and severity affect patient compliance? I would argue that in 2020 it does. People have very active, busy lives and they don’t want a lot of downtime. I can tell you that in Manhattan they want no downtime,” said Dr. Nehal, professor of dermatology at Weill Cornell Medicine, New York.

Even though a traditional 4-week, twice-daily course of 5% 5-FU cream has been convincingly shown in a recent large randomized Dutch trial (N Engl J Med. 2019 Mar 7;380[10]:935-46) to be the most effective field therapy for eradicating AKs – outperforming in descending order of efficacy at 12 months of follow-up imiquimod (Zyclara), photodynamic therapy, and ingenol mebutate (Picato) – Dr. Nehal finds few takers for 5-FU. People balk at the downtime. Her female patients with a significant AK burden typically opt for photodynamic therapy because of the aesthetic side benefit and shorter downtime, while the men – even those who’ve already had a large SCC – are more likely to prefer a watch-and-wait approach, dealing with an SCC if and when it arises.

“I love the science behind using calcipotriol with 5-FU, but I wish it was more friendly to dermatologists,” said fellow panelist Paul Nghiem, MD, PhD. “Of all the things we should have a combination product for, the pharmaceutical industry should really prepare a [calcipotriol/5-FU] cream and market it with the improved efficacy data.”

Bruce Jancin/MDedge News

He added that he has no use for the conventional 2- to 4-week, twice-daily 5-FU regimens employed by many dermatologists.

“I don’t understand this need to feel like you’ve got to treat patients until they look like they’ve fallen off a motorcycle at 50 mph. I just can’t see that,” said Dr. Nghiem, professor and chair of dermatology at the University of Washington, Seattle.

Instead, he routinely utilizes the nearly 3-decade-old Pearlman technique of weekly pulsed dosing of topical 5-FU (J Am Acad Dermatol. 1991 Oct;25[4]:665-7).

“I almost never even ask my patients, ‘Are you OK with having a bunch of downtime?’ I just say, ‘Treat with the 5-FU until you get some erythema, until you’re bothered by it, and then stop for a while,’ ” he explained. “I’ve treated many patients with that technique over the years. It might not be quite as effective, but I hardly have to do any treatment with liquid nitrogen.”

Session chair Ashfaq A. Marghoob, MD, is of a similar mind.

“I also don’t go to the point that you’re fire engine red. Once the irritation sets in, we stop,” said Dr. Marghoob, director of clinical dermatology, Memorial Sloan Kettering Skin Cancer Center Hauppauge (New York).

Neither Dr. Nehal nor Dr. Nghiem has used short-course calcipotriol plus 5-FU therapy. When they polled the large audience as to who has, only a few hands went up.

“I feel like residents who are keeping up with the literature are using it,” Dr. Nehal observed. “My fellows say, ‘Yup, that’s what we’re doing,’ but I’m not using it.”

“I use it,” volunteered fellow panelist Trilokraj Tejasvi, MBBS. “I was educated by one of my residents, and now I use it all the time, especially in my VA population. I’ve been using it for a year. Things get red, but it clears fast,” said Dr. Tejasvi, director of the cutaneous lymphoma program and director of teledermatology services at the University of Michigan, Ann Arbor, and chief of the dermatology service at Ann Arbor Veteran Affairs Hospital.

Dr. Nehal reported having no conflicts of interest regarding her presentation.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
 

[email protected]

LAHAINA, HAWAII – The most intriguing recent development in the treatment of actinic keratosis is a study in which a short-course of topical field therapy with calcipotriol plus 5-fluorouracil was shown to create a population of persistent epidermal memory T cells directed against actinic keratoses, with a resultant markedly reduced risk of developing squamous cell carcinoma within the next 3 years, Kishwer S. Nehal, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/MDedge News

The annual cost of treating actinic keratoses (AKs) exceeds $1 billion in the United States, so the billion-dollar question in dermatology is, does AK reduction lead to long-term protection against cancer? And this 3-year study by investigators at Washington University in St. Louis and Massachusetts General Hospital in Boston suggests the answer may be yes – when topical immunotherapy is utilized to induce robust T cell immunity, said Dr. Nehal, director of Mohs micrographic and dermatologic surgery, and codirector of the multidisciplinary skin cancer management program at Memorial Sloan Kettering Cancer Center in New York.

The investigators previously conducted a randomized, double-blind clinical trial in which 130 participants with a substantial AK burden received a 4-day course of 0.005% calcipotriol ointment plus 5% 5-FU cream or Vaseline plus 5-FU. The combination therapy proved more effective than the comparator in eliminating AKs at 8 weeks of follow-up. Moreover, tissue analysis pointed to the mechanism of benefit: The combination treatment induced keratinocyte expression of thymic stromal lymphopoietin (TSLP) cytokine, which led to a powerful CD4+ T cell response against AKs.

The researchers’ follow-up study addressed two key questions: Whether this epidermal T cell immunity persists long term, and if it actually achieves a reduced risk of squamous cell carcinoma (SCC) over time. The answers were yes and yes.

Seventy of the original 130 patients were prospectively followed for 3 years. Only 2 of 30 (7%) in the short-course combination therapy group developed SCC in treated areas of the face and scalp, compared with 11 of 40 controls (28%), a statistically significant difference, which constitutes a 79% relative risk reduction. This chemopreventive effect was long lasting at the cellular level, as the combination therapy group still retained measurable T cell immunity in the skin at the 3-year mark. As expected, the topical therapy had no impact on the development of basal cell carcinoma. The question now becomes how long the chemopreventive effect extends beyond 3 years.

“These remarkable findings substantiate the use of immunotherapeutic agents with minimal side effects and high efficacy against precancerous lesions in order to reduce the risk of cancer development and recurrence, which may be broadly applicable to skin and internal malignancies,” the investigators wrote in the study (JCI Insight. 2019 Mar 21;4(6). pii: 125476. doi: 10.1172/jci.insight.125476). Dr. Nehal said that this study requires confirmation in light of its post hoc design and the relatively small numbers of patients and SCCs. But the potential public health implications are profound, since roughly 40 million Americans have AKs, subclinical AKs are 10 times more common than visible ones, AKs are known precursors for SCC, and high-risk SCC is the cause of roughly 10,000 deaths per year, an underappreciated mortality burden that’s actually comparable to that of melanoma.

While awaiting further studies, this short-course combination therapy also offers the ready appeal of a field therapy without much downtime due to treatment-induced inflammation. In the study, 4 days of combo therapy resulted in moderate inflammation which quickly resolved.

“Does treatment duration and severity affect patient compliance? I would argue that in 2020 it does. People have very active, busy lives and they don’t want a lot of downtime. I can tell you that in Manhattan they want no downtime,” said Dr. Nehal, professor of dermatology at Weill Cornell Medicine, New York.

Even though a traditional 4-week, twice-daily course of 5% 5-FU cream has been convincingly shown in a recent large randomized Dutch trial (N Engl J Med. 2019 Mar 7;380[10]:935-46) to be the most effective field therapy for eradicating AKs – outperforming in descending order of efficacy at 12 months of follow-up imiquimod (Zyclara), photodynamic therapy, and ingenol mebutate (Picato) – Dr. Nehal finds few takers for 5-FU. People balk at the downtime. Her female patients with a significant AK burden typically opt for photodynamic therapy because of the aesthetic side benefit and shorter downtime, while the men – even those who’ve already had a large SCC – are more likely to prefer a watch-and-wait approach, dealing with an SCC if and when it arises.

“I love the science behind using calcipotriol with 5-FU, but I wish it was more friendly to dermatologists,” said fellow panelist Paul Nghiem, MD, PhD. “Of all the things we should have a combination product for, the pharmaceutical industry should really prepare a [calcipotriol/5-FU] cream and market it with the improved efficacy data.”

Bruce Jancin/MDedge News

He added that he has no use for the conventional 2- to 4-week, twice-daily 5-FU regimens employed by many dermatologists.

“I don’t understand this need to feel like you’ve got to treat patients until they look like they’ve fallen off a motorcycle at 50 mph. I just can’t see that,” said Dr. Nghiem, professor and chair of dermatology at the University of Washington, Seattle.

Instead, he routinely utilizes the nearly 3-decade-old Pearlman technique of weekly pulsed dosing of topical 5-FU (J Am Acad Dermatol. 1991 Oct;25[4]:665-7).

“I almost never even ask my patients, ‘Are you OK with having a bunch of downtime?’ I just say, ‘Treat with the 5-FU until you get some erythema, until you’re bothered by it, and then stop for a while,’ ” he explained. “I’ve treated many patients with that technique over the years. It might not be quite as effective, but I hardly have to do any treatment with liquid nitrogen.”

Session chair Ashfaq A. Marghoob, MD, is of a similar mind.

“I also don’t go to the point that you’re fire engine red. Once the irritation sets in, we stop,” said Dr. Marghoob, director of clinical dermatology, Memorial Sloan Kettering Skin Cancer Center Hauppauge (New York).

Neither Dr. Nehal nor Dr. Nghiem has used short-course calcipotriol plus 5-FU therapy. When they polled the large audience as to who has, only a few hands went up.

“I feel like residents who are keeping up with the literature are using it,” Dr. Nehal observed. “My fellows say, ‘Yup, that’s what we’re doing,’ but I’m not using it.”

“I use it,” volunteered fellow panelist Trilokraj Tejasvi, MBBS. “I was educated by one of my residents, and now I use it all the time, especially in my VA population. I’ve been using it for a year. Things get red, but it clears fast,” said Dr. Tejasvi, director of the cutaneous lymphoma program and director of teledermatology services at the University of Michigan, Ann Arbor, and chief of the dermatology service at Ann Arbor Veteran Affairs Hospital.

Dr. Nehal reported having no conflicts of interest regarding her presentation.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
 

[email protected]

LAHAINA, HAWAII – The most intriguing recent development in the treatment of actinic keratosis is a study in which a short-course of topical field therapy with calcipotriol plus 5-fluorouracil was shown to create a population of persistent epidermal memory T cells directed against actinic keratoses, with a resultant markedly reduced risk of developing squamous cell carcinoma within the next 3 years, Kishwer S. Nehal, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/MDedge News

The annual cost of treating actinic keratoses (AKs) exceeds $1 billion in the United States, so the billion-dollar question in dermatology is, does AK reduction lead to long-term protection against cancer? And this 3-year study by investigators at Washington University in St. Louis and Massachusetts General Hospital in Boston suggests the answer may be yes – when topical immunotherapy is utilized to induce robust T cell immunity, said Dr. Nehal, director of Mohs micrographic and dermatologic surgery, and codirector of the multidisciplinary skin cancer management program at Memorial Sloan Kettering Cancer Center in New York.

The investigators previously conducted a randomized, double-blind clinical trial in which 130 participants with a substantial AK burden received a 4-day course of 0.005% calcipotriol ointment plus 5% 5-FU cream or Vaseline plus 5-FU. The combination therapy proved more effective than the comparator in eliminating AKs at 8 weeks of follow-up. Moreover, tissue analysis pointed to the mechanism of benefit: The combination treatment induced keratinocyte expression of thymic stromal lymphopoietin (TSLP) cytokine, which led to a powerful CD4+ T cell response against AKs.

The researchers’ follow-up study addressed two key questions: Whether this epidermal T cell immunity persists long term, and if it actually achieves a reduced risk of squamous cell carcinoma (SCC) over time. The answers were yes and yes.

Seventy of the original 130 patients were prospectively followed for 3 years. Only 2 of 30 (7%) in the short-course combination therapy group developed SCC in treated areas of the face and scalp, compared with 11 of 40 controls (28%), a statistically significant difference, which constitutes a 79% relative risk reduction. This chemopreventive effect was long lasting at the cellular level, as the combination therapy group still retained measurable T cell immunity in the skin at the 3-year mark. As expected, the topical therapy had no impact on the development of basal cell carcinoma. The question now becomes how long the chemopreventive effect extends beyond 3 years.

“These remarkable findings substantiate the use of immunotherapeutic agents with minimal side effects and high efficacy against precancerous lesions in order to reduce the risk of cancer development and recurrence, which may be broadly applicable to skin and internal malignancies,” the investigators wrote in the study (JCI Insight. 2019 Mar 21;4(6). pii: 125476. doi: 10.1172/jci.insight.125476). Dr. Nehal said that this study requires confirmation in light of its post hoc design and the relatively small numbers of patients and SCCs. But the potential public health implications are profound, since roughly 40 million Americans have AKs, subclinical AKs are 10 times more common than visible ones, AKs are known precursors for SCC, and high-risk SCC is the cause of roughly 10,000 deaths per year, an underappreciated mortality burden that’s actually comparable to that of melanoma.

While awaiting further studies, this short-course combination therapy also offers the ready appeal of a field therapy without much downtime due to treatment-induced inflammation. In the study, 4 days of combo therapy resulted in moderate inflammation which quickly resolved.

“Does treatment duration and severity affect patient compliance? I would argue that in 2020 it does. People have very active, busy lives and they don’t want a lot of downtime. I can tell you that in Manhattan they want no downtime,” said Dr. Nehal, professor of dermatology at Weill Cornell Medicine, New York.

Even though a traditional 4-week, twice-daily course of 5% 5-FU cream has been convincingly shown in a recent large randomized Dutch trial (N Engl J Med. 2019 Mar 7;380[10]:935-46) to be the most effective field therapy for eradicating AKs – outperforming in descending order of efficacy at 12 months of follow-up imiquimod (Zyclara), photodynamic therapy, and ingenol mebutate (Picato) – Dr. Nehal finds few takers for 5-FU. People balk at the downtime. Her female patients with a significant AK burden typically opt for photodynamic therapy because of the aesthetic side benefit and shorter downtime, while the men – even those who’ve already had a large SCC – are more likely to prefer a watch-and-wait approach, dealing with an SCC if and when it arises.

“I love the science behind using calcipotriol with 5-FU, but I wish it was more friendly to dermatologists,” said fellow panelist Paul Nghiem, MD, PhD. “Of all the things we should have a combination product for, the pharmaceutical industry should really prepare a [calcipotriol/5-FU] cream and market it with the improved efficacy data.”

Bruce Jancin/MDedge News

He added that he has no use for the conventional 2- to 4-week, twice-daily 5-FU regimens employed by many dermatologists.

“I don’t understand this need to feel like you’ve got to treat patients until they look like they’ve fallen off a motorcycle at 50 mph. I just can’t see that,” said Dr. Nghiem, professor and chair of dermatology at the University of Washington, Seattle.

Instead, he routinely utilizes the nearly 3-decade-old Pearlman technique of weekly pulsed dosing of topical 5-FU (J Am Acad Dermatol. 1991 Oct;25[4]:665-7).

“I almost never even ask my patients, ‘Are you OK with having a bunch of downtime?’ I just say, ‘Treat with the 5-FU until you get some erythema, until you’re bothered by it, and then stop for a while,’ ” he explained. “I’ve treated many patients with that technique over the years. It might not be quite as effective, but I hardly have to do any treatment with liquid nitrogen.”

Session chair Ashfaq A. Marghoob, MD, is of a similar mind.

“I also don’t go to the point that you’re fire engine red. Once the irritation sets in, we stop,” said Dr. Marghoob, director of clinical dermatology, Memorial Sloan Kettering Skin Cancer Center Hauppauge (New York).

Neither Dr. Nehal nor Dr. Nghiem has used short-course calcipotriol plus 5-FU therapy. When they polled the large audience as to who has, only a few hands went up.

“I feel like residents who are keeping up with the literature are using it,” Dr. Nehal observed. “My fellows say, ‘Yup, that’s what we’re doing,’ but I’m not using it.”

“I use it,” volunteered fellow panelist Trilokraj Tejasvi, MBBS. “I was educated by one of my residents, and now I use it all the time, especially in my VA population. I’ve been using it for a year. Things get red, but it clears fast,” said Dr. Tejasvi, director of the cutaneous lymphoma program and director of teledermatology services at the University of Michigan, Ann Arbor, and chief of the dermatology service at Ann Arbor Veteran Affairs Hospital.

Dr. Nehal reported having no conflicts of interest regarding her presentation.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
 

[email protected]

Self-injurious behaviors are common and can be either volitional or unintentional. Often people who perform these behaviors receive “tongue lashings” from family, friends, and loved ones. We recently treated a patient whose lesion in the oral cavity was thought to be caused by some form of self-injury, though the prognosis clearly depended on the true culprit. It is important for clinicians to identify the cause of the injury when encountering patients with oral cavity lesions.

Case Presentation

A 40-year-old white male with a medical history of bipolar disorder, posttraumatic stress disorder, polysubstance abuse, and recently diagnosed temporomandibular joint (TMJ) syndrome was seen in outpatient primary care for a bleeding lesion in his mouth for the past 3 weeks. The lesion was under the surface of his right tongue. He first noted the lesion after he had burned himself tasting some homemade rice pudding while under the influence of marijuana. The next day, an impression was taken of his mouth by a dental assistant who was fitting him for an oral appliance for his TMJ syndrome; according to his history, she did not perform a visual inspection of his mouth nor could he recall his last dental examination. He had neither lost weight nor experienced dysphagia. He was not taking any prescribed medications, had an 8 pack-year history of smoking cigarettes, and had smoked crack cocaine intermittently for several years. The also patient had chewed one-half tin per day of chewing tobacco for 5 years, though he had quit 7 years before presentation. He was consuming 6 alcoholic drinks daily and had no history of chewing betel nuts.

On physical examination, the patient seemed extremely anxious, but his vital signs were unremarkable. The nasal dorsum was straight, and the nares were widely patent. There were no suspicious cutaneous lesions noted of the face, head, trunk, or extremities. The salivary glands were soft and showed no lesions or masses within the parotid or submandibular glands bilaterally. There was no obvious obstruction of Stenson or Wharton ducts bilaterally. He had normal lips and oral competence. The dentition was noted to be fair.

A nonfriable, 1.5 cm-wide lesion was found on the ventral surface of the right tongue (Figure 1). The tongue was mobile. The mouth floor was soft and without evidence of masses or lesions. The tonsils, tonsillar pillars, palate, and base of tongue did not show any concerning lesions or masses. The neck revealed a nonenlarged thyroid and no lymphadenopathy. The remainder of the examination was unremarkable.

Diagnosis

Given his risk factors of alcohol use disorder and a history of both inhaled and chewing tobacco, oral squamous cell carcinoma (SCC) was considered. The differential diagnosis also included pyogenic granuloma, mucocele, sublingual fibroma, and metastasis to the oral soft tissue. Due to its implications with respect to morbidity and mortality, we thought it necessary to rule out SCC of the oral cavity. SCC comprises more than 90% of oral malignancies, and tobacco-related products, alcohol, and human papilloma virus are well-established risk factors.¹

Pyogenic granuloma, also known as eruptive hemangioma and lobular capillary hemangioma, is a relatively common benign lesion of the skin and mucosal surfaces that often presents as a solitary, rapidly enlarging papule or nodule that is extremely friable.² Interestingly, pyogenic granuloma is a misnomer, since it is neither infectious in origin nor granulomatous when visualized under the microscope and is thought to arise from an exuberant tissue response to localized irritation or trauma. An individual lesion can range in size from a few millimeters to a few centimeters and generally reaches its maximum size within a matter of weeks; they often arise at sites of minor trauma.³ While the pathogenesis of pyogenic granuloma has not been clearly established, it seems to be related to an imbalance of angiogenesis secondary to overexpression of vascular endothelial growth factor and basic fibroblast growth factor.⁴ While they can occur at any age, pyogenic granulomas are frequently seen in pediatric patients and during pregnancy.

A fibroma, also known as an irritation fibroma, is one of the more common fibrous tumorlike growths and is often caused by trauma or irritation. It usually presents as a smooth-surfaced, painless solid lesion, though it can be nodular and histopathologically shows collagen and connective tissue.⁵ While fibromas can occur anywhere in the oral cavity, they commonly arise on the buccal mucosa along the plane of occlusion between the maxillary and mandibular teeth.

Mucoceles are the most common benign lesions in the mouth and are commonly found on the lower lip and are mucus-filled cavities, arising from the accumulation of mucus from trauma or lip-biting and alteration of minor salivary glands.⁶ Our patient’s rapid evolution and history of trauma were consistent with a mucocele. Although the lower lip is the most common site of involvement, mucoceles also occur on the tongue, cheek, palate, and mouth floor.Metastases to the oral cavity are rare and comprise only 1% of all oral cavity malignancies.⁷ Although most commonly seen in the jaw, nearly one-third of oral cavity metastases are in the soft tissue.⁸ They generally occur late in the course of disease, and the time between appearance and death is usually short.⁸ Our patient’s lack of known primary malignancy and lack of weight loss rendered this diagnosis unlikely.

Other possibilities include peripheral giant cell granuloma, a reactive hyperplastic lesion of the oral cavity originating from the periosteum or periodontal membrane following local irritation or chronic trauma,⁹ and peripheral ossifying fibroma, a reactive soft tissue growth usually seen on the interdental papilla.¹⁰

Surgical excision was performed and revealed reactive epidermal hyperplasia, ulceration, granulation tissue formation, and marked inflammation with reactive changes. There was no evidence of malignancy and was interpreted as consistent with pyogenic granuloma (Figures 2 and 3) likely due to the trauma from the thermal burn or poor dentition.

Management

The patient was relieved to be informed of the diagnosis of an unusual presentation of pyogenic granuloma with no evidence of cancer. Current treatment strategies for pyogenic granuloma include surgical excision, shave excision with cautery, cryotherapy, sclerotherapy, carbon dioxide or pulsed dye laser, as well as expectant management. However, recurrence after initial treatment can occur, with lower recurrence rates occurring with surgical excision.¹¹

Although we wouldn’t state that we gave the patient a “tongue-lashing,” we strongly advised him that he return to his dentist and abstain from tobacco products, alcohol, illicit drugs, and taste-testing scalding food directly from the pot.

Self-injurious behaviors are common and can be either volitional or unintentional. Often people who perform these behaviors receive “tongue lashings” from family, friends, and loved ones. We recently treated a patient whose lesion in the oral cavity was thought to be caused by some form of self-injury, though the prognosis clearly depended on the true culprit. It is important for clinicians to identify the cause of the injury when encountering patients with oral cavity lesions.

Case Presentation

A 40-year-old white male with a medical history of bipolar disorder, posttraumatic stress disorder, polysubstance abuse, and recently diagnosed temporomandibular joint (TMJ) syndrome was seen in outpatient primary care for a bleeding lesion in his mouth for the past 3 weeks. The lesion was under the surface of his right tongue. He first noted the lesion after he had burned himself tasting some homemade rice pudding while under the influence of marijuana. The next day, an impression was taken of his mouth by a dental assistant who was fitting him for an oral appliance for his TMJ syndrome; according to his history, she did not perform a visual inspection of his mouth nor could he recall his last dental examination. He had neither lost weight nor experienced dysphagia. He was not taking any prescribed medications, had an 8 pack-year history of smoking cigarettes, and had smoked crack cocaine intermittently for several years. The also patient had chewed one-half tin per day of chewing tobacco for 5 years, though he had quit 7 years before presentation. He was consuming 6 alcoholic drinks daily and had no history of chewing betel nuts.

On physical examination, the patient seemed extremely anxious, but his vital signs were unremarkable. The nasal dorsum was straight, and the nares were widely patent. There were no suspicious cutaneous lesions noted of the face, head, trunk, or extremities. The salivary glands were soft and showed no lesions or masses within the parotid or submandibular glands bilaterally. There was no obvious obstruction of Stenson or Wharton ducts bilaterally. He had normal lips and oral competence. The dentition was noted to be fair.

A nonfriable, 1.5 cm-wide lesion was found on the ventral surface of the right tongue (Figure 1). The tongue was mobile. The mouth floor was soft and without evidence of masses or lesions. The tonsils, tonsillar pillars, palate, and base of tongue did not show any concerning lesions or masses. The neck revealed a nonenlarged thyroid and no lymphadenopathy. The remainder of the examination was unremarkable.

Diagnosis

Given his risk factors of alcohol use disorder and a history of both inhaled and chewing tobacco, oral squamous cell carcinoma (SCC) was considered. The differential diagnosis also included pyogenic granuloma, mucocele, sublingual fibroma, and metastasis to the oral soft tissue. Due to its implications with respect to morbidity and mortality, we thought it necessary to rule out SCC of the oral cavity. SCC comprises more than 90% of oral malignancies, and tobacco-related products, alcohol, and human papilloma virus are well-established risk factors.¹

Pyogenic granuloma, also known as eruptive hemangioma and lobular capillary hemangioma, is a relatively common benign lesion of the skin and mucosal surfaces that often presents as a solitary, rapidly enlarging papule or nodule that is extremely friable.² Interestingly, pyogenic granuloma is a misnomer, since it is neither infectious in origin nor granulomatous when visualized under the microscope and is thought to arise from an exuberant tissue response to localized irritation or trauma. An individual lesion can range in size from a few millimeters to a few centimeters and generally reaches its maximum size within a matter of weeks; they often arise at sites of minor trauma.³ While the pathogenesis of pyogenic granuloma has not been clearly established, it seems to be related to an imbalance of angiogenesis secondary to overexpression of vascular endothelial growth factor and basic fibroblast growth factor.⁴ While they can occur at any age, pyogenic granulomas are frequently seen in pediatric patients and during pregnancy.

A fibroma, also known as an irritation fibroma, is one of the more common fibrous tumorlike growths and is often caused by trauma or irritation. It usually presents as a smooth-surfaced, painless solid lesion, though it can be nodular and histopathologically shows collagen and connective tissue.⁵ While fibromas can occur anywhere in the oral cavity, they commonly arise on the buccal mucosa along the plane of occlusion between the maxillary and mandibular teeth.

Mucoceles are the most common benign lesions in the mouth and are commonly found on the lower lip and are mucus-filled cavities, arising from the accumulation of mucus from trauma or lip-biting and alteration of minor salivary glands.⁶ Our patient’s rapid evolution and history of trauma were consistent with a mucocele. Although the lower lip is the most common site of involvement, mucoceles also occur on the tongue, cheek, palate, and mouth floor.Metastases to the oral cavity are rare and comprise only 1% of all oral cavity malignancies.⁷ Although most commonly seen in the jaw, nearly one-third of oral cavity metastases are in the soft tissue.⁸ They generally occur late in the course of disease, and the time between appearance and death is usually short.⁸ Our patient’s lack of known primary malignancy and lack of weight loss rendered this diagnosis unlikely.

Other possibilities include peripheral giant cell granuloma, a reactive hyperplastic lesion of the oral cavity originating from the periosteum or periodontal membrane following local irritation or chronic trauma,⁹ and peripheral ossifying fibroma, a reactive soft tissue growth usually seen on the interdental papilla.¹⁰

Surgical excision was performed and revealed reactive epidermal hyperplasia, ulceration, granulation tissue formation, and marked inflammation with reactive changes. There was no evidence of malignancy and was interpreted as consistent with pyogenic granuloma (Figures 2 and 3) likely due to the trauma from the thermal burn or poor dentition.

Management

The patient was relieved to be informed of the diagnosis of an unusual presentation of pyogenic granuloma with no evidence of cancer. Current treatment strategies for pyogenic granuloma include surgical excision, shave excision with cautery, cryotherapy, sclerotherapy, carbon dioxide or pulsed dye laser, as well as expectant management. However, recurrence after initial treatment can occur, with lower recurrence rates occurring with surgical excision.¹¹

Although we wouldn’t state that we gave the patient a “tongue-lashing,” we strongly advised him that he return to his dentist and abstain from tobacco products, alcohol, illicit drugs, and taste-testing scalding food directly from the pot.

Self-injurious behaviors are common and can be either volitional or unintentional. Often people who perform these behaviors receive “tongue lashings” from family, friends, and loved ones. We recently treated a patient whose lesion in the oral cavity was thought to be caused by some form of self-injury, though the prognosis clearly depended on the true culprit. It is important for clinicians to identify the cause of the injury when encountering patients with oral cavity lesions.

Case Presentation

A 40-year-old white male with a medical history of bipolar disorder, posttraumatic stress disorder, polysubstance abuse, and recently diagnosed temporomandibular joint (TMJ) syndrome was seen in outpatient primary care for a bleeding lesion in his mouth for the past 3 weeks. The lesion was under the surface of his right tongue. He first noted the lesion after he had burned himself tasting some homemade rice pudding while under the influence of marijuana. The next day, an impression was taken of his mouth by a dental assistant who was fitting him for an oral appliance for his TMJ syndrome; according to his history, she did not perform a visual inspection of his mouth nor could he recall his last dental examination. He had neither lost weight nor experienced dysphagia. He was not taking any prescribed medications, had an 8 pack-year history of smoking cigarettes, and had smoked crack cocaine intermittently for several years. The also patient had chewed one-half tin per day of chewing tobacco for 5 years, though he had quit 7 years before presentation. He was consuming 6 alcoholic drinks daily and had no history of chewing betel nuts.

On physical examination, the patient seemed extremely anxious, but his vital signs were unremarkable. The nasal dorsum was straight, and the nares were widely patent. There were no suspicious cutaneous lesions noted of the face, head, trunk, or extremities. The salivary glands were soft and showed no lesions or masses within the parotid or submandibular glands bilaterally. There was no obvious obstruction of Stenson or Wharton ducts bilaterally. He had normal lips and oral competence. The dentition was noted to be fair.

A nonfriable, 1.5 cm-wide lesion was found on the ventral surface of the right tongue (Figure 1). The tongue was mobile. The mouth floor was soft and without evidence of masses or lesions. The tonsils, tonsillar pillars, palate, and base of tongue did not show any concerning lesions or masses. The neck revealed a nonenlarged thyroid and no lymphadenopathy. The remainder of the examination was unremarkable.

Diagnosis

Given his risk factors of alcohol use disorder and a history of both inhaled and chewing tobacco, oral squamous cell carcinoma (SCC) was considered. The differential diagnosis also included pyogenic granuloma, mucocele, sublingual fibroma, and metastasis to the oral soft tissue. Due to its implications with respect to morbidity and mortality, we thought it necessary to rule out SCC of the oral cavity. SCC comprises more than 90% of oral malignancies, and tobacco-related products, alcohol, and human papilloma virus are well-established risk factors.¹

Pyogenic granuloma, also known as eruptive hemangioma and lobular capillary hemangioma, is a relatively common benign lesion of the skin and mucosal surfaces that often presents as a solitary, rapidly enlarging papule or nodule that is extremely friable.² Interestingly, pyogenic granuloma is a misnomer, since it is neither infectious in origin nor granulomatous when visualized under the microscope and is thought to arise from an exuberant tissue response to localized irritation or trauma. An individual lesion can range in size from a few millimeters to a few centimeters and generally reaches its maximum size within a matter of weeks; they often arise at sites of minor trauma.³ While the pathogenesis of pyogenic granuloma has not been clearly established, it seems to be related to an imbalance of angiogenesis secondary to overexpression of vascular endothelial growth factor and basic fibroblast growth factor.⁴ While they can occur at any age, pyogenic granulomas are frequently seen in pediatric patients and during pregnancy.

A fibroma, also known as an irritation fibroma, is one of the more common fibrous tumorlike growths and is often caused by trauma or irritation. It usually presents as a smooth-surfaced, painless solid lesion, though it can be nodular and histopathologically shows collagen and connective tissue.⁵ While fibromas can occur anywhere in the oral cavity, they commonly arise on the buccal mucosa along the plane of occlusion between the maxillary and mandibular teeth.

Mucoceles are the most common benign lesions in the mouth and are commonly found on the lower lip and are mucus-filled cavities, arising from the accumulation of mucus from trauma or lip-biting and alteration of minor salivary glands.⁶ Our patient’s rapid evolution and history of trauma were consistent with a mucocele. Although the lower lip is the most common site of involvement, mucoceles also occur on the tongue, cheek, palate, and mouth floor.Metastases to the oral cavity are rare and comprise only 1% of all oral cavity malignancies.⁷ Although most commonly seen in the jaw, nearly one-third of oral cavity metastases are in the soft tissue.⁸ They generally occur late in the course of disease, and the time between appearance and death is usually short.⁸ Our patient’s lack of known primary malignancy and lack of weight loss rendered this diagnosis unlikely.

Other possibilities include peripheral giant cell granuloma, a reactive hyperplastic lesion of the oral cavity originating from the periosteum or periodontal membrane following local irritation or chronic trauma,⁹ and peripheral ossifying fibroma, a reactive soft tissue growth usually seen on the interdental papilla.¹⁰

Surgical excision was performed and revealed reactive epidermal hyperplasia, ulceration, granulation tissue formation, and marked inflammation with reactive changes. There was no evidence of malignancy and was interpreted as consistent with pyogenic granuloma (Figures 2 and 3) likely due to the trauma from the thermal burn or poor dentition.

Management

The patient was relieved to be informed of the diagnosis of an unusual presentation of pyogenic granuloma with no evidence of cancer. Current treatment strategies for pyogenic granuloma include surgical excision, shave excision with cautery, cryotherapy, sclerotherapy, carbon dioxide or pulsed dye laser, as well as expectant management. However, recurrence after initial treatment can occur, with lower recurrence rates occurring with surgical excision.¹¹

Although we wouldn’t state that we gave the patient a “tongue-lashing,” we strongly advised him that he return to his dentist and abstain from tobacco products, alcohol, illicit drugs, and taste-testing scalding food directly from the pot.

Cataract surgery is one of the most common ambulatory procedures performed in the US.^1-3 With the aging of the US population, the number of Americans with cataracts is projected to increase from 24.4 million in 2010 to 38.7 million in 2030.⁴

Approximately 20% of all cataract patients have preoperative astigmatism of > 1.5 diopters (D), underscoring the importance of training residents in the placement of toric intraocular lenses (IOLs).⁵ However, the implantation of toric IOLs is more challenging than monofocal IOLs, requiring precise surgical alignment of the IOL.⁶ Successful toric IOL implantation also requires accurate calculation of the IOL cylinder power and target axis of alignment. It is unclear which toric IOL calculation formula offers the most accurate refractive predictions, and practitioners have designed strategies to apply different formulae depending on the biometric dimensions of the target eye.^7-9

Previous studies of resident-performed cataract surgery using toric IOLs^6,10-13 and studies that compare the performance of the Barrett and Holladay toric formulae have been limited by their small sample sizes (< 107 eyes).^7,14-16 Moreover, none of the studies that evaluate the comparative effectiveness of these biometric formulae were conducted at a teaching hospital.^7,14-16

Given the added complexity of toric IOL placement and variable surgical experience of residents as ophthalmologists-in-training, it is important to assess outcomes in teaching hospitals.¹³ The primary aims of this study were to assess the visual and refractive outcomes of cataract surgery using toric IOLs in a US Department of Veterans Affairs (VA) teaching hospital and to compare the relative accuracy of the Holladay 2 or Barrett toric biometric formulae in predicting postoperative refraction outcomes.

Methods

The Providence VA Medical Center (PVAMC) Institutional Review Board approved this study. This retrospective chart review included patients with cataract and corneal astigmatism who underwent cataract surgery using Acrysof toric IOLs, model SN6AT (Alcon) at the PVAMC teaching hospital between November 2013 and May 2018.

Only 1 eye was included from each study subject to avoid compounding of data with the use of bilateral eyes.¹⁷ In addition, bilateral cataract surgery was only performed on some patients at the PVAMC, so including both eyes from eligible patients would disproportionately weigh those patients’ outcomes. If both eyes had cataract surgery and their postoperative visual acuities were unequal, we chose the eye with the better postoperative visual acuity since refraction accuracy decreases with worsening best-corrected visual acuity (BCVA). If both eyes had cataract surgery and the postoperative visual acuity was the same, the first operated eye was chosen.^17,18

Exclusion criteria included worse than 20/40 BCVA, posterior capsular rupture, sulcus IOL, history of corneal disease, history of refractive surgery (laser-assisted in situ keratomileusis [LASIK]/photorefractive keratectomy [PRK]), axial length not measurable by the Lenstar optical biometer (Haag-Streit USA), or no postoperative refraction within 3 weeks to 4 months.^19,20

Patient age, race/ethnicity, gender, preoperative refraction, preoperative BCVA, postoperative refraction, postoperative BCVA, and IOL power were recorded from patient charts (Table 1). Preoperative and postoperative refractive values were converted to spherical equivalents. The preoperative biometry and most of the postoperative refractions were performed by experienced technicians certified by the Joint Commission on Allied Health Personnel in Ophthalmology. The main outcomes for the assessment of surgeries included the postoperative BCVA, postoperative spherical equivalent refraction, and postoperative residual refractive astigmatism.

Axial length (AL), preoperative anterior chamber depth (ACD), preoperative flat corneal front power (K1), preoperative steep corneal front power (K2), lens thickness, horizontal white-to-white (WTW) corneal diameter, and central corneal thickness (CCT) were recorded from the Lenstar biometric device. Predicted postoperative refractions for the Holladay 2 formula were calculated using Holladay IOL Consultant software (Holladay Consulting). Predicted postoperative refractions for the Barrett toric IOL formula were calculated using the online Barrett toric formula calculator.²¹ Since previous studies have shown that both the Holladay and Barrett formulae account for posterior corneal astigmatism, a comparison of refractive outcomes in eyes with against-the-rule astigmatism vs with-the-rule astigmatism was not performed.¹⁴ An estimated standardized value for surgically-induced astigmatism was entered into both formulae; 0.3 diopter (D) was chosen based on previously published averages.^22-24

A formula’s prediction error is defined as the predicted postoperative refraction minus the actual postoperative refraction. The mean absolute prediction error (MAE), defined as the mean of the absolute values of the prediction errors, and the median absolute prediction error (MedAE), defined as the median of the absolute values of the prediction errors, were used to assess the overall accuracy of each formula. Also, the percentages of eyes with postoperative refraction within ≥ 0.25 D, ≥ 0.50 D, and ≥ 1.0 D were calculated for both formulae. Two-tailed t tests were performed to compare the MAE between the formulae. Subgroup analyses were performed for short eyes (AL < 22 mm), medium length eyes (AL = 22-25 mm), and long eyes (AL > 25 mm). Statistical analysis was performed using STATA 11 (STATA Corp). The preoperative corneal astigmatism and postoperative refractive astigmatism of all the cases were compared in double-angle plots to assess how well the toric IOL neutralized the corneal astigmatism.

Results

Of 325 charts reviewed during the study period, 34 patients were excluded due to lack of postoperative refraction within the designated follow-up period, 5 for worse than 20/40 postoperative BCVA (4 had preexisting ocular disease), 2 for complications, and 1 for missing data. We included 283 eyes from 283 patients in the final study. Resident ophthalmologists were the primary surgeons in 87.6% (248/283) of the cases.

The median postoperative BCVA was 20/20, and 92% of patients had a postoperative BCVA of 20/25 or better. The prediction outcomes of the toric SN6AT IOLs are shown in Table 2. The Barrett toric formula had a lower MAE than the Holladay 2 formula, but this difference was not statistically significant. The Barrett toric formula also predicted a higher percentage of eyes with postoperative refraction within ≥ 0.25 D (53.2%), ≥ 0.5 D (77.3%), and ≥ 1.0 D (96.1%). For both formulae, > 95% of eyes had prediction errors that fell within 1.0 D.

While the Barrett formula demonstrated a lower MAE in all 3 AL groups, no statistically significant differences were found between the Barrett and Holladay formulae (P = .94, P = .49, and P = .08 for short, medium, and long eyes, respectively). Both formulae produced the lowest MAE in the long AL group: Barrett had a MAE of 0.221 D and Holladay 2 had one of 0.329 D. The Barrett formula produced its highest percentage of eyes with prediction errors falling within 0.25 D and 0.5 D in the long AL group. In comparison, both formulae had the highest MAEs in the short AL group (Barrett toric, 0.598 D; Holladay 2, 0.613 D) and produced the lowest percentage of eyes with prediction errors falling within ≥ 0.25 D and ≥ 0.5 D in the short AL group.

A cumulative histogram of the preoperative corneal and postoperative refractive astigmatism magnitude is shown in Figure 1. The same data are presented as double-angle plots in the Appendix, which shows that the centroid values for preoperative corneal astigmatism were greatlyreduced when compared with the postoperative refractive astigmatism (mean absolute value of 1.77 D ≥ 0.73 D to 0.5 D ≥ 0.50 D).

Preoperative corneal astigmatism and postoperative refractive astigmatism were compared since preoperative refractive astigmatism has noncorneal contributions, including lenticular astigmatism, and there is minimal expected change between preoperative and postoperative corneal astigmatism.¹⁴ For comparison, double-angle plots of postoperative refractive astigmatism prediction errors for the Holladay and Barrett formulae are shown in Figure 2.

Discussion

To our knowledge, this is the largest study of resident-performed cataract surgery using toric IOLs, the largest study that compared the performance of the Barrett toric and Holladay 2 formulae, and the first that compared these formulae in a teaching hospital setting. This study found no significant difference in the predictive accuracy of the Barrett and Holladay 2 biometric formulae for cataract surgery using toric IOLs. In addition, our refractive outcomes were consistent with the results of previous toric IOL outcome studies conducted in teaching and nonteaching hospital settings.^6,10-13

In 4 previous studies that compared the MAE of the Barrett and Holladay formulae for toric IOLs, the Barrett formula produced a lower MAE than the Holladay 2 formula.^7,14-16 However, this difference was significant in only 2 of the studies, which had sample sizes of only 68 and 107 eyes.^14,16 Furthermore, the Barrett toric formula produced the lower MAE for the entire AL range, though this was not statistically significant at our sample size. In addition, both formulae produced the lowest MAE in the long AL group and the highest MAE in the short AL group. The unique anatomy and high IOL power needed in short eyes may explain the challenges in attaining accurate IOL power predictions in this AL group.^19,25

Limitations

The sample size of this study may have prevented us from detecting statistically significant differences in the performance of the Barrett and Holladay formulae. However, our findings are consistent with studies that compare the accuracy of these formulae in teaching and nonteaching hospital settings. Second, the study was conducted at a VA hospital, and a high proportion of patients were male; thus, our findings may not be generalizable to patients who receive cataract surgery with toric IOLs in other settings.

Conclusions

In a single VA teaching hospital, the Barrett and Holladay 2 biometric formulae provide similar refractive predictions for cataract surgery using toric IOLs. Larger studies would be necessary to detect smaller differences in the relative performance of the biometric formulae.

Cataract surgery is one of the most common ambulatory procedures performed in the US.^1-3 With the aging of the US population, the number of Americans with cataracts is projected to increase from 24.4 million in 2010 to 38.7 million in 2030.⁴

Approximately 20% of all cataract patients have preoperative astigmatism of > 1.5 diopters (D), underscoring the importance of training residents in the placement of toric intraocular lenses (IOLs).⁵ However, the implantation of toric IOLs is more challenging than monofocal IOLs, requiring precise surgical alignment of the IOL.⁶ Successful toric IOL implantation also requires accurate calculation of the IOL cylinder power and target axis of alignment. It is unclear which toric IOL calculation formula offers the most accurate refractive predictions, and practitioners have designed strategies to apply different formulae depending on the biometric dimensions of the target eye.^7-9

Previous studies of resident-performed cataract surgery using toric IOLs^6,10-13 and studies that compare the performance of the Barrett and Holladay toric formulae have been limited by their small sample sizes (< 107 eyes).^7,14-16 Moreover, none of the studies that evaluate the comparative effectiveness of these biometric formulae were conducted at a teaching hospital.^7,14-16

Given the added complexity of toric IOL placement and variable surgical experience of residents as ophthalmologists-in-training, it is important to assess outcomes in teaching hospitals.¹³ The primary aims of this study were to assess the visual and refractive outcomes of cataract surgery using toric IOLs in a US Department of Veterans Affairs (VA) teaching hospital and to compare the relative accuracy of the Holladay 2 or Barrett toric biometric formulae in predicting postoperative refraction outcomes.

Methods

The Providence VA Medical Center (PVAMC) Institutional Review Board approved this study. This retrospective chart review included patients with cataract and corneal astigmatism who underwent cataract surgery using Acrysof toric IOLs, model SN6AT (Alcon) at the PVAMC teaching hospital between November 2013 and May 2018.

Only 1 eye was included from each study subject to avoid compounding of data with the use of bilateral eyes.¹⁷ In addition, bilateral cataract surgery was only performed on some patients at the PVAMC, so including both eyes from eligible patients would disproportionately weigh those patients’ outcomes. If both eyes had cataract surgery and their postoperative visual acuities were unequal, we chose the eye with the better postoperative visual acuity since refraction accuracy decreases with worsening best-corrected visual acuity (BCVA). If both eyes had cataract surgery and the postoperative visual acuity was the same, the first operated eye was chosen.^17,18

Exclusion criteria included worse than 20/40 BCVA, posterior capsular rupture, sulcus IOL, history of corneal disease, history of refractive surgery (laser-assisted in situ keratomileusis [LASIK]/photorefractive keratectomy [PRK]), axial length not measurable by the Lenstar optical biometer (Haag-Streit USA), or no postoperative refraction within 3 weeks to 4 months.^19,20

Patient age, race/ethnicity, gender, preoperative refraction, preoperative BCVA, postoperative refraction, postoperative BCVA, and IOL power were recorded from patient charts (Table 1). Preoperative and postoperative refractive values were converted to spherical equivalents. The preoperative biometry and most of the postoperative refractions were performed by experienced technicians certified by the Joint Commission on Allied Health Personnel in Ophthalmology. The main outcomes for the assessment of surgeries included the postoperative BCVA, postoperative spherical equivalent refraction, and postoperative residual refractive astigmatism.

Axial length (AL), preoperative anterior chamber depth (ACD), preoperative flat corneal front power (K1), preoperative steep corneal front power (K2), lens thickness, horizontal white-to-white (WTW) corneal diameter, and central corneal thickness (CCT) were recorded from the Lenstar biometric device. Predicted postoperative refractions for the Holladay 2 formula were calculated using Holladay IOL Consultant software (Holladay Consulting). Predicted postoperative refractions for the Barrett toric IOL formula were calculated using the online Barrett toric formula calculator.²¹ Since previous studies have shown that both the Holladay and Barrett formulae account for posterior corneal astigmatism, a comparison of refractive outcomes in eyes with against-the-rule astigmatism vs with-the-rule astigmatism was not performed.¹⁴ An estimated standardized value for surgically-induced astigmatism was entered into both formulae; 0.3 diopter (D) was chosen based on previously published averages.^22-24

A formula’s prediction error is defined as the predicted postoperative refraction minus the actual postoperative refraction. The mean absolute prediction error (MAE), defined as the mean of the absolute values of the prediction errors, and the median absolute prediction error (MedAE), defined as the median of the absolute values of the prediction errors, were used to assess the overall accuracy of each formula. Also, the percentages of eyes with postoperative refraction within ≥ 0.25 D, ≥ 0.50 D, and ≥ 1.0 D were calculated for both formulae. Two-tailed t tests were performed to compare the MAE between the formulae. Subgroup analyses were performed for short eyes (AL < 22 mm), medium length eyes (AL = 22-25 mm), and long eyes (AL > 25 mm). Statistical analysis was performed using STATA 11 (STATA Corp). The preoperative corneal astigmatism and postoperative refractive astigmatism of all the cases were compared in double-angle plots to assess how well the toric IOL neutralized the corneal astigmatism.

Results

Of 325 charts reviewed during the study period, 34 patients were excluded due to lack of postoperative refraction within the designated follow-up period, 5 for worse than 20/40 postoperative BCVA (4 had preexisting ocular disease), 2 for complications, and 1 for missing data. We included 283 eyes from 283 patients in the final study. Resident ophthalmologists were the primary surgeons in 87.6% (248/283) of the cases.

The median postoperative BCVA was 20/20, and 92% of patients had a postoperative BCVA of 20/25 or better. The prediction outcomes of the toric SN6AT IOLs are shown in Table 2. The Barrett toric formula had a lower MAE than the Holladay 2 formula, but this difference was not statistically significant. The Barrett toric formula also predicted a higher percentage of eyes with postoperative refraction within ≥ 0.25 D (53.2%), ≥ 0.5 D (77.3%), and ≥ 1.0 D (96.1%). For both formulae, > 95% of eyes had prediction errors that fell within 1.0 D.

While the Barrett formula demonstrated a lower MAE in all 3 AL groups, no statistically significant differences were found between the Barrett and Holladay formulae (P = .94, P = .49, and P = .08 for short, medium, and long eyes, respectively). Both formulae produced the lowest MAE in the long AL group: Barrett had a MAE of 0.221 D and Holladay 2 had one of 0.329 D. The Barrett formula produced its highest percentage of eyes with prediction errors falling within 0.25 D and 0.5 D in the long AL group. In comparison, both formulae had the highest MAEs in the short AL group (Barrett toric, 0.598 D; Holladay 2, 0.613 D) and produced the lowest percentage of eyes with prediction errors falling within ≥ 0.25 D and ≥ 0.5 D in the short AL group.

A cumulative histogram of the preoperative corneal and postoperative refractive astigmatism magnitude is shown in Figure 1. The same data are presented as double-angle plots in the Appendix, which shows that the centroid values for preoperative corneal astigmatism were greatlyreduced when compared with the postoperative refractive astigmatism (mean absolute value of 1.77 D ≥ 0.73 D to 0.5 D ≥ 0.50 D).

Preoperative corneal astigmatism and postoperative refractive astigmatism were compared since preoperative refractive astigmatism has noncorneal contributions, including lenticular astigmatism, and there is minimal expected change between preoperative and postoperative corneal astigmatism.¹⁴ For comparison, double-angle plots of postoperative refractive astigmatism prediction errors for the Holladay and Barrett formulae are shown in Figure 2.

Discussion

To our knowledge, this is the largest study of resident-performed cataract surgery using toric IOLs, the largest study that compared the performance of the Barrett toric and Holladay 2 formulae, and the first that compared these formulae in a teaching hospital setting. This study found no significant difference in the predictive accuracy of the Barrett and Holladay 2 biometric formulae for cataract surgery using toric IOLs. In addition, our refractive outcomes were consistent with the results of previous toric IOL outcome studies conducted in teaching and nonteaching hospital settings.^6,10-13

In 4 previous studies that compared the MAE of the Barrett and Holladay formulae for toric IOLs, the Barrett formula produced a lower MAE than the Holladay 2 formula.^7,14-16 However, this difference was significant in only 2 of the studies, which had sample sizes of only 68 and 107 eyes.^14,16 Furthermore, the Barrett toric formula produced the lower MAE for the entire AL range, though this was not statistically significant at our sample size. In addition, both formulae produced the lowest MAE in the long AL group and the highest MAE in the short AL group. The unique anatomy and high IOL power needed in short eyes may explain the challenges in attaining accurate IOL power predictions in this AL group.^19,25

Limitations

The sample size of this study may have prevented us from detecting statistically significant differences in the performance of the Barrett and Holladay formulae. However, our findings are consistent with studies that compare the accuracy of these formulae in teaching and nonteaching hospital settings. Second, the study was conducted at a VA hospital, and a high proportion of patients were male; thus, our findings may not be generalizable to patients who receive cataract surgery with toric IOLs in other settings.

Conclusions

In a single VA teaching hospital, the Barrett and Holladay 2 biometric formulae provide similar refractive predictions for cataract surgery using toric IOLs. Larger studies would be necessary to detect smaller differences in the relative performance of the biometric formulae.

Cataract surgery is one of the most common ambulatory procedures performed in the US.^1-3 With the aging of the US population, the number of Americans with cataracts is projected to increase from 24.4 million in 2010 to 38.7 million in 2030.⁴

Approximately 20% of all cataract patients have preoperative astigmatism of > 1.5 diopters (D), underscoring the importance of training residents in the placement of toric intraocular lenses (IOLs).⁵ However, the implantation of toric IOLs is more challenging than monofocal IOLs, requiring precise surgical alignment of the IOL.⁶ Successful toric IOL implantation also requires accurate calculation of the IOL cylinder power and target axis of alignment. It is unclear which toric IOL calculation formula offers the most accurate refractive predictions, and practitioners have designed strategies to apply different formulae depending on the biometric dimensions of the target eye.^7-9

Previous studies of resident-performed cataract surgery using toric IOLs^6,10-13 and studies that compare the performance of the Barrett and Holladay toric formulae have been limited by their small sample sizes (< 107 eyes).^7,14-16 Moreover, none of the studies that evaluate the comparative effectiveness of these biometric formulae were conducted at a teaching hospital.^7,14-16

Given the added complexity of toric IOL placement and variable surgical experience of residents as ophthalmologists-in-training, it is important to assess outcomes in teaching hospitals.¹³ The primary aims of this study were to assess the visual and refractive outcomes of cataract surgery using toric IOLs in a US Department of Veterans Affairs (VA) teaching hospital and to compare the relative accuracy of the Holladay 2 or Barrett toric biometric formulae in predicting postoperative refraction outcomes.

Methods

The Providence VA Medical Center (PVAMC) Institutional Review Board approved this study. This retrospective chart review included patients with cataract and corneal astigmatism who underwent cataract surgery using Acrysof toric IOLs, model SN6AT (Alcon) at the PVAMC teaching hospital between November 2013 and May 2018.

Only 1 eye was included from each study subject to avoid compounding of data with the use of bilateral eyes.¹⁷ In addition, bilateral cataract surgery was only performed on some patients at the PVAMC, so including both eyes from eligible patients would disproportionately weigh those patients’ outcomes. If both eyes had cataract surgery and their postoperative visual acuities were unequal, we chose the eye with the better postoperative visual acuity since refraction accuracy decreases with worsening best-corrected visual acuity (BCVA). If both eyes had cataract surgery and the postoperative visual acuity was the same, the first operated eye was chosen.^17,18

Exclusion criteria included worse than 20/40 BCVA, posterior capsular rupture, sulcus IOL, history of corneal disease, history of refractive surgery (laser-assisted in situ keratomileusis [LASIK]/photorefractive keratectomy [PRK]), axial length not measurable by the Lenstar optical biometer (Haag-Streit USA), or no postoperative refraction within 3 weeks to 4 months.^19,20

Patient age, race/ethnicity, gender, preoperative refraction, preoperative BCVA, postoperative refraction, postoperative BCVA, and IOL power were recorded from patient charts (Table 1). Preoperative and postoperative refractive values were converted to spherical equivalents. The preoperative biometry and most of the postoperative refractions were performed by experienced technicians certified by the Joint Commission on Allied Health Personnel in Ophthalmology. The main outcomes for the assessment of surgeries included the postoperative BCVA, postoperative spherical equivalent refraction, and postoperative residual refractive astigmatism.

Axial length (AL), preoperative anterior chamber depth (ACD), preoperative flat corneal front power (K1), preoperative steep corneal front power (K2), lens thickness, horizontal white-to-white (WTW) corneal diameter, and central corneal thickness (CCT) were recorded from the Lenstar biometric device. Predicted postoperative refractions for the Holladay 2 formula were calculated using Holladay IOL Consultant software (Holladay Consulting). Predicted postoperative refractions for the Barrett toric IOL formula were calculated using the online Barrett toric formula calculator.²¹ Since previous studies have shown that both the Holladay and Barrett formulae account for posterior corneal astigmatism, a comparison of refractive outcomes in eyes with against-the-rule astigmatism vs with-the-rule astigmatism was not performed.¹⁴ An estimated standardized value for surgically-induced astigmatism was entered into both formulae; 0.3 diopter (D) was chosen based on previously published averages.^22-24

A formula’s prediction error is defined as the predicted postoperative refraction minus the actual postoperative refraction. The mean absolute prediction error (MAE), defined as the mean of the absolute values of the prediction errors, and the median absolute prediction error (MedAE), defined as the median of the absolute values of the prediction errors, were used to assess the overall accuracy of each formula. Also, the percentages of eyes with postoperative refraction within ≥ 0.25 D, ≥ 0.50 D, and ≥ 1.0 D were calculated for both formulae. Two-tailed t tests were performed to compare the MAE between the formulae. Subgroup analyses were performed for short eyes (AL < 22 mm), medium length eyes (AL = 22-25 mm), and long eyes (AL > 25 mm). Statistical analysis was performed using STATA 11 (STATA Corp). The preoperative corneal astigmatism and postoperative refractive astigmatism of all the cases were compared in double-angle plots to assess how well the toric IOL neutralized the corneal astigmatism.

Results

Of 325 charts reviewed during the study period, 34 patients were excluded due to lack of postoperative refraction within the designated follow-up period, 5 for worse than 20/40 postoperative BCVA (4 had preexisting ocular disease), 2 for complications, and 1 for missing data. We included 283 eyes from 283 patients in the final study. Resident ophthalmologists were the primary surgeons in 87.6% (248/283) of the cases.

The median postoperative BCVA was 20/20, and 92% of patients had a postoperative BCVA of 20/25 or better. The prediction outcomes of the toric SN6AT IOLs are shown in Table 2. The Barrett toric formula had a lower MAE than the Holladay 2 formula, but this difference was not statistically significant. The Barrett toric formula also predicted a higher percentage of eyes with postoperative refraction within ≥ 0.25 D (53.2%), ≥ 0.5 D (77.3%), and ≥ 1.0 D (96.1%). For both formulae, > 95% of eyes had prediction errors that fell within 1.0 D.

While the Barrett formula demonstrated a lower MAE in all 3 AL groups, no statistically significant differences were found between the Barrett and Holladay formulae (P = .94, P = .49, and P = .08 for short, medium, and long eyes, respectively). Both formulae produced the lowest MAE in the long AL group: Barrett had a MAE of 0.221 D and Holladay 2 had one of 0.329 D. The Barrett formula produced its highest percentage of eyes with prediction errors falling within 0.25 D and 0.5 D in the long AL group. In comparison, both formulae had the highest MAEs in the short AL group (Barrett toric, 0.598 D; Holladay 2, 0.613 D) and produced the lowest percentage of eyes with prediction errors falling within ≥ 0.25 D and ≥ 0.5 D in the short AL group.

A cumulative histogram of the preoperative corneal and postoperative refractive astigmatism magnitude is shown in Figure 1. The same data are presented as double-angle plots in the Appendix, which shows that the centroid values for preoperative corneal astigmatism were greatlyreduced when compared with the postoperative refractive astigmatism (mean absolute value of 1.77 D ≥ 0.73 D to 0.5 D ≥ 0.50 D).

Preoperative corneal astigmatism and postoperative refractive astigmatism were compared since preoperative refractive astigmatism has noncorneal contributions, including lenticular astigmatism, and there is minimal expected change between preoperative and postoperative corneal astigmatism.¹⁴ For comparison, double-angle plots of postoperative refractive astigmatism prediction errors for the Holladay and Barrett formulae are shown in Figure 2.

Discussion

To our knowledge, this is the largest study of resident-performed cataract surgery using toric IOLs, the largest study that compared the performance of the Barrett toric and Holladay 2 formulae, and the first that compared these formulae in a teaching hospital setting. This study found no significant difference in the predictive accuracy of the Barrett and Holladay 2 biometric formulae for cataract surgery using toric IOLs. In addition, our refractive outcomes were consistent with the results of previous toric IOL outcome studies conducted in teaching and nonteaching hospital settings.^6,10-13

In 4 previous studies that compared the MAE of the Barrett and Holladay formulae for toric IOLs, the Barrett formula produced a lower MAE than the Holladay 2 formula.^7,14-16 However, this difference was significant in only 2 of the studies, which had sample sizes of only 68 and 107 eyes.^14,16 Furthermore, the Barrett toric formula produced the lower MAE for the entire AL range, though this was not statistically significant at our sample size. In addition, both formulae produced the lowest MAE in the long AL group and the highest MAE in the short AL group. The unique anatomy and high IOL power needed in short eyes may explain the challenges in attaining accurate IOL power predictions in this AL group.^19,25

Limitations

The sample size of this study may have prevented us from detecting statistically significant differences in the performance of the Barrett and Holladay formulae. However, our findings are consistent with studies that compare the accuracy of these formulae in teaching and nonteaching hospital settings. Second, the study was conducted at a VA hospital, and a high proportion of patients were male; thus, our findings may not be generalizable to patients who receive cataract surgery with toric IOLs in other settings.

Conclusions

In a single VA teaching hospital, the Barrett and Holladay 2 biometric formulae provide similar refractive predictions for cataract surgery using toric IOLs. Larger studies would be necessary to detect smaller differences in the relative performance of the biometric formulae.

The nature of combat and associated injuries in Operation Iraqi Freedom (OIF), Operation Enduring Freedom (OEF), Operation New Dawn (OND), and Afghanistan War is different from previous conflicts. Multiple protracted deployments with infrequent breaks after September 11, 2001 (9/11) have further compounded the problem.

Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are the signature wounds of recent wars, with a higher incidence among the veterans of OEF and OIF compared with those from previous conflicts.^1,2 More than 2.7 million who served in Iraq and Afghanistan suffer from PTSD.^3,4 Symptoms of PTSD may appear within the first 3 months after exposure to a traumatic event or after many months and, in some cases, after a delay of many years and continue for life.⁵ Although delayed onset of PTSD in the absence of prior symptoms is rare,^6,7 its incidence rises with increasing frequency of exposure to traumatic events^8,9 and over time.¹⁰

According to the Brain Injury Association of America, TBI is “an alteration in brain function, or other evidence of brain pathology, caused by an external force.”⁸ TBI is often associated with increased risk of PTSD, depression, and posttraumatic headache,^11-13 which may lead to broader cognitive, somatic, neurobiological, and psychosocial dysfunctions.^14-17 According to Veterans Health Administration (VHA) data, 201,435 veterans from all eras enrolled with the US Department of Veterans Affairs (VA) have a diagnosis associated with TBI and 56,695 OEF/OIF veterans have been evaluated for a TBI-related condition.² According to the Defense and Veterans Brain Injury Center (DVBIC), > 361,000 veterans have been diagnosed with TBI, with a peak of 32,000 cases in 2011.^1,18 Moreover, the reported incidence and prevalence of PTSD and TBI among US veterans are not consistent. The incidence of PTSD has been estimated at 15% to 20% in recent wars^3,19 compared with 10% to 30% in previous wars.^3,19,20

When PTSD or TBI is deemed “related” to military service, the veteran may receive a service-connected disability rating ranging from 0% (no life-interfering symptoms due to injury) to 100% (totally disabling injury). The percentage of service connection associated with an injury is a quantifiable measure of the debilitating effect of injury on the individual. A significant majority (94%) of those who seek mental health services and treatment at VHA clinics apply for PTSD-related disability benefits.²¹ The estimated cost related to PTSD/TBI service-connected pensions is $20.28 billion per year and approximately $514 billion over 50 years.²² The cost of VA and Social Security disability payments combined with health care costs and treatment of PTSD is estimated to exceed $1 trillion over the next 30 years.²²

The National Vietnam Veterans Readjustment Study (NVVRS) provided valuable information on prevalence rates of PTSD and other postwar psychological problems.²³ Meanwhile, there have been no recent large-scale studies to compare the demographics of veterans diagnosed with PTSD and TBI who served prior to and after 9/11. A better understanding of demographic changes is considered essential for designing and tailoring therapeutic interventions to manage the rising cost.²²

The present study focused on identifying changing trends in the demographics of veterans who served prior to and after 9/11 and who received a VA inpatient or outpatient diagnosis of PTSD and/or TBI. Specifically, this study addressed the changes in demographics of veterans with PTSD, TBI, or PTSD+TBI seen at the VHA clinics between December 1,1998 and May 31, 2014 (before and after September 11, 2001) for diagnosis, treatment and health care policy issues.

Methods

This study was approved by the Kansas City VA Medical Center Institutional Review Board. VHA data from the Corporate Data Warehouse (CDW) and the National Patient Care Database were extracted using the VA Informatics and Computing Infrastructure (VINCI) workspace. CDW uses a unique identifier to identify veterans across treatment episodes at more than 1,400 VHA centers organized under 21 Veterans Integrated Service Networks (VISNs). These sources of VA data are widely used for retrospective longitudinal studies.

Study Population

The study population consisted of 1,339,937 veterans with a VA inpatient/outpatient diagnosis of PTSD or TBI using International Statistical Classification of Diseases and Related Health Problems, Ninth Revision (ICD-9) codes between December 1, 1998 and May 31, 2014. Demographic (gender classification, race, ethnicity, marital status, age at date of data extraction, and date of death if indicated), service-connection disability rating, and geographic distribution within VISN data on each veteran were then extracted.

Veterans in the cohort were assigned to 1 of 4 US military services period groups. The pre-9/11 group included veterans who entered and left the military prior to September 11, 2001. This group mostly included veterans from World War II, Korean War, Vietnam War, and the first Gulf War (1990-1991). The post-9/11 group included veterans who first entered military services after September 11, 2001. The overlap group included veterans who entered military services prior to 9/11, remained in service and left after September 11, 2001. The reentered group included veterans who entered and left service prior to September 11, 2001, and then reentered military service after September 11, 2001 (Figure 1). Using ICD-9 codes, veterans also were placed into the following categories: PTSD alone (ICD-9 309.81 only), TBI alone (ICD-9 850.0-859.9, V15.52), and PTSD+TBI (any combination of ICD-9 codes from the other categories).

Statistical Analysis 

Descriptive statistics were applied using proportions and means. Relationships between variables were examined using χ² tests, t tests, analysis of variance, and nonparametric tests. All hypotheses were 2-sided at 95% CI. Results are presented as absolute numbers.

Results

PTSD only (n = 1,132,356, 85%) was the predominant diagnosis category followed by PTSD+TBI (n = 106,792, 8%) and TBI only (n = 100,789, 7%) (Figure 2). Most of the veterans in the study served pre-9/11 (77%), followed by post-9/11 (15%); 7% were in the overlap group, and 1% in the reentered group (Table 1). It is notable that the proportion of veterans diagnosed with PTSD decreased from pre-9/11 (88%) to post-9/11 (71%), overlap (77%), and reentered (74%) service periods. Increases were noted in those with PTSD+TBI diagnosis category from pre-9/11 (4%) to post-9/11 (23%), overlap (17%), and reentered (22%) service periods (Figure 3). In general, the relative distribution of diagnostic categories in all the service periods showed a similar trend, with the majority of veterans diagnosed with PTSD only. Across all service periods, significantly smaller proportions of veterans were diagnosed with TBI only (P < .001).

Distribution by Gender and Age

The cohort was 92% male (n = 1,239,295), but there was a marked increase in the percentage of nonmale veterans in post-9/11 groups. Study population ages ranged from 18 to 99 years based on date of birth to the date data were obtained; or date of birth to date of death, for those who were reported deceased at the time the data were obtained. The average (SD) ages for veterans in the pre-9/11 group were significantly older (66.3 [11.2] years) compared with the ages of veterans in the post-9/11 group (36.1 [8.7] years), the overlap group (41.4 [8.2] years), and the reentered group (46.9 [9.2] years), respectively.

Distribution by Race and Marital Status

The cohort identified as 65.7% white and 18.2% African American with much smaller percentages of Asians, American Indian/Alaska Natives (AI/AN) and Native Hawaiian/Pacific Islanders (Table 2). The relative proportion of AI/AN and Native Hawaiian/Pacific Islanders remained constant across all groups, whereas the number of Asians diagnosed with PTSD, TBI, or PTSD+TBI increased in the post-9/11 group. The number of African Americans diagnosed with PTSD, TBI, or both markedly increased in the overlap and reentered groups when compared with the pre-9/11 group, yet it went down in the post-9/11/group.

Half the cohort identified themselves as married (n = 675,145) (Table 3). A slightly larger proportion of those diagnosed with PTSD alone were married (51.7%), compared with those diagnosed with TBI only (40.3%), or PTSD+TBI (45.8%). Veterans in the post-9/11 group were less likely to identify as married (45.2%) compared with the pre-9/11 (51.2%), overlap (52.6%), or reentered (53.2%) groups. Divorce rates among pre-9/11 group, overlap group, and reentered group were higher compared with that of the post-9/11 group in all diagnosis categories.

Geographic Distribution

Veterans diagnosed with PTSD, TBI, or both were not evenly distributed across the VISNs VISNs 7, 8, 10, and 22 treated the most veterans, whereas VISN 9 and 15 treated the fewest. Taken together, the top 3 VISNs accounted for 27% to 28% of the total while lowest 3 accounted for 8% to 9% of the total cohort.

Service-Connected Disability

Of 1,339,937 veterans in the cohort, 1,067,691 had a service-connected disability rating for PTSD and/or TBI. Most were diagnosed with PTSD (n = 923,523, 86.5%) followed by both PTSD+TBI (n = 94,051, 8.8%). Three-quarters of the veterans with a service-connected disability were in the pre-9/11 group. Nearly 80% of veterans with a service-connected disability rating had a rating of > 50%. The average (SD) age of veterans with PTSD+TBI and a > 50% service-connected disability was 66.3 (11.2) years in the pre-9/11 group compared with 36.1 (8.7) years in the post-9/11 group.

Discussion

The demographic profile of veterans diagnosed with PTSD+TBI has changed across the service periods covered in this study. Compared with pre-9/11 veterans, the post-9/11 cohort: (1) higher percentage were diagnosed with PTSD+TBI; (2) higher proportion were nonmale veterans; (3) included more young veterans with > 50% service-connected disability; (4) were more racially diverse; and (5) were less likely to be married and divorced and more likely to be self-identified as single. Additionally, data revealed that veterans tended to locate more to some geographic regions than to others.

The nature of the warfare has changed remarkably over the past few decades. Gunshot wounds accounted for 65% of all injuries in World War I, 35% during Vietnam War, and 16% to 23% in the First Gulf War.²⁴ In post-9/11 military conflicts, 81% of injuries were explosion related.^24,25 Although improvements in personal protective gear and battlefield trauma care led to increased survival, several factors may have contributed to increased reporting of TBI, which peaked in 2011 at 32,000 cases.^24-26

Increases in PTSD Diagnosis

Increasing media awareness, mandatory battlefield concussion screening programs instituted by the US Department of Defense (DoD), and stressful conditions that exacerbate mild TBI (mTBI) may have all contributed to the increase in numbers of veterans seeking evaluations and being diagnosed with PTSD and/or TBI in the post-9/11 groups. Additionally, the 2007 National Defense Authorization Act requested the Secretary of Defense to develop a comprehensive, systematic approach for the identification, treatment, disposition, and documentation of TBI in combat and peacetime. By a conservative estimate, significant numbers of veterans will continue to be seen for mTBI at about 20,000 new cases per year.^25-27

More frequent diagnosis of mTBI may have contributed to the increase in veterans diagnosed with PTSD+TBI in the post-9/11 groups. A recent study found that almost 44% of US Army infantry soldiers in Iraq did not lose consciousness but reported symptoms consistent with TBI.¹⁴ Compared with veterans of previous wars, veterans of the post-9/11 conflicts (OIF, OED, and OND) have experienced multiple, protracted deployments with infrequent breaks that can have a cumulative effect on the development of PTSD.^8-10

The findings from the NVVRS study led to creation of specialized PTSD programs in the late 1980s. Since then, there has been an explosion of knowledge and awareness about PTSD, TBI, and the associated service-connected disability ratings and benefits, leading to an increased number of veterans seeking care for PTSD. For example, media coverage of the 50th anniversary of the D-day celebrations resulted in a surge of World War II veterans seeking treatment for PTSD and a surge of Vietnam veterans sought treatment for PTSD during the wars in Iraq and Afghanistan.²⁸ An increased number of veterans reporting PTSD symptoms prompted the DoD to increase screening for PTSD, and to encourage service members to seek treatment when appropriate.

The VA has instituted training programs for clinicians and psychologists to screen and provide care for PTSD. Beginning in 2007, the VA implemented mandatory TBI screening for all veterans who served in combat operations and separated from active-duty service after September 11, 2001. The 4-question screen identifies veterans who are at increased risk of TBI and who experience symptoms that may be related to specific event(s).²⁹ A positive screen does not diagnose TBI but rather indicates a need for further evaluation, which may or may not be responsible for inflated reporting of TBI. Renewed research also has led providers to recognize and study PTSD resulting from noncombat trauma and moral injury. The possibility of delayed onset also drives up the number of veterans diagnosed with PTSD.^5-7

Prevalence

A wide variability exists in the reported prevalence of PTSD among US war veterans with estimates ranging from 15% to 20% of veterans from recent conflicts^3,20 and 10% to 30% of veterans from previous wars.^3,19 These rates are higher than estimates from allied forces from other countries.¹⁹ Meta-analyses suggest that the prevalence of PTSD is 2% to 15% among Vietnam War veterans, 1% to 13% among first (pre-9/11) Gulf War veterans, 4% to 17% among OEF/OIF/OND veterans; these veterans have a lifetime prevalence of 6% to 31%.^{3,11,19,30-38} The prevalence of PTSD is 2 to 4 times higher among the US veterans^19,39 when compared with that of civilians.^40,41 According to one study, concomitant PTSD and TBI appears to be much higher in US war veterans (4%-17%) compared with United Kingdom Iraq War veterans (3%-6%).¹⁹

This study’s finding of an increase in nonmale soldiers with PTSD and/or TBI was not surprising. There is a paucity of data on the effect of war zone exposure on women veterans. Recently, women have been more actively involved in combat roles with 41,000 women deployed to a combat zone. Results of this study indicate a 2- to 3-fold increase in veterans identifying themselves as nonmale in post-9/11 groups with a higher proportion diagnosed with either PTSD alone or PTSD and TBI. Women are at a higher risk for PTSD than are men due in part to exposure to abuse/trauma prior to deployment, experience of higher rates of discrimination, and/or sexual assault.^31-33 One study involving First Gulf War female veterans reported higher precombat psychiatric histories as well as higher rates of physical and sexual abuse when compared with that of men.³¹

In this study, the average age of veterans adjudicated and compensated for PTSD and/or TBI pre-9/11, was 66 years compared with 36 years for post-9/11 veterans. Sixty-six percent of veterans from the post-9/11 group had ≥ 50% service-connected disability at age 36 years; 75% of veterans from the overlap group had ≥ 50% service-connected disability at age 41 years; and 76% veterans from the reentered group had ≥ 50% service-connected disability at age 46 years. Younger age at diagnosis and higher rates of disability not only pose unique challenges for veterans and family members, but also suggest implications for career prospects, family earnings, loss of productivity, and disease-adjusted life years. Also noted in the results, this younger cohort has a higher percentage of single/unmarried veterans, suggesting familial support systems may be more parental than spousal. Treatment for this younger cohort will likely need to focus on early and sustained rehabilitation that can be integrated with career plans.

For treatment to be effective, there must be evidence for veterans enrolling, remaining, and reporting benefits from the treatment. Limited research has shown currently advocated evidence-based therapies to have low enrollment rates, high drop-out rates, and mixed outcomes.⁴²

Results showing a gradual increase in the proportion of nonwhite, non-African American veterans diagnosed with PTSD alone, TBI alone, or both, likely reflect the changing demographic profile of the US as well as the Army. However, the reason that more African Americans were diagnosed with PTSD and/or TBI in the overlap and reentered groups when compared with the pre-9/11 group could not be ascertained. It is possible that more veterans identified themselves as African Americans as evident from a decrease in the number of veterans in the unknown category post-9/11 when compared with the pre-9/11 group. In 2016, the American Community Survey showed that Hispanic and African American veterans were more likely to use VA health care and other benefits than were any other racial group.⁴⁰ Improved screening for PTSD and TBI diagnoses, increased awareness, and education about the availability of VA services and benefits may have contributed to the increased use of VA benefits in these groups.

Data from this study are concordant with data from the National Center for Veterans Analysis and Statistics reporting on the younger age of diagnosis and higher rates of initial service-connected disability in veterans with PTSD and PTSD+TBI.⁴³ One study analyzing records from 1999 to 2004 showed that the number of PTSD cases grew by 79.5%, resulting in 148.7% increase in benefits payment from $1.7 billion to $4.3 billion per year.⁴⁴ In contrast, the compensation cost for all other disability categories increased by only 41.7% over this period. This study also revealed that while veterans with PTSD represented only 8.7% of compensation recipients, they received 20.5% of all compensation payments, driven in large part by an increase in > 50% service-connected disability ratings.⁴⁴

Thus, from financial as well as treatment points of view, the change in the demographic profile of the veteran must be considered when developing PTSD treatment strategies. While treatment in the past focused solely on addressing trauma-associated psychiatric issues, TBI and PTSD association will likely shift the focus to concurrent psychiatric and physical symptomology. Similarly, PTSD/TBI treatment modalities must consider that the profile of post-9/11 service members includes more women, younger age, and a greater racial diversity. For instance, younger age for a disabled veteran brings additional challenges, including reliance on parental or buddy support systems vs a spousal support system, integrating career with treatment, selecting geographic locations that can support both career and treatment, sustaining rehabilitation over time. The treatment needs of a 35-year-old soldier with PTSD and/or TBI, whether male or female, Asian or African American are likely to be very different from the treatment needs of a 65-year-old white male. Newer treatment approaches will have to address the needs of all soldiers.

Limitations

Our study may underestimate the actual PTSD and/or TBI disease burden because of the social stigma associated with diagnosis, military culture, limitations in data collection.^45-50 In addition, in this retrospective database cohort study, we considered and tried to minimize the impact of any of the usual potential limitations, including (1) accuracy of data quality and linkage; (2) identifying cohort appropriately (study groups); (3) defining endpoints clearly to avoid misclassifications; and (4) incorporating all important confounders. We identified veterans utilizing medical services at VA hospitals during a defined period and diagnosed with PTSD and TBI using ICD-9 codes and divided in 4 well-defined groups. In addition, another limitation of our study is to not accurately capture the veterans who have alternative health coverage and may choose not to enroll and/or participate in VA health care. In addition, some service members leaving war zones may not disclose or downplay the mental health symptoms to avoid any delay in their return home.

Conclusions

This study highlights the changing profile of the soldier diagnosed with PTSD and/or TBI who served pre-9/11 compared with that of those who served post-9/11. Treatment modalities must address the changes in warfare and demographics of US service members. Future treatment will need to focus more on concurrent PTSD/TBI therapies, the needs of younger soldiers, the needs of women injured in combat, and the needs of a more racially and ethnically diverse population. Severe injuries at a younger age will require early detection and rehabilitation for return to optimum functioning over a lifetime. The current study underscores a need for identifying the gaps in ongoing programs and services, developing alternatives, and implementing improved systems of care. More studies are needed to identify the cost implications and the effectiveness of current therapies for PTSD and/or TBI.

Acknowledgments

This study was supported by VA Medical Center and Midwest BioMedical Research Foundation (MBRF), Kansas City, Missouri. The manuscript received support, in part, from NIH-RO1 DK107490. These agencies did not participate in the design/conduct of the study or, in the interpretation of the data.

The nature of combat and associated injuries in Operation Iraqi Freedom (OIF), Operation Enduring Freedom (OEF), Operation New Dawn (OND), and Afghanistan War is different from previous conflicts. Multiple protracted deployments with infrequent breaks after September 11, 2001 (9/11) have further compounded the problem.

Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are the signature wounds of recent wars, with a higher incidence among the veterans of OEF and OIF compared with those from previous conflicts.^1,2 More than 2.7 million who served in Iraq and Afghanistan suffer from PTSD.^3,4 Symptoms of PTSD may appear within the first 3 months after exposure to a traumatic event or after many months and, in some cases, after a delay of many years and continue for life.⁵ Although delayed onset of PTSD in the absence of prior symptoms is rare,^6,7 its incidence rises with increasing frequency of exposure to traumatic events^8,9 and over time.¹⁰

According to the Brain Injury Association of America, TBI is “an alteration in brain function, or other evidence of brain pathology, caused by an external force.”⁸ TBI is often associated with increased risk of PTSD, depression, and posttraumatic headache,^11-13 which may lead to broader cognitive, somatic, neurobiological, and psychosocial dysfunctions.^14-17 According to Veterans Health Administration (VHA) data, 201,435 veterans from all eras enrolled with the US Department of Veterans Affairs (VA) have a diagnosis associated with TBI and 56,695 OEF/OIF veterans have been evaluated for a TBI-related condition.² According to the Defense and Veterans Brain Injury Center (DVBIC), > 361,000 veterans have been diagnosed with TBI, with a peak of 32,000 cases in 2011.^1,18 Moreover, the reported incidence and prevalence of PTSD and TBI among US veterans are not consistent. The incidence of PTSD has been estimated at 15% to 20% in recent wars^3,19 compared with 10% to 30% in previous wars.^3,19,20

When PTSD or TBI is deemed “related” to military service, the veteran may receive a service-connected disability rating ranging from 0% (no life-interfering symptoms due to injury) to 100% (totally disabling injury). The percentage of service connection associated with an injury is a quantifiable measure of the debilitating effect of injury on the individual. A significant majority (94%) of those who seek mental health services and treatment at VHA clinics apply for PTSD-related disability benefits.²¹ The estimated cost related to PTSD/TBI service-connected pensions is $20.28 billion per year and approximately $514 billion over 50 years.²² The cost of VA and Social Security disability payments combined with health care costs and treatment of PTSD is estimated to exceed $1 trillion over the next 30 years.²²

The National Vietnam Veterans Readjustment Study (NVVRS) provided valuable information on prevalence rates of PTSD and other postwar psychological problems.²³ Meanwhile, there have been no recent large-scale studies to compare the demographics of veterans diagnosed with PTSD and TBI who served prior to and after 9/11. A better understanding of demographic changes is considered essential for designing and tailoring therapeutic interventions to manage the rising cost.²²

The present study focused on identifying changing trends in the demographics of veterans who served prior to and after 9/11 and who received a VA inpatient or outpatient diagnosis of PTSD and/or TBI. Specifically, this study addressed the changes in demographics of veterans with PTSD, TBI, or PTSD+TBI seen at the VHA clinics between December 1,1998 and May 31, 2014 (before and after September 11, 2001) for diagnosis, treatment and health care policy issues.

Methods

This study was approved by the Kansas City VA Medical Center Institutional Review Board. VHA data from the Corporate Data Warehouse (CDW) and the National Patient Care Database were extracted using the VA Informatics and Computing Infrastructure (VINCI) workspace. CDW uses a unique identifier to identify veterans across treatment episodes at more than 1,400 VHA centers organized under 21 Veterans Integrated Service Networks (VISNs). These sources of VA data are widely used for retrospective longitudinal studies.

Study Population

The study population consisted of 1,339,937 veterans with a VA inpatient/outpatient diagnosis of PTSD or TBI using International Statistical Classification of Diseases and Related Health Problems, Ninth Revision (ICD-9) codes between December 1, 1998 and May 31, 2014. Demographic (gender classification, race, ethnicity, marital status, age at date of data extraction, and date of death if indicated), service-connection disability rating, and geographic distribution within VISN data on each veteran were then extracted.

Veterans in the cohort were assigned to 1 of 4 US military services period groups. The pre-9/11 group included veterans who entered and left the military prior to September 11, 2001. This group mostly included veterans from World War II, Korean War, Vietnam War, and the first Gulf War (1990-1991). The post-9/11 group included veterans who first entered military services after September 11, 2001. The overlap group included veterans who entered military services prior to 9/11, remained in service and left after September 11, 2001. The reentered group included veterans who entered and left service prior to September 11, 2001, and then reentered military service after September 11, 2001 (Figure 1). Using ICD-9 codes, veterans also were placed into the following categories: PTSD alone (ICD-9 309.81 only), TBI alone (ICD-9 850.0-859.9, V15.52), and PTSD+TBI (any combination of ICD-9 codes from the other categories).

Statistical Analysis 

Descriptive statistics were applied using proportions and means. Relationships between variables were examined using χ² tests, t tests, analysis of variance, and nonparametric tests. All hypotheses were 2-sided at 95% CI. Results are presented as absolute numbers.

Results

PTSD only (n = 1,132,356, 85%) was the predominant diagnosis category followed by PTSD+TBI (n = 106,792, 8%) and TBI only (n = 100,789, 7%) (Figure 2). Most of the veterans in the study served pre-9/11 (77%), followed by post-9/11 (15%); 7% were in the overlap group, and 1% in the reentered group (Table 1). It is notable that the proportion of veterans diagnosed with PTSD decreased from pre-9/11 (88%) to post-9/11 (71%), overlap (77%), and reentered (74%) service periods. Increases were noted in those with PTSD+TBI diagnosis category from pre-9/11 (4%) to post-9/11 (23%), overlap (17%), and reentered (22%) service periods (Figure 3). In general, the relative distribution of diagnostic categories in all the service periods showed a similar trend, with the majority of veterans diagnosed with PTSD only. Across all service periods, significantly smaller proportions of veterans were diagnosed with TBI only (P < .001).

Distribution by Gender and Age

The cohort was 92% male (n = 1,239,295), but there was a marked increase in the percentage of nonmale veterans in post-9/11 groups. Study population ages ranged from 18 to 99 years based on date of birth to the date data were obtained; or date of birth to date of death, for those who were reported deceased at the time the data were obtained. The average (SD) ages for veterans in the pre-9/11 group were significantly older (66.3 [11.2] years) compared with the ages of veterans in the post-9/11 group (36.1 [8.7] years), the overlap group (41.4 [8.2] years), and the reentered group (46.9 [9.2] years), respectively.

Distribution by Race and Marital Status

The cohort identified as 65.7% white and 18.2% African American with much smaller percentages of Asians, American Indian/Alaska Natives (AI/AN) and Native Hawaiian/Pacific Islanders (Table 2). The relative proportion of AI/AN and Native Hawaiian/Pacific Islanders remained constant across all groups, whereas the number of Asians diagnosed with PTSD, TBI, or PTSD+TBI increased in the post-9/11 group. The number of African Americans diagnosed with PTSD, TBI, or both markedly increased in the overlap and reentered groups when compared with the pre-9/11 group, yet it went down in the post-9/11/group.

Half the cohort identified themselves as married (n = 675,145) (Table 3). A slightly larger proportion of those diagnosed with PTSD alone were married (51.7%), compared with those diagnosed with TBI only (40.3%), or PTSD+TBI (45.8%). Veterans in the post-9/11 group were less likely to identify as married (45.2%) compared with the pre-9/11 (51.2%), overlap (52.6%), or reentered (53.2%) groups. Divorce rates among pre-9/11 group, overlap group, and reentered group were higher compared with that of the post-9/11 group in all diagnosis categories.

Geographic Distribution

Veterans diagnosed with PTSD, TBI, or both were not evenly distributed across the VISNs VISNs 7, 8, 10, and 22 treated the most veterans, whereas VISN 9 and 15 treated the fewest. Taken together, the top 3 VISNs accounted for 27% to 28% of the total while lowest 3 accounted for 8% to 9% of the total cohort.

Service-Connected Disability

Of 1,339,937 veterans in the cohort, 1,067,691 had a service-connected disability rating for PTSD and/or TBI. Most were diagnosed with PTSD (n = 923,523, 86.5%) followed by both PTSD+TBI (n = 94,051, 8.8%). Three-quarters of the veterans with a service-connected disability were in the pre-9/11 group. Nearly 80% of veterans with a service-connected disability rating had a rating of > 50%. The average (SD) age of veterans with PTSD+TBI and a > 50% service-connected disability was 66.3 (11.2) years in the pre-9/11 group compared with 36.1 (8.7) years in the post-9/11 group.

Discussion

The demographic profile of veterans diagnosed with PTSD+TBI has changed across the service periods covered in this study. Compared with pre-9/11 veterans, the post-9/11 cohort: (1) higher percentage were diagnosed with PTSD+TBI; (2) higher proportion were nonmale veterans; (3) included more young veterans with > 50% service-connected disability; (4) were more racially diverse; and (5) were less likely to be married and divorced and more likely to be self-identified as single. Additionally, data revealed that veterans tended to locate more to some geographic regions than to others.

The nature of the warfare has changed remarkably over the past few decades. Gunshot wounds accounted for 65% of all injuries in World War I, 35% during Vietnam War, and 16% to 23% in the First Gulf War.²⁴ In post-9/11 military conflicts, 81% of injuries were explosion related.^24,25 Although improvements in personal protective gear and battlefield trauma care led to increased survival, several factors may have contributed to increased reporting of TBI, which peaked in 2011 at 32,000 cases.^24-26

Increases in PTSD Diagnosis

Increasing media awareness, mandatory battlefield concussion screening programs instituted by the US Department of Defense (DoD), and stressful conditions that exacerbate mild TBI (mTBI) may have all contributed to the increase in numbers of veterans seeking evaluations and being diagnosed with PTSD and/or TBI in the post-9/11 groups. Additionally, the 2007 National Defense Authorization Act requested the Secretary of Defense to develop a comprehensive, systematic approach for the identification, treatment, disposition, and documentation of TBI in combat and peacetime. By a conservative estimate, significant numbers of veterans will continue to be seen for mTBI at about 20,000 new cases per year.^25-27

More frequent diagnosis of mTBI may have contributed to the increase in veterans diagnosed with PTSD+TBI in the post-9/11 groups. A recent study found that almost 44% of US Army infantry soldiers in Iraq did not lose consciousness but reported symptoms consistent with TBI.¹⁴ Compared with veterans of previous wars, veterans of the post-9/11 conflicts (OIF, OED, and OND) have experienced multiple, protracted deployments with infrequent breaks that can have a cumulative effect on the development of PTSD.^8-10

The findings from the NVVRS study led to creation of specialized PTSD programs in the late 1980s. Since then, there has been an explosion of knowledge and awareness about PTSD, TBI, and the associated service-connected disability ratings and benefits, leading to an increased number of veterans seeking care for PTSD. For example, media coverage of the 50th anniversary of the D-day celebrations resulted in a surge of World War II veterans seeking treatment for PTSD and a surge of Vietnam veterans sought treatment for PTSD during the wars in Iraq and Afghanistan.²⁸ An increased number of veterans reporting PTSD symptoms prompted the DoD to increase screening for PTSD, and to encourage service members to seek treatment when appropriate.

The VA has instituted training programs for clinicians and psychologists to screen and provide care for PTSD. Beginning in 2007, the VA implemented mandatory TBI screening for all veterans who served in combat operations and separated from active-duty service after September 11, 2001. The 4-question screen identifies veterans who are at increased risk of TBI and who experience symptoms that may be related to specific event(s).²⁹ A positive screen does not diagnose TBI but rather indicates a need for further evaluation, which may or may not be responsible for inflated reporting of TBI. Renewed research also has led providers to recognize and study PTSD resulting from noncombat trauma and moral injury. The possibility of delayed onset also drives up the number of veterans diagnosed with PTSD.^5-7

Prevalence

A wide variability exists in the reported prevalence of PTSD among US war veterans with estimates ranging from 15% to 20% of veterans from recent conflicts^3,20 and 10% to 30% of veterans from previous wars.^3,19 These rates are higher than estimates from allied forces from other countries.¹⁹ Meta-analyses suggest that the prevalence of PTSD is 2% to 15% among Vietnam War veterans, 1% to 13% among first (pre-9/11) Gulf War veterans, 4% to 17% among OEF/OIF/OND veterans; these veterans have a lifetime prevalence of 6% to 31%.^{3,11,19,30-38} The prevalence of PTSD is 2 to 4 times higher among the US veterans^19,39 when compared with that of civilians.^40,41 According to one study, concomitant PTSD and TBI appears to be much higher in US war veterans (4%-17%) compared with United Kingdom Iraq War veterans (3%-6%).¹⁹

This study’s finding of an increase in nonmale soldiers with PTSD and/or TBI was not surprising. There is a paucity of data on the effect of war zone exposure on women veterans. Recently, women have been more actively involved in combat roles with 41,000 women deployed to a combat zone. Results of this study indicate a 2- to 3-fold increase in veterans identifying themselves as nonmale in post-9/11 groups with a higher proportion diagnosed with either PTSD alone or PTSD and TBI. Women are at a higher risk for PTSD than are men due in part to exposure to abuse/trauma prior to deployment, experience of higher rates of discrimination, and/or sexual assault.^31-33 One study involving First Gulf War female veterans reported higher precombat psychiatric histories as well as higher rates of physical and sexual abuse when compared with that of men.³¹

In this study, the average age of veterans adjudicated and compensated for PTSD and/or TBI pre-9/11, was 66 years compared with 36 years for post-9/11 veterans. Sixty-six percent of veterans from the post-9/11 group had ≥ 50% service-connected disability at age 36 years; 75% of veterans from the overlap group had ≥ 50% service-connected disability at age 41 years; and 76% veterans from the reentered group had ≥ 50% service-connected disability at age 46 years. Younger age at diagnosis and higher rates of disability not only pose unique challenges for veterans and family members, but also suggest implications for career prospects, family earnings, loss of productivity, and disease-adjusted life years. Also noted in the results, this younger cohort has a higher percentage of single/unmarried veterans, suggesting familial support systems may be more parental than spousal. Treatment for this younger cohort will likely need to focus on early and sustained rehabilitation that can be integrated with career plans.

For treatment to be effective, there must be evidence for veterans enrolling, remaining, and reporting benefits from the treatment. Limited research has shown currently advocated evidence-based therapies to have low enrollment rates, high drop-out rates, and mixed outcomes.⁴²

Results showing a gradual increase in the proportion of nonwhite, non-African American veterans diagnosed with PTSD alone, TBI alone, or both, likely reflect the changing demographic profile of the US as well as the Army. However, the reason that more African Americans were diagnosed with PTSD and/or TBI in the overlap and reentered groups when compared with the pre-9/11 group could not be ascertained. It is possible that more veterans identified themselves as African Americans as evident from a decrease in the number of veterans in the unknown category post-9/11 when compared with the pre-9/11 group. In 2016, the American Community Survey showed that Hispanic and African American veterans were more likely to use VA health care and other benefits than were any other racial group.⁴⁰ Improved screening for PTSD and TBI diagnoses, increased awareness, and education about the availability of VA services and benefits may have contributed to the increased use of VA benefits in these groups.

Data from this study are concordant with data from the National Center for Veterans Analysis and Statistics reporting on the younger age of diagnosis and higher rates of initial service-connected disability in veterans with PTSD and PTSD+TBI.⁴³ One study analyzing records from 1999 to 2004 showed that the number of PTSD cases grew by 79.5%, resulting in 148.7% increase in benefits payment from $1.7 billion to $4.3 billion per year.⁴⁴ In contrast, the compensation cost for all other disability categories increased by only 41.7% over this period. This study also revealed that while veterans with PTSD represented only 8.7% of compensation recipients, they received 20.5% of all compensation payments, driven in large part by an increase in > 50% service-connected disability ratings.⁴⁴

Thus, from financial as well as treatment points of view, the change in the demographic profile of the veteran must be considered when developing PTSD treatment strategies. While treatment in the past focused solely on addressing trauma-associated psychiatric issues, TBI and PTSD association will likely shift the focus to concurrent psychiatric and physical symptomology. Similarly, PTSD/TBI treatment modalities must consider that the profile of post-9/11 service members includes more women, younger age, and a greater racial diversity. For instance, younger age for a disabled veteran brings additional challenges, including reliance on parental or buddy support systems vs a spousal support system, integrating career with treatment, selecting geographic locations that can support both career and treatment, sustaining rehabilitation over time. The treatment needs of a 35-year-old soldier with PTSD and/or TBI, whether male or female, Asian or African American are likely to be very different from the treatment needs of a 65-year-old white male. Newer treatment approaches will have to address the needs of all soldiers.

Limitations

Our study may underestimate the actual PTSD and/or TBI disease burden because of the social stigma associated with diagnosis, military culture, limitations in data collection.^45-50 In addition, in this retrospective database cohort study, we considered and tried to minimize the impact of any of the usual potential limitations, including (1) accuracy of data quality and linkage; (2) identifying cohort appropriately (study groups); (3) defining endpoints clearly to avoid misclassifications; and (4) incorporating all important confounders. We identified veterans utilizing medical services at VA hospitals during a defined period and diagnosed with PTSD and TBI using ICD-9 codes and divided in 4 well-defined groups. In addition, another limitation of our study is to not accurately capture the veterans who have alternative health coverage and may choose not to enroll and/or participate in VA health care. In addition, some service members leaving war zones may not disclose or downplay the mental health symptoms to avoid any delay in their return home.

Conclusions

This study highlights the changing profile of the soldier diagnosed with PTSD and/or TBI who served pre-9/11 compared with that of those who served post-9/11. Treatment modalities must address the changes in warfare and demographics of US service members. Future treatment will need to focus more on concurrent PTSD/TBI therapies, the needs of younger soldiers, the needs of women injured in combat, and the needs of a more racially and ethnically diverse population. Severe injuries at a younger age will require early detection and rehabilitation for return to optimum functioning over a lifetime. The current study underscores a need for identifying the gaps in ongoing programs and services, developing alternatives, and implementing improved systems of care. More studies are needed to identify the cost implications and the effectiveness of current therapies for PTSD and/or TBI.

Acknowledgments

This study was supported by VA Medical Center and Midwest BioMedical Research Foundation (MBRF), Kansas City, Missouri. The manuscript received support, in part, from NIH-RO1 DK107490. These agencies did not participate in the design/conduct of the study or, in the interpretation of the data.

The nature of combat and associated injuries in Operation Iraqi Freedom (OIF), Operation Enduring Freedom (OEF), Operation New Dawn (OND), and Afghanistan War is different from previous conflicts. Multiple protracted deployments with infrequent breaks after September 11, 2001 (9/11) have further compounded the problem.

Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are the signature wounds of recent wars, with a higher incidence among the veterans of OEF and OIF compared with those from previous conflicts.^1,2 More than 2.7 million who served in Iraq and Afghanistan suffer from PTSD.^3,4 Symptoms of PTSD may appear within the first 3 months after exposure to a traumatic event or after many months and, in some cases, after a delay of many years and continue for life.⁵ Although delayed onset of PTSD in the absence of prior symptoms is rare,^6,7 its incidence rises with increasing frequency of exposure to traumatic events^8,9 and over time.¹⁰

According to the Brain Injury Association of America, TBI is “an alteration in brain function, or other evidence of brain pathology, caused by an external force.”⁸ TBI is often associated with increased risk of PTSD, depression, and posttraumatic headache,^11-13 which may lead to broader cognitive, somatic, neurobiological, and psychosocial dysfunctions.^14-17 According to Veterans Health Administration (VHA) data, 201,435 veterans from all eras enrolled with the US Department of Veterans Affairs (VA) have a diagnosis associated with TBI and 56,695 OEF/OIF veterans have been evaluated for a TBI-related condition.² According to the Defense and Veterans Brain Injury Center (DVBIC), > 361,000 veterans have been diagnosed with TBI, with a peak of 32,000 cases in 2011.^1,18 Moreover, the reported incidence and prevalence of PTSD and TBI among US veterans are not consistent. The incidence of PTSD has been estimated at 15% to 20% in recent wars^3,19 compared with 10% to 30% in previous wars.^3,19,20

When PTSD or TBI is deemed “related” to military service, the veteran may receive a service-connected disability rating ranging from 0% (no life-interfering symptoms due to injury) to 100% (totally disabling injury). The percentage of service connection associated with an injury is a quantifiable measure of the debilitating effect of injury on the individual. A significant majority (94%) of those who seek mental health services and treatment at VHA clinics apply for PTSD-related disability benefits.²¹ The estimated cost related to PTSD/TBI service-connected pensions is $20.28 billion per year and approximately $514 billion over 50 years.²² The cost of VA and Social Security disability payments combined with health care costs and treatment of PTSD is estimated to exceed $1 trillion over the next 30 years.²²

The National Vietnam Veterans Readjustment Study (NVVRS) provided valuable information on prevalence rates of PTSD and other postwar psychological problems.²³ Meanwhile, there have been no recent large-scale studies to compare the demographics of veterans diagnosed with PTSD and TBI who served prior to and after 9/11. A better understanding of demographic changes is considered essential for designing and tailoring therapeutic interventions to manage the rising cost.²²

The present study focused on identifying changing trends in the demographics of veterans who served prior to and after 9/11 and who received a VA inpatient or outpatient diagnosis of PTSD and/or TBI. Specifically, this study addressed the changes in demographics of veterans with PTSD, TBI, or PTSD+TBI seen at the VHA clinics between December 1,1998 and May 31, 2014 (before and after September 11, 2001) for diagnosis, treatment and health care policy issues.

Methods

This study was approved by the Kansas City VA Medical Center Institutional Review Board. VHA data from the Corporate Data Warehouse (CDW) and the National Patient Care Database were extracted using the VA Informatics and Computing Infrastructure (VINCI) workspace. CDW uses a unique identifier to identify veterans across treatment episodes at more than 1,400 VHA centers organized under 21 Veterans Integrated Service Networks (VISNs). These sources of VA data are widely used for retrospective longitudinal studies.

Study Population

The study population consisted of 1,339,937 veterans with a VA inpatient/outpatient diagnosis of PTSD or TBI using International Statistical Classification of Diseases and Related Health Problems, Ninth Revision (ICD-9) codes between December 1, 1998 and May 31, 2014. Demographic (gender classification, race, ethnicity, marital status, age at date of data extraction, and date of death if indicated), service-connection disability rating, and geographic distribution within VISN data on each veteran were then extracted.

Veterans in the cohort were assigned to 1 of 4 US military services period groups. The pre-9/11 group included veterans who entered and left the military prior to September 11, 2001. This group mostly included veterans from World War II, Korean War, Vietnam War, and the first Gulf War (1990-1991). The post-9/11 group included veterans who first entered military services after September 11, 2001. The overlap group included veterans who entered military services prior to 9/11, remained in service and left after September 11, 2001. The reentered group included veterans who entered and left service prior to September 11, 2001, and then reentered military service after September 11, 2001 (Figure 1). Using ICD-9 codes, veterans also were placed into the following categories: PTSD alone (ICD-9 309.81 only), TBI alone (ICD-9 850.0-859.9, V15.52), and PTSD+TBI (any combination of ICD-9 codes from the other categories).

Statistical Analysis 

Descriptive statistics were applied using proportions and means. Relationships between variables were examined using χ² tests, t tests, analysis of variance, and nonparametric tests. All hypotheses were 2-sided at 95% CI. Results are presented as absolute numbers.

Results

PTSD only (n = 1,132,356, 85%) was the predominant diagnosis category followed by PTSD+TBI (n = 106,792, 8%) and TBI only (n = 100,789, 7%) (Figure 2). Most of the veterans in the study served pre-9/11 (77%), followed by post-9/11 (15%); 7% were in the overlap group, and 1% in the reentered group (Table 1). It is notable that the proportion of veterans diagnosed with PTSD decreased from pre-9/11 (88%) to post-9/11 (71%), overlap (77%), and reentered (74%) service periods. Increases were noted in those with PTSD+TBI diagnosis category from pre-9/11 (4%) to post-9/11 (23%), overlap (17%), and reentered (22%) service periods (Figure 3). In general, the relative distribution of diagnostic categories in all the service periods showed a similar trend, with the majority of veterans diagnosed with PTSD only. Across all service periods, significantly smaller proportions of veterans were diagnosed with TBI only (P < .001).

Distribution by Gender and Age

The cohort was 92% male (n = 1,239,295), but there was a marked increase in the percentage of nonmale veterans in post-9/11 groups. Study population ages ranged from 18 to 99 years based on date of birth to the date data were obtained; or date of birth to date of death, for those who were reported deceased at the time the data were obtained. The average (SD) ages for veterans in the pre-9/11 group were significantly older (66.3 [11.2] years) compared with the ages of veterans in the post-9/11 group (36.1 [8.7] years), the overlap group (41.4 [8.2] years), and the reentered group (46.9 [9.2] years), respectively.

Distribution by Race and Marital Status

The cohort identified as 65.7% white and 18.2% African American with much smaller percentages of Asians, American Indian/Alaska Natives (AI/AN) and Native Hawaiian/Pacific Islanders (Table 2). The relative proportion of AI/AN and Native Hawaiian/Pacific Islanders remained constant across all groups, whereas the number of Asians diagnosed with PTSD, TBI, or PTSD+TBI increased in the post-9/11 group. The number of African Americans diagnosed with PTSD, TBI, or both markedly increased in the overlap and reentered groups when compared with the pre-9/11 group, yet it went down in the post-9/11/group.

Half the cohort identified themselves as married (n = 675,145) (Table 3). A slightly larger proportion of those diagnosed with PTSD alone were married (51.7%), compared with those diagnosed with TBI only (40.3%), or PTSD+TBI (45.8%). Veterans in the post-9/11 group were less likely to identify as married (45.2%) compared with the pre-9/11 (51.2%), overlap (52.6%), or reentered (53.2%) groups. Divorce rates among pre-9/11 group, overlap group, and reentered group were higher compared with that of the post-9/11 group in all diagnosis categories.

Geographic Distribution

Veterans diagnosed with PTSD, TBI, or both were not evenly distributed across the VISNs VISNs 7, 8, 10, and 22 treated the most veterans, whereas VISN 9 and 15 treated the fewest. Taken together, the top 3 VISNs accounted for 27% to 28% of the total while lowest 3 accounted for 8% to 9% of the total cohort.

Service-Connected Disability

Of 1,339,937 veterans in the cohort, 1,067,691 had a service-connected disability rating for PTSD and/or TBI. Most were diagnosed with PTSD (n = 923,523, 86.5%) followed by both PTSD+TBI (n = 94,051, 8.8%). Three-quarters of the veterans with a service-connected disability were in the pre-9/11 group. Nearly 80% of veterans with a service-connected disability rating had a rating of > 50%. The average (SD) age of veterans with PTSD+TBI and a > 50% service-connected disability was 66.3 (11.2) years in the pre-9/11 group compared with 36.1 (8.7) years in the post-9/11 group.

Discussion

The demographic profile of veterans diagnosed with PTSD+TBI has changed across the service periods covered in this study. Compared with pre-9/11 veterans, the post-9/11 cohort: (1) higher percentage were diagnosed with PTSD+TBI; (2) higher proportion were nonmale veterans; (3) included more young veterans with > 50% service-connected disability; (4) were more racially diverse; and (5) were less likely to be married and divorced and more likely to be self-identified as single. Additionally, data revealed that veterans tended to locate more to some geographic regions than to others.

The nature of the warfare has changed remarkably over the past few decades. Gunshot wounds accounted for 65% of all injuries in World War I, 35% during Vietnam War, and 16% to 23% in the First Gulf War.²⁴ In post-9/11 military conflicts, 81% of injuries were explosion related.^24,25 Although improvements in personal protective gear and battlefield trauma care led to increased survival, several factors may have contributed to increased reporting of TBI, which peaked in 2011 at 32,000 cases.^24-26

Increases in PTSD Diagnosis

Increasing media awareness, mandatory battlefield concussion screening programs instituted by the US Department of Defense (DoD), and stressful conditions that exacerbate mild TBI (mTBI) may have all contributed to the increase in numbers of veterans seeking evaluations and being diagnosed with PTSD and/or TBI in the post-9/11 groups. Additionally, the 2007 National Defense Authorization Act requested the Secretary of Defense to develop a comprehensive, systematic approach for the identification, treatment, disposition, and documentation of TBI in combat and peacetime. By a conservative estimate, significant numbers of veterans will continue to be seen for mTBI at about 20,000 new cases per year.^25-27

More frequent diagnosis of mTBI may have contributed to the increase in veterans diagnosed with PTSD+TBI in the post-9/11 groups. A recent study found that almost 44% of US Army infantry soldiers in Iraq did not lose consciousness but reported symptoms consistent with TBI.¹⁴ Compared with veterans of previous wars, veterans of the post-9/11 conflicts (OIF, OED, and OND) have experienced multiple, protracted deployments with infrequent breaks that can have a cumulative effect on the development of PTSD.^8-10

The findings from the NVVRS study led to creation of specialized PTSD programs in the late 1980s. Since then, there has been an explosion of knowledge and awareness about PTSD, TBI, and the associated service-connected disability ratings and benefits, leading to an increased number of veterans seeking care for PTSD. For example, media coverage of the 50th anniversary of the D-day celebrations resulted in a surge of World War II veterans seeking treatment for PTSD and a surge of Vietnam veterans sought treatment for PTSD during the wars in Iraq and Afghanistan.²⁸ An increased number of veterans reporting PTSD symptoms prompted the DoD to increase screening for PTSD, and to encourage service members to seek treatment when appropriate.

The VA has instituted training programs for clinicians and psychologists to screen and provide care for PTSD. Beginning in 2007, the VA implemented mandatory TBI screening for all veterans who served in combat operations and separated from active-duty service after September 11, 2001. The 4-question screen identifies veterans who are at increased risk of TBI and who experience symptoms that may be related to specific event(s).²⁹ A positive screen does not diagnose TBI but rather indicates a need for further evaluation, which may or may not be responsible for inflated reporting of TBI. Renewed research also has led providers to recognize and study PTSD resulting from noncombat trauma and moral injury. The possibility of delayed onset also drives up the number of veterans diagnosed with PTSD.^5-7

Prevalence

A wide variability exists in the reported prevalence of PTSD among US war veterans with estimates ranging from 15% to 20% of veterans from recent conflicts^3,20 and 10% to 30% of veterans from previous wars.^3,19 These rates are higher than estimates from allied forces from other countries.¹⁹ Meta-analyses suggest that the prevalence of PTSD is 2% to 15% among Vietnam War veterans, 1% to 13% among first (pre-9/11) Gulf War veterans, 4% to 17% among OEF/OIF/OND veterans; these veterans have a lifetime prevalence of 6% to 31%.^{3,11,19,30-38} The prevalence of PTSD is 2 to 4 times higher among the US veterans^19,39 when compared with that of civilians.^40,41 According to one study, concomitant PTSD and TBI appears to be much higher in US war veterans (4%-17%) compared with United Kingdom Iraq War veterans (3%-6%).¹⁹

This study’s finding of an increase in nonmale soldiers with PTSD and/or TBI was not surprising. There is a paucity of data on the effect of war zone exposure on women veterans. Recently, women have been more actively involved in combat roles with 41,000 women deployed to a combat zone. Results of this study indicate a 2- to 3-fold increase in veterans identifying themselves as nonmale in post-9/11 groups with a higher proportion diagnosed with either PTSD alone or PTSD and TBI. Women are at a higher risk for PTSD than are men due in part to exposure to abuse/trauma prior to deployment, experience of higher rates of discrimination, and/or sexual assault.^31-33 One study involving First Gulf War female veterans reported higher precombat psychiatric histories as well as higher rates of physical and sexual abuse when compared with that of men.³¹

In this study, the average age of veterans adjudicated and compensated for PTSD and/or TBI pre-9/11, was 66 years compared with 36 years for post-9/11 veterans. Sixty-six percent of veterans from the post-9/11 group had ≥ 50% service-connected disability at age 36 years; 75% of veterans from the overlap group had ≥ 50% service-connected disability at age 41 years; and 76% veterans from the reentered group had ≥ 50% service-connected disability at age 46 years. Younger age at diagnosis and higher rates of disability not only pose unique challenges for veterans and family members, but also suggest implications for career prospects, family earnings, loss of productivity, and disease-adjusted life years. Also noted in the results, this younger cohort has a higher percentage of single/unmarried veterans, suggesting familial support systems may be more parental than spousal. Treatment for this younger cohort will likely need to focus on early and sustained rehabilitation that can be integrated with career plans.

For treatment to be effective, there must be evidence for veterans enrolling, remaining, and reporting benefits from the treatment. Limited research has shown currently advocated evidence-based therapies to have low enrollment rates, high drop-out rates, and mixed outcomes.⁴²

Results showing a gradual increase in the proportion of nonwhite, non-African American veterans diagnosed with PTSD alone, TBI alone, or both, likely reflect the changing demographic profile of the US as well as the Army. However, the reason that more African Americans were diagnosed with PTSD and/or TBI in the overlap and reentered groups when compared with the pre-9/11 group could not be ascertained. It is possible that more veterans identified themselves as African Americans as evident from a decrease in the number of veterans in the unknown category post-9/11 when compared with the pre-9/11 group. In 2016, the American Community Survey showed that Hispanic and African American veterans were more likely to use VA health care and other benefits than were any other racial group.⁴⁰ Improved screening for PTSD and TBI diagnoses, increased awareness, and education about the availability of VA services and benefits may have contributed to the increased use of VA benefits in these groups.

Data from this study are concordant with data from the National Center for Veterans Analysis and Statistics reporting on the younger age of diagnosis and higher rates of initial service-connected disability in veterans with PTSD and PTSD+TBI.⁴³ One study analyzing records from 1999 to 2004 showed that the number of PTSD cases grew by 79.5%, resulting in 148.7% increase in benefits payment from $1.7 billion to $4.3 billion per year.⁴⁴ In contrast, the compensation cost for all other disability categories increased by only 41.7% over this period. This study also revealed that while veterans with PTSD represented only 8.7% of compensation recipients, they received 20.5% of all compensation payments, driven in large part by an increase in > 50% service-connected disability ratings.⁴⁴

Thus, from financial as well as treatment points of view, the change in the demographic profile of the veteran must be considered when developing PTSD treatment strategies. While treatment in the past focused solely on addressing trauma-associated psychiatric issues, TBI and PTSD association will likely shift the focus to concurrent psychiatric and physical symptomology. Similarly, PTSD/TBI treatment modalities must consider that the profile of post-9/11 service members includes more women, younger age, and a greater racial diversity. For instance, younger age for a disabled veteran brings additional challenges, including reliance on parental or buddy support systems vs a spousal support system, integrating career with treatment, selecting geographic locations that can support both career and treatment, sustaining rehabilitation over time. The treatment needs of a 35-year-old soldier with PTSD and/or TBI, whether male or female, Asian or African American are likely to be very different from the treatment needs of a 65-year-old white male. Newer treatment approaches will have to address the needs of all soldiers.

Limitations

Our study may underestimate the actual PTSD and/or TBI disease burden because of the social stigma associated with diagnosis, military culture, limitations in data collection.^45-50 In addition, in this retrospective database cohort study, we considered and tried to minimize the impact of any of the usual potential limitations, including (1) accuracy of data quality and linkage; (2) identifying cohort appropriately (study groups); (3) defining endpoints clearly to avoid misclassifications; and (4) incorporating all important confounders. We identified veterans utilizing medical services at VA hospitals during a defined period and diagnosed with PTSD and TBI using ICD-9 codes and divided in 4 well-defined groups. In addition, another limitation of our study is to not accurately capture the veterans who have alternative health coverage and may choose not to enroll and/or participate in VA health care. In addition, some service members leaving war zones may not disclose or downplay the mental health symptoms to avoid any delay in their return home.

Conclusions

This study highlights the changing profile of the soldier diagnosed with PTSD and/or TBI who served pre-9/11 compared with that of those who served post-9/11. Treatment modalities must address the changes in warfare and demographics of US service members. Future treatment will need to focus more on concurrent PTSD/TBI therapies, the needs of younger soldiers, the needs of women injured in combat, and the needs of a more racially and ethnically diverse population. Severe injuries at a younger age will require early detection and rehabilitation for return to optimum functioning over a lifetime. The current study underscores a need for identifying the gaps in ongoing programs and services, developing alternatives, and implementing improved systems of care. More studies are needed to identify the cost implications and the effectiveness of current therapies for PTSD and/or TBI.

Acknowledgments

This study was supported by VA Medical Center and Midwest BioMedical Research Foundation (MBRF), Kansas City, Missouri. The manuscript received support, in part, from NIH-RO1 DK107490. These agencies did not participate in the design/conduct of the study or, in the interpretation of the data.

A 53-year-old male veteran with a history of heavy tobacco and alcohol use presented with abdominal pain, emesis, and no bowel movements for 2 days. He had no history of surgical procedures, malignancies, diverticulitis, inflammatory bowel disease, traveling abroad, parasitic infections, tuberculosis exposure, or hospital admissions for abdominal pain. He reported experiencing no flushing, diarrhea, or cardiac symptoms. His medical history included hypertension, depression, and osteoarthritis. His vital signs were within normal limits.

A physical examination revealed a distended abdomen with mild tenderness. He had no inguinal or ventral hernias. He also had no abnormal skin lesions. A rectal examination did not reveal any masses or blood. His laboratory values were normal. X-ray and computed tomography (CT) scan revealed dilated loops of proximal small bowel, mild wall thickening in a segment of the midileum, and narrowing of the distal small bowel suggestive of a partial small bowel obstruction (Figure 1). A 1-cm nonspecific omental nodule also was seen on the CT scan, but no enlarged lymph nodes or mesenteric calcifications were seen. There was no thickening of the terminal ileum.

The patient underwent an exploratory laparotomy, which revealed no adhesions. In the midileum there was an area of thickened bowel with some nodularity associated with the thickness, but no discrete mass. In the mesentery there were multiple hard, white, calcified nodules, with the majority clustered near the thickened ileal segment. There also was a 1-cm hard, peritoneal mass on the anterior abdominal wall. The segment of thickened ileum, the adjacent mesentery, and the peritoneal nodule were resected.

Pathologic examination of the resected tissue showed immunohistochemical stains that were positive for CD79a, CD10, and BCL-2 and negative for CD23, CD5, and CD3. Nineteen mesenteric lymph nodes were negative for malignancy. The postoperative staging positron emission tomography (PET) scan did not reveal any fluorodeoxyglucose avid masses anywhere else, and bone marrow biopsy showed no infiltration.

• What is your diagnosis?
• How would you treat this patient?
   

   

Diagnosis

Based on the pathologic examination of the resected tissue and immunohistochemical stains, this patient was diagnosed with malignant non-Hodgkin B-cell lymphoma, follicular type, grade 1. PET scan and bone marrow biopsy revealed no other lesions, making this a primary lymphoma of the small intestine. The resected tissue showed negative margins and negative lymph nodes, indicating the full extent of the patient’s tumor was removed. He then underwent nasogastric tube decompression and IV fluid resuscitation. Two days later, he had a large bowel movement, and his abdominal pain resolved. He was provided the treatment options of observation only, radiation therapy, or rituximab treatment. Based on the high risk of enteritis following radiation therapy, the patient elected for observation only, with a repeat scan in 6 months. He also was counseled on alcohol and tobacco cessation. At the 6-month oncology follow-up, the patient showed no evidence of disease recurrence.

Discussion

Small bowel obstruction accounts for about 350,000 hospitalizations annually in the US.¹ The incidence is equal in men and women and can present at any age.^2,3 Patients typically present nonspecifically, with intermittent, colicky abdominal pain, nausea, vomiting, and constipation.² A physical examination may reveal abdominal distention, rigidity, and hypoactive or absent bowel sounds.¹ The 2 most common etiologies of small bowel obstruction are adhesions from prior abdominal surgery (65%) and incarcerated inguinal hernias (10%).¹ However, in a patient presenting with a small bowel obstruction in a surgically naïve abdomen with no hernias, a more detailed history covering current malignancies, past hospital admissions for abdominal pains, pelvic inflammatory disease, diverticulitis, inflammatory bowel disease, and risks for parasite infection must be taken. The differential should include intraluminal causes, including small bowel malignancy, which accounts for 5% of small bowel obstructions,¹ as well as extraluminal causes, including adhesions from diverticulitis, Meckel diverticulum, Ladd bands, and undiagnosed prior appendicitis.

To provide a tissue diagnosis and definitive treatment, surgical exploration was needed for this patient. Exploratory laparotomy revealed an area of thickened ileum and calcified nodules in its mesentery. Pathologic examination of the resected tissue revealed large lymphoid nodules in a follicular pattern with coarse chromatin (Figure 2). Taken together with the immunohistochemical stains, this was consistent with malignant B-cell non-Hodgkin lymphoma, follicular type, grade 1.

Small bowel malignancy accounts for > 5% of all gastrointestinal tumors.⁴ Of these, small bowel neuroendocrine tumors are the most common, followed by adenocarcinomas, lymphomas, and stromal tumors.⁴ Primary follicular lymphoma (PFL) is a B-cell non-Hodgkin lymphoma, and comprises between 3.8% and 11% of gastrointestinal lymphomas, commonly in the duodenum and terminal ileum.⁵

PFL typically occurs in middle-aged females and can be difficult to diagnose, as most patients are asymptomatic or present with unspecified abdominal pain. Many are diagnosed incidentally when endoscopy biopsies are performed for other reasons.^4,5 Histologically, PFL is composed of a mixed population of small (centrocytes) and large (centroblasts) lymphoid cells, with higher proportions of centroblasts corresponding to a higher grade lymphoma.⁶ The classic immunophenotype of PFL shows coexpression of CD79a (or CD20), CD10, and BCL-2; however, in rare cases, low-grade PFL may stain negative for BCL-2 and have diminished staining for CD10 in interfollicular areas.⁷

PFL generally carries a favorable prognosis. Most patients achieving complete disease regression or stable disease following treatment and a low recurrence rate. Treatment can include surgical resection, radiation, rituximab therapy, chemotherapy, or observation.⁸ Patient also should be counseled in alcohol and tobacco cessation to reduce recurrence risk.

Other small bowel malignancies may present as small bowel obstructions as well. Neuroendocrine tumors and adenocarcinomas are both more common than small bowel lymphomas and can present as small bowel obstruction. However, neuroendocrine tumors are derived from serotonin-expressing enterochromaffin cells of the midgut and often present with classic carcinoid syndrome symptoms, including diarrhea, flushing, and right heart fibrosis, which the patient lacked.⁹ Immunohistology of small bowel adenocarcinoma often shows expression of MUC1 or MUC5AC with tumor markers CEA and CA 19-9.¹⁰

Primary intestinal melanoma, another small bowel malignancy, is extremely rare. More commonly, the etiology of intestinal melanoma is cutaneous melanoma that metastasizes to the gastrointestinal tract.¹¹ This patient had no skin lesions to suggest metastatic melanoma. With intestinal melanoma, immunohistochemical evaluation may show S-100, the most sensitive marker for melanoma, or HMB-45, MART-1/Melan-A, tyrosinase, and MITF.¹²

Conclusion

This case is notable because it highlights the importance of examining the cause of small bowel obstruction in a surgically naïve abdomen, as exploration led to the discovery and curative treatment of a primary intestinal malignancy. It also underscores the nonspecific presentation that PFLs of the small intestine can have and the importance of understanding the different histopathology and immunohistochemical profiles of small bowel malignancies.

A 53-year-old male veteran with a history of heavy tobacco and alcohol use presented with abdominal pain, emesis, and no bowel movements for 2 days. He had no history of surgical procedures, malignancies, diverticulitis, inflammatory bowel disease, traveling abroad, parasitic infections, tuberculosis exposure, or hospital admissions for abdominal pain. He reported experiencing no flushing, diarrhea, or cardiac symptoms. His medical history included hypertension, depression, and osteoarthritis. His vital signs were within normal limits.

A physical examination revealed a distended abdomen with mild tenderness. He had no inguinal or ventral hernias. He also had no abnormal skin lesions. A rectal examination did not reveal any masses or blood. His laboratory values were normal. X-ray and computed tomography (CT) scan revealed dilated loops of proximal small bowel, mild wall thickening in a segment of the midileum, and narrowing of the distal small bowel suggestive of a partial small bowel obstruction (Figure 1). A 1-cm nonspecific omental nodule also was seen on the CT scan, but no enlarged lymph nodes or mesenteric calcifications were seen. There was no thickening of the terminal ileum.

The patient underwent an exploratory laparotomy, which revealed no adhesions. In the midileum there was an area of thickened bowel with some nodularity associated with the thickness, but no discrete mass. In the mesentery there were multiple hard, white, calcified nodules, with the majority clustered near the thickened ileal segment. There also was a 1-cm hard, peritoneal mass on the anterior abdominal wall. The segment of thickened ileum, the adjacent mesentery, and the peritoneal nodule were resected.

Pathologic examination of the resected tissue showed immunohistochemical stains that were positive for CD79a, CD10, and BCL-2 and negative for CD23, CD5, and CD3. Nineteen mesenteric lymph nodes were negative for malignancy. The postoperative staging positron emission tomography (PET) scan did not reveal any fluorodeoxyglucose avid masses anywhere else, and bone marrow biopsy showed no infiltration.

• What is your diagnosis?
• How would you treat this patient?
   

   

Diagnosis

Based on the pathologic examination of the resected tissue and immunohistochemical stains, this patient was diagnosed with malignant non-Hodgkin B-cell lymphoma, follicular type, grade 1. PET scan and bone marrow biopsy revealed no other lesions, making this a primary lymphoma of the small intestine. The resected tissue showed negative margins and negative lymph nodes, indicating the full extent of the patient’s tumor was removed. He then underwent nasogastric tube decompression and IV fluid resuscitation. Two days later, he had a large bowel movement, and his abdominal pain resolved. He was provided the treatment options of observation only, radiation therapy, or rituximab treatment. Based on the high risk of enteritis following radiation therapy, the patient elected for observation only, with a repeat scan in 6 months. He also was counseled on alcohol and tobacco cessation. At the 6-month oncology follow-up, the patient showed no evidence of disease recurrence.

Discussion

Small bowel obstruction accounts for about 350,000 hospitalizations annually in the US.¹ The incidence is equal in men and women and can present at any age.^2,3 Patients typically present nonspecifically, with intermittent, colicky abdominal pain, nausea, vomiting, and constipation.² A physical examination may reveal abdominal distention, rigidity, and hypoactive or absent bowel sounds.¹ The 2 most common etiologies of small bowel obstruction are adhesions from prior abdominal surgery (65%) and incarcerated inguinal hernias (10%).¹ However, in a patient presenting with a small bowel obstruction in a surgically naïve abdomen with no hernias, a more detailed history covering current malignancies, past hospital admissions for abdominal pains, pelvic inflammatory disease, diverticulitis, inflammatory bowel disease, and risks for parasite infection must be taken. The differential should include intraluminal causes, including small bowel malignancy, which accounts for 5% of small bowel obstructions,¹ as well as extraluminal causes, including adhesions from diverticulitis, Meckel diverticulum, Ladd bands, and undiagnosed prior appendicitis.

To provide a tissue diagnosis and definitive treatment, surgical exploration was needed for this patient. Exploratory laparotomy revealed an area of thickened ileum and calcified nodules in its mesentery. Pathologic examination of the resected tissue revealed large lymphoid nodules in a follicular pattern with coarse chromatin (Figure 2). Taken together with the immunohistochemical stains, this was consistent with malignant B-cell non-Hodgkin lymphoma, follicular type, grade 1.

Small bowel malignancy accounts for > 5% of all gastrointestinal tumors.⁴ Of these, small bowel neuroendocrine tumors are the most common, followed by adenocarcinomas, lymphomas, and stromal tumors.⁴ Primary follicular lymphoma (PFL) is a B-cell non-Hodgkin lymphoma, and comprises between 3.8% and 11% of gastrointestinal lymphomas, commonly in the duodenum and terminal ileum.⁵

PFL typically occurs in middle-aged females and can be difficult to diagnose, as most patients are asymptomatic or present with unspecified abdominal pain. Many are diagnosed incidentally when endoscopy biopsies are performed for other reasons.^4,5 Histologically, PFL is composed of a mixed population of small (centrocytes) and large (centroblasts) lymphoid cells, with higher proportions of centroblasts corresponding to a higher grade lymphoma.⁶ The classic immunophenotype of PFL shows coexpression of CD79a (or CD20), CD10, and BCL-2; however, in rare cases, low-grade PFL may stain negative for BCL-2 and have diminished staining for CD10 in interfollicular areas.⁷

PFL generally carries a favorable prognosis. Most patients achieving complete disease regression or stable disease following treatment and a low recurrence rate. Treatment can include surgical resection, radiation, rituximab therapy, chemotherapy, or observation.⁸ Patient also should be counseled in alcohol and tobacco cessation to reduce recurrence risk.

Other small bowel malignancies may present as small bowel obstructions as well. Neuroendocrine tumors and adenocarcinomas are both more common than small bowel lymphomas and can present as small bowel obstruction. However, neuroendocrine tumors are derived from serotonin-expressing enterochromaffin cells of the midgut and often present with classic carcinoid syndrome symptoms, including diarrhea, flushing, and right heart fibrosis, which the patient lacked.⁹ Immunohistology of small bowel adenocarcinoma often shows expression of MUC1 or MUC5AC with tumor markers CEA and CA 19-9.¹⁰

Primary intestinal melanoma, another small bowel malignancy, is extremely rare. More commonly, the etiology of intestinal melanoma is cutaneous melanoma that metastasizes to the gastrointestinal tract.¹¹ This patient had no skin lesions to suggest metastatic melanoma. With intestinal melanoma, immunohistochemical evaluation may show S-100, the most sensitive marker for melanoma, or HMB-45, MART-1/Melan-A, tyrosinase, and MITF.¹²

Conclusion

This case is notable because it highlights the importance of examining the cause of small bowel obstruction in a surgically naïve abdomen, as exploration led to the discovery and curative treatment of a primary intestinal malignancy. It also underscores the nonspecific presentation that PFLs of the small intestine can have and the importance of understanding the different histopathology and immunohistochemical profiles of small bowel malignancies.

A 53-year-old male veteran with a history of heavy tobacco and alcohol use presented with abdominal pain, emesis, and no bowel movements for 2 days. He had no history of surgical procedures, malignancies, diverticulitis, inflammatory bowel disease, traveling abroad, parasitic infections, tuberculosis exposure, or hospital admissions for abdominal pain. He reported experiencing no flushing, diarrhea, or cardiac symptoms. His medical history included hypertension, depression, and osteoarthritis. His vital signs were within normal limits.

A physical examination revealed a distended abdomen with mild tenderness. He had no inguinal or ventral hernias. He also had no abnormal skin lesions. A rectal examination did not reveal any masses or blood. His laboratory values were normal. X-ray and computed tomography (CT) scan revealed dilated loops of proximal small bowel, mild wall thickening in a segment of the midileum, and narrowing of the distal small bowel suggestive of a partial small bowel obstruction (Figure 1). A 1-cm nonspecific omental nodule also was seen on the CT scan, but no enlarged lymph nodes or mesenteric calcifications were seen. There was no thickening of the terminal ileum.

The patient underwent an exploratory laparotomy, which revealed no adhesions. In the midileum there was an area of thickened bowel with some nodularity associated with the thickness, but no discrete mass. In the mesentery there were multiple hard, white, calcified nodules, with the majority clustered near the thickened ileal segment. There also was a 1-cm hard, peritoneal mass on the anterior abdominal wall. The segment of thickened ileum, the adjacent mesentery, and the peritoneal nodule were resected.

Pathologic examination of the resected tissue showed immunohistochemical stains that were positive for CD79a, CD10, and BCL-2 and negative for CD23, CD5, and CD3. Nineteen mesenteric lymph nodes were negative for malignancy. The postoperative staging positron emission tomography (PET) scan did not reveal any fluorodeoxyglucose avid masses anywhere else, and bone marrow biopsy showed no infiltration.

• What is your diagnosis?
• How would you treat this patient?
   

   

Diagnosis

Based on the pathologic examination of the resected tissue and immunohistochemical stains, this patient was diagnosed with malignant non-Hodgkin B-cell lymphoma, follicular type, grade 1. PET scan and bone marrow biopsy revealed no other lesions, making this a primary lymphoma of the small intestine. The resected tissue showed negative margins and negative lymph nodes, indicating the full extent of the patient’s tumor was removed. He then underwent nasogastric tube decompression and IV fluid resuscitation. Two days later, he had a large bowel movement, and his abdominal pain resolved. He was provided the treatment options of observation only, radiation therapy, or rituximab treatment. Based on the high risk of enteritis following radiation therapy, the patient elected for observation only, with a repeat scan in 6 months. He also was counseled on alcohol and tobacco cessation. At the 6-month oncology follow-up, the patient showed no evidence of disease recurrence.

Discussion

Small bowel obstruction accounts for about 350,000 hospitalizations annually in the US.¹ The incidence is equal in men and women and can present at any age.^2,3 Patients typically present nonspecifically, with intermittent, colicky abdominal pain, nausea, vomiting, and constipation.² A physical examination may reveal abdominal distention, rigidity, and hypoactive or absent bowel sounds.¹ The 2 most common etiologies of small bowel obstruction are adhesions from prior abdominal surgery (65%) and incarcerated inguinal hernias (10%).¹ However, in a patient presenting with a small bowel obstruction in a surgically naïve abdomen with no hernias, a more detailed history covering current malignancies, past hospital admissions for abdominal pains, pelvic inflammatory disease, diverticulitis, inflammatory bowel disease, and risks for parasite infection must be taken. The differential should include intraluminal causes, including small bowel malignancy, which accounts for 5% of small bowel obstructions,¹ as well as extraluminal causes, including adhesions from diverticulitis, Meckel diverticulum, Ladd bands, and undiagnosed prior appendicitis.

To provide a tissue diagnosis and definitive treatment, surgical exploration was needed for this patient. Exploratory laparotomy revealed an area of thickened ileum and calcified nodules in its mesentery. Pathologic examination of the resected tissue revealed large lymphoid nodules in a follicular pattern with coarse chromatin (Figure 2). Taken together with the immunohistochemical stains, this was consistent with malignant B-cell non-Hodgkin lymphoma, follicular type, grade 1.

Small bowel malignancy accounts for > 5% of all gastrointestinal tumors.⁴ Of these, small bowel neuroendocrine tumors are the most common, followed by adenocarcinomas, lymphomas, and stromal tumors.⁴ Primary follicular lymphoma (PFL) is a B-cell non-Hodgkin lymphoma, and comprises between 3.8% and 11% of gastrointestinal lymphomas, commonly in the duodenum and terminal ileum.⁵

PFL typically occurs in middle-aged females and can be difficult to diagnose, as most patients are asymptomatic or present with unspecified abdominal pain. Many are diagnosed incidentally when endoscopy biopsies are performed for other reasons.^4,5 Histologically, PFL is composed of a mixed population of small (centrocytes) and large (centroblasts) lymphoid cells, with higher proportions of centroblasts corresponding to a higher grade lymphoma.⁶ The classic immunophenotype of PFL shows coexpression of CD79a (or CD20), CD10, and BCL-2; however, in rare cases, low-grade PFL may stain negative for BCL-2 and have diminished staining for CD10 in interfollicular areas.⁷

PFL generally carries a favorable prognosis. Most patients achieving complete disease regression or stable disease following treatment and a low recurrence rate. Treatment can include surgical resection, radiation, rituximab therapy, chemotherapy, or observation.⁸ Patient also should be counseled in alcohol and tobacco cessation to reduce recurrence risk.

Other small bowel malignancies may present as small bowel obstructions as well. Neuroendocrine tumors and adenocarcinomas are both more common than small bowel lymphomas and can present as small bowel obstruction. However, neuroendocrine tumors are derived from serotonin-expressing enterochromaffin cells of the midgut and often present with classic carcinoid syndrome symptoms, including diarrhea, flushing, and right heart fibrosis, which the patient lacked.⁹ Immunohistology of small bowel adenocarcinoma often shows expression of MUC1 or MUC5AC with tumor markers CEA and CA 19-9.¹⁰

Primary intestinal melanoma, another small bowel malignancy, is extremely rare. More commonly, the etiology of intestinal melanoma is cutaneous melanoma that metastasizes to the gastrointestinal tract.¹¹ This patient had no skin lesions to suggest metastatic melanoma. With intestinal melanoma, immunohistochemical evaluation may show S-100, the most sensitive marker for melanoma, or HMB-45, MART-1/Melan-A, tyrosinase, and MITF.¹²

Conclusion

This case is notable because it highlights the importance of examining the cause of small bowel obstruction in a surgically naïve abdomen, as exploration led to the discovery and curative treatment of a primary intestinal malignancy. It also underscores the nonspecific presentation that PFLs of the small intestine can have and the importance of understanding the different histopathology and immunohistochemical profiles of small bowel malignancies.

Diabetic foot ulcers (DFUs) are devastating, common, and costly. This burden is borne disproportionately by veterans who have high prevalence of type 2 diabetes mellitus (T2DM) and other precipitating risk factors.¹ The mortality of veterans following a DFU is sobering, and ulceration is recognized as a significant marker of disease severity.

A 2017 study by Brennan and colleagues reported a 19% mortality rate within 1 year, and only 29% survive past 5 years.² DFUs are often complicated by peripheral arterial disease (PAD) and diabetic immune dysfunction, contributing to chronic wounds and infection.^3,4 About 60% of all foot ulcers become infected, and > 20% of patients with a diabetic foot infection require amputation.^5,6

A 2010 retrospective study reports that > 3,400 veterans have a diabetes-related lower extremity amputation annually, vastly surpassing the rate of amputation secondary to trauma in the Veterans Health Administration (VHA).^7,8 The inpatient costs for each amputation exceeded $60,000 in fiscal year 2010, and these amputation-related costs represent only 1 component of the total expense to the VHA attributable to diabetic foot complications.⁷ A recent systematic review by Chan and colleagues estimated mean annual costs in the year following a foot ulcer to be $44,200 to the public payer.⁹ This implies that direct expenditures for treatment of DFUs within the VHA exceeds $3 billion annually.

Diabetic Foot Ulcer Prevention

Given the dramatic impact of diabetic foot complications to the veteran and the US health care system, the VHA has long recognized the importance of preventive care for those at risk. In 2017 US Department of Veterans Affairs (VA) and Department of Defense issued a clinical practice guideline for the management of T2DM that recommended prophylactic foot care for early identification of any deformity or skin breakdown.¹⁰ The guidelines note that a “person who has had a foot ulcer is at lifelong risk of further ulceration,” reflecting the high rate of recurrence among all patients, including veterans. Multiple studies suggest that as many as 40% of patients experience recidivism in the first year after healing from a wound.^11-16

The VA is well equipped to deliver quality preventive care because of its innovative and long-standing PAVE (Prevention of Amputations for Veterans Everywhere) program.¹⁷ PAVE provides screening, education, appropriate footwear, and stratified care guidelines for veterans at risk for diabetes-related foot complications (Table 1). The practices encouraged by PAVE are evidence-based and synergistic with the objectives of the VA’s patient aligned care team (PACT) delivery approach.¹⁸ The granular data collected through PAVE are used to guide best practices and provide benchmarks for diabetic foot outcomes.

Unfortunately, despite PAVE guidelines requiring annual specialist foot care for at-risk veterans, a 2013 report by the VA Office of the Inspector General (OIG) found that one-third of all patients had no documentation of this minimal requirement of preventive foot care.¹⁹ Although the VA has worked to address this issue, the data hint at the missed opportunities for prevention of complications and the challenges of ensuring that a large at-risk veteran population has systematic and routine screening with access to specialist foot care.

Given the large proportion of veterans at high risk of chronic wound formation and the challenges of ensuring that this cohort receives good preventive foot care, expanding telemedicine has been suggested. Telemedicine solutions have the potential to reduce the impact of chronic wounds on overburdened clinic resources, schedules, and local and federal budgets.²⁰ Interestingly, the only preventive practice for the diabetic foot that has been proven effective through multiple randomized controlled trials and national and international clinical guidance documents is once-daily foot temperature monitoring.^21-26 Daily monitoring has the potential to reduce the burden of DFUs to veterans, improve veteran access to needed preventive care, and reduce costs incurred by the VHA treating diabetic foot complications. Yet despite a recent national guidance document detailing its appropriate use in PAVE 3 veterans, it remains underutilized.²⁷

The purpose of this review is to: (1) discuss the evidence supporting once-daily remote temperature monitoring (RTM), a telemedicine approach critical to improving both veteran access to care and diabetic foot outcomes; (2) summarize a 2017 study that presented an advanced clinical understanding of RTM use among veterans; (3) provide previously unpublished data from this study comparing high-risk VA and non-VA cohorts, highlighting the opportunity for additional focus on foot ulcer prevention within the VA; and (4) report on recent VA utilization of a RTM technology based on this research, emphasizing lessons learned and best practices.

Remote Temperature Monitoring

The objective of daily foot temperature monitoring is to identify impending inflammatory foot conditions, such as DFUs, infection, and acute Charcot neuroarthropathy episodes. The patient and care team then act to resolve the cause of detected inflammation before clinical presentation (prevention) and begin treatment earlier than would otherwise be possible to avoid expensive complications, such as infection (early detection). Preventive therapies are low risk to the patient and inexpensive.

RTM is recommended by multiple clinical practice guidelines, including those of the International Working Group on the Diabetic Foot, the American College of Foot and Ankle Surgeons, and the Wound Healing Society.^24-26 Its use is supported by evidence from 3 National Institutes of Health-funded and well-designed randomized controlled trials, 1 of which was additionally supported by a VA Health Services Research and Development Service Merit Award.^21-23,28 Conducted between 2004 and 2007, these studies demonstrated the potential to reduce foot ulcer incidence by as much as 85% using a dermal thermometer to identify inflammation and prompt decreased ambulation. Investigators established a clinical monitoring protocol comparing the temperatures between 6 matched locations on the left and right feet. Persistent differences in contralateral temperatures exceeding 2.2°C (4.0°F) were used as a marker for elevated risk and to initiate preventive care. Based on the encouraging results from these studies, a 2017 effectiveness review prepared for the Agency for Healthcare Research and Quality concluded that “home monitoring of foot skin temperature is effective for reducing foot ulcer incidence and recurrence.”²⁹

Accuracy of RTM

A 2017 longitudinal study (NCT02647346) has provided novel data to advance understanding of RTM for the prediction and prevention of DFUs.³⁰ This study was the first to systematically analyze the accuracy of RTM over different monitoring thresholds. The results enable practitioners to deliver risk-stratified preventive care. Policy makers can use the data from this study to weigh the cost and benefits of RTM for population health.

The multicenter trials had 129 participants from 4 VA health care systems: VA Long Beach Healthcare System in California, Miami VA Healthcare System in Florida, Phoenix VA Healthcare System in Arizona, and VA West Los Angeles Healthcare System in California. Each participant was followed for 34 weeks under standard preventive foot care and was instructed to step on a telemedicine SmartMat (Podimetrics, Inc) RTM mat for 20 seconds daily. Participants and investigators were blinded to the temperature data so that the accuracy of temperature monitoring could be assessed. All participants had a history of T2DM and healed DFU. Principal exclusion criteria included unhealed plantar wound, history of proximal lower extremity amputation (ie, above ankle), active Charcot foot disease, and comorbidities that could potentially inhibit an inflammatory response, such as end-stage renal disease, active malignancy, and immunosuppressive diseases.

The investigators reported that RTM with the study mat detected 97% of nonacute plantar DFUs using the most commonly studied threshold (sustained 2.2°C temperature difference). The lead time averaged 37 days before clinical identification of the wound under standard care. Although the false-positive rate of 57% was high, corresponding to approximately 3.0 notifications per patient per year on average in the research setting, it is important to note that this study only considered the prediction of plantar DFUs. Thus, detection of foot inflammation secondary to other conditions, such as preulcerative lesion, dorsal wound, Charcot neuroarthropathy, or foot infection, were reported as a false positive per the study’s definitions. Further, Crisologo and Lavery noted in a translational medicine summary of this research, because the intervention is noninvasive and minimally impactful to the patient and the health care system, “the potential to arrest re-ulceration is worth the perceived inconvenience to the patient.”³¹

Secondary outcomes related to adherence and ease of use were encouraging. Eighty-eight percent of participants reported that the mat was “very easy to use,” the highest possible score, and 98% were able to set up the mat for home use without difficulty. At the end of the 34-week study, more than 74% of participants remained engaged in routine use of the mat under a per-protocol assessment of adherence. These results are especially impressive given the documented poor adherence of at-risk patients to routine use of therapeutic footwear, which has been reported to be as low as 15%.³²

New Research

The data collected during this study has led to new research and advancements in RTM. A recent publication by Gordon and colleagues investigated whether RTM is less accurate in cohorts with perceived challenges.³³ They include patients with recently healed wounds and those with a history of partial foot amputation. There was no difference in the accuracy or lead time for either cohort relative to the entire cohort, suggesting that RTM is appropriate for monitoring patients with recently healed DFUs or partial foot amputations.

In another recent study, the data were used to derive a novel approach to monitor a single at-risk foot.³⁴ The practice of RTM has traditionally required comparing temperatures between contralaterally matched plantar locations on the feet, thus limiting its use in patients with a history of major lower extremity amputation and patients being treated for a wound, which may be bandaged or in an off-loading cast or boot. Because the risk factors for DFUs exist in both limbs, these patients are at high risk for developing complications to the contralateral foot and may benefit from preventive once-daily foot temperature monitoring. The investigators empirically derived a novel monitoring approach for patients without a contralateral control. This approach was found to predict 91% of impending plantar DFUs on average 41 days before clinical presentation with a false positive rate of 54%.

Additional Focus on Prevention

Table 2 shows previously unpublished data from a subgroup analysis between veteran and nonveteran participants in the study.²⁵ These descriptive statistics reinforce some widely held assumptions regarding the high-risk veteran population and challenge others. For example, compared with the nonveteran participants, the veteran cohort unsurprisingly had a larger ratio of male participants (P < .01), had a higher rate of cigarette use (P < .01), and was more likely to live alone (although not at a statistically significant level). Veterans in the study had body mass index, rates of alcohol use, frequency of exercise, and glucose control comparable to that of nonveterans.

The potential impact of the PAVE program is clear in several of these comparisons. Although as few as 15% of patients use therapeutic shoes routinely, PAVE ensures that the majority of veterans receive them. Nearly 95% of veterans have therapeutic shoes compared with about 80% of nonveteran participants (P < .05). Veterans also had higher ankle-brachial index results (P < .05), although on average both cohorts were within normal clinical parameters. Veterans had a significantly longer duration since healing from the most recent wound, and fewer veteran participants had a wound that healed in the 3 months prior to the study. Despite this, during the study veterans had annualized DFU incidence equal to that of nonveterans. Furthermore, veterans also had significantly higher rates of amputation prior to participation. That these critical outcomes for veterans are no better than those observed in other care environments despite PAVE suggests that approaches recommended via PAVE alone are insufficient to significantly arrest DFU recurrence, and even more focus on prevention in the VA may be warranted.

From Research to Practice

Since the publication of the 2017 study, the VHA has been at the vanguard of translating the evidence and research underlying RTM into clinical practice. A clinical guidance document governing appropriate use of RTM with the study mat was recently published by the VA Prosthetic and Sensory Aids Service in collaboration with the National Podiatry Program office.²⁷ This guidance document recommends once-daily RTM for at-risk veterans designated PAVE level 3. It defines roles and responsibilities required for the successful implementation of a RTM program with the study device. The document additionally presents various clinical monitoring protocols for veterans, although the protocol and thresholds used are at the discretion of the prescribing clinician and should reflect the risk profile of the veteran in question.

A staged response to inflammation has proven popular, whereby an initial high-sensitivity threshold is chosen for monitoring. The initial response is telephone outreach by a designee supplied by the clinic or device manufacturer, typically a trained registered nurse, to the veteran to collect subjective history and instruct off-loading and reduced ambulation, with a target of 50% baseline reduction in step count. Should the inflammation persist despite off-loading, an examination may be necessary to identify and resolve its cause. For recalcitrant inflammation, more targeted pressure off-loading of the affected area may be accomplished with custom orthotics, accommodative insoles, removable cast walkers, and total contact casting. After 2 to 4 weeks without signs of inflammation, the cause is deemed to have been resolved and lowered the acute risk for developing further diabetic foot complications.

More than 600 veterans have been monitored for > 1,000 patient-years—13 VA medical centers are practicing RTM with the study mat as of this writing. The monitoring program has been integrated into many veteran daily routines as evidenced by > 70% retaining full engagement after having been monitored for > 1 year. The total number of alerts/patient-years across these veterans has been 1.4, significantly lower than the 3.0 alerts/patient-year observed in the study. This is potentially due to successful interventions in response to detected inflammation, resolving inflammation, and avoiding unnecessary alerts occurring in the research setting, which did not employ interventions that resolved inflammation episodes. In the past 6 months, 68% of all inflammation detected resolved via off-loading alone without requiring further clinical intervention. In the cases that required an examination, 76% of patients reported clinically meaningful preventive care (eg, preulcerative callus was debrided, a subungual hemorrhage was treated, a foot ulcer was identified).

Organizational Best Practices

Several best practices have been cultivated related to initiating a RTM program at a new site, for promoting the success of a RTM program, and provisioning excellent preventive care to support the RTM program. Although we advise adhering to the recommendations in the VA guidance document,²⁷ the authors have observed several additional organizational best practices that are not explicitly addressed.

Partnering with PACT. Collaboration between PAVE and PACT has the potential not only to improve outcomes for patients at risk for diabetic foot complications, but also can help identify appropriate high-risk veteran candidates for preventive care with RTM who may not be followed for routine care from a specialty provider, such as a podiatrist, as highlighted by the 2013 OIG report.

Prescreening eligible patients. Several programs have used PAVE data or appointment schedules to identify and target high-risk veterans proactively. This approach has several benefits. It simplifies clinical coordination and streamlines workflow for patient identification and onboarding. It also allows those veterans at highest risk to receive needed and recommended preventive care at their next scheduled appointment. Finally, if PAVE data are used to identify eligible patients, it has the added benefit of ensuring a baseline level of telemedicine preventive foot care for veterans who have become lost to follow-up and have not been seen recently for a routine foot examination.

Implementing foot monitoring during wound treatment. Recent research has expanded the reach of once-daily RTM with the mat to patients being treated for a wound to only 1 foot. This practice has 2 benefits: The patient is able to establish a preventive routine before healing, an important advantage because research strongly suggests that recurrence is most likely in the first months after healing. Second, 48% of patients with a history of DFUs will develop new wounds to the contralateral foot because risk factors, such as neuropathy and peripheral arterial disease, exist in both limbs.³⁵ Furthermore, ongoing treatment for a wound to 1 foot may result in gait deviation and elevated pressure to the sound foot, additionally predisposing the veteran to complications, resulting in a high rate of wounds occurring to the unwounded foot during treatment (0.2 DFU/DFU-year).³⁴ Thus, there is potential benefit in monitoring the sound foot while undergoing treatment for a wound; further, the patient will have immediate access to the device for prevention of recurrence once the wound has resolved.

Utilizing foot monitoring as an extension of telemedicine. Many VA facilities have large geographic catchment areas, making routine follow-up difficult for veterans living in rural areas. RTM serves as an extension of the patient’s daily self-examination and the clinician’s ability to monitor patients with objective information daily. The veterans using the system become more invested and feel as though they are taking an active role in their health care.

Investing in ongoing medical education. Multidisciplinary education sessions reviewing supporting clinical data and resultant clinical practice guidelines raise awareness for those providers and trainees unaware of preventive best practices for the diabetic foot, including those related to foot RTM. These sessions also are helpful for those familiar with foot temperature monitoring or who are responsible for administration of an ongoing program to remain current with contemporary best practices and to discuss improvements for patient care. Familiarity also can help address clinical inertia when benefits and evidence are clearly communicated with health care providers (HCPs).

Clinical Best Practices

Treating preulcerative lesions urgently and aggressively. Callus and other preulcerative lesions often cause progressive tissue damage and poor outcomes. When identified, these lesions should be promptly treated to ensure best outcomes.²⁴

Recognizing the limits of patient self-examinations. Comorbidities such as visual impairment and reduced joint mobility often preclude patients from completing rigorous self-examinations of the foot, which is especially critical while collecting subjective history from the patient during triage of inflammation. A caregiver or spouse can help inspect the foot during outreach and provide additional context.³⁶

Interpreting a benign foot on examination. Because RTM has been demonstrated to detect inflammation preceding a foot ulcer as many as 5 weeks before presentation to the clinic, some veterans may have few signs or symptoms of acute risk during examination. Often, the damage is to subcutaneous tissue resulting from repetitive microtrauma. Research suggests that clinical examination in these cases is often unreliable for identifying the earliest signs of risk, such as palpation to identify subtle temperature changes secondary to inflammation.³⁷ If a patient has refractory inflammation requiring examination and presents with an otherwise unremarkable foot, it is an opportunity to evaluate whether the patient’s shoewear remains appropriate or has worn out, to communicate the veteran’s ongoing elevated risk, and to educate on the importance of diligence in daily foot self-examinations, daily use of the foot temperature monitoring, and continued off-loading until the inflammation resolves.

Communicating the distinction between healing and remission. Although healing is the goal of wound care, patients should be educated that the underlying disease remains after epithelialization. In some cases, tissue deep to the skin has not completed remodeling, and the patient is at acute risk of recurrence. Remission is a powerful metaphor that better describes the patient’s ongoing risk to encourage continued healthy routines and diligent self-care.³⁸Considering the entirety of both feet for recurrence. Critical risk factors for diabetic foot complications, such as peripheral neuropathy and PAD, exist in both limbs, and patients with a history of wounds often develop new complications to different ipsilateral locations, or in as many as 48% of cases, to the contralateral foot.³⁵ For best outcomes, detected inflammation should be treated aggressively independent of whether the location coincides with an area of previous concern.

Encouraging adherence, routine, and empowerment. Advanced diabetes mellitus and neuropathy may impact a patient’s executive function, and multiple studies have reported that patients at risk for inflammatory foot diseases exhibit fatalism toward their foot care and outcomes.^39-41 Consistent education, encouragement, empowerment, and establishment of positive routines are needed to ensure high adherence with all preventive care regimens, including RTM.

Case Presentations

The following case series illustrates many of these clinical best practices and characterizes the potential benefits of RTM to veterans within the VA.

Case 1: Prevention After Healing

A veteran underwent a Chopart amputation and was recommended to use the mat after healing was perceived. Immediately on use of the study mat, the patient was found to have inflammation to the surgical incision (Figure 1). Clinical staff was alerted to the findings, and the patient was instructed to limit further walking and continue off-loading in his removable cast walker, per protocol. The inflammation of the operative foot quickly reduced, and the patient continued healing successfully, potentially avoiding incisional dehiscence and possible postoperative infection.

This case illustrates that patients’ wounds or surgical incisions may not be completely healed on epithelialization. In the immediate phase after closure, HCPs should consider additional protection to avoid complications. This case demonstrates that RTM can provide objective data to help guide care in that critical period.

Case 2: Identifying Preulcerative Lesions

An 88-year-old veteran had a chronic callus under the second metatarsal head. In addition to routine foot care and therapeutic shoes, he was followed with once-daily RTM. Inflammation was noted, and the veteran was seen in the podiatry clinic where debridement of the callus was performed. The difference in temperatures between feet detected by thermography prior to the clinic visits rapidly resolved after callus debridement, indicating that the underlying inflammation had subsided. RTM was used by the clinical staff to determine the appropriate time interval between clinic visits to avoid callus breakdown and subsequent ulceration.

Case 3: Extending the Clinic Into the Home

An 80-year-old veteran with T2DM and neuropathy was deemed a high-risk patient due to recurrent ulcerations to the left great toe. He was issued a RTM mat and was adherent with routine use. After nearly a year without hot-spot development, inflammation was noted (Figure 2).

Unfortunately, the patient had missed several routine foot care visits and likely that was the reason for the noted inflammation. The patient was called and became reengaged in regular visits for routine foot care. On debridement of his callus, a superficial, noninfected ulceration was discovered. Had remote monitoring not detected the inflammation and impending ulceration, the patient likely would not have been seen in the regular clinic and may have developed a wound infection, potentially resulting in a worse and more costly outcome.

Paradigm Shift to Prevention

Given the exceedingly high burden of diabetic foot complications in the VA, a paradigm shift is needed among HCPs from a culture of treatment to one of prevention. Bus and colleagues reported that in Europe, for every euro spent on ulcer prevention, 10 are spent on ulcer healing, and for every randomized clinical trial conducted on prevention, 10 are conducted on treatment.^42-44 Hicks and colleagues showed that the cost of curative care for DFUs is 5 to 30 times greater than the cost of preventive care.⁴⁵ For RTM in high-risk cohorts (ie, PAVE level 3), the number-needed-to-treat for DFU prevention may be as low as 6, assuming that a 70% reduction in incidence is possible, consistent with previous research. In the year following a DFU, costs exceed $44,000.⁹ Thus, it seems natural that future direction in diabetic foot care should emphasize prevention strategies.

Foot ulcers that become infected often lead to hospitalization and result in an increased burden to an already overburdened VA health care system. Research suggests that about two-thirds of all diabetic foot costs are attributable to inpatient management.⁴⁶ The impact of diabetic foot complications on hospital resource utilization is staggering. A 2017 study by Skrepnik analyzed the risk of hospitalization for various diseases.⁴⁷ The investigators found that the inpatient admission odds ratio (OR) for congestive heart failure was 2.6, surpassed only by DFUs (OR, 3.4) and diabetic foot infection (OR, 6.7). A 2019 point-prevalence study found that > 10% of hospital admissions have a foot-related condition as the primary or secondary reason, and the majority of these are due to foot diseases, such as ulcers, infections, and Charcot neuroarthropathy.⁴⁸

It is therefore incumbent on VA HCPs to avert wound recurrence in the interest of avoiding veteran hospitalizations and for administrators to encourage and incentivize best practices for managing the diabetic foot, with an emphasis on prevention therapies. In evaluating the financial impact of prevention with foot RTM, administrators should consider that the cost benefit is likely to be realized across the medical center, with budgets related to inpatient management likely to receive the largest returns.

Prevention has the potential to rein in costs as well as reduce strain on the hospital and clinic by preventing outcomes that require frequent visits for treatment or hospitalization. Wound treatment is very burdensome to the clinic; patients require frequent (in many cases, weekly) examinations, and chronic wounds often require hospitalization, necessitating rounding and additional coordination in care. Thus, preventing wounds or reducing their severity at presentation substantially reduces burden on the clinic, even after accounting for the modest clinical resources needed to administer preventative care. For example, a brief examination may be necessary if the inflammation detected by the study mat is secondary to a callus that must be debrided. However, if the patient was not seen until the callus had progressed to a wound, weekly follow-up and substantial clinical and budgetary resources may be required to heal the wound. Preventive care allows for substantially better patient outcomes, and the minimal time invested prevents the clinical burden of extensive wound treatment.

The success of preventive efforts relies on multidisciplinary management of this high-risk patient cohort. Often, it is the responsibility of the primary care provider to follow diabetic foot clinical reminders and appropriately refer to specialty care. Successful, open communication between PACT, PAVE, and the Podiatry Service has been shown to reduce poor outcomes, including lower extremity amputations. Traditionally, the model of preventive care has included podiatrist-driven interventions, including integrated routine foot care and comprehensive diabetic foot education. Collaboration between routine evaluation and prompt referral of at-risk patients for specialist foot care, therapeutic footwear recommendations, daily self-foot examinations, and in-home temperature monitoring are critically effective when performed consistently.

When trying to translate research science to effective clinical practice for preventing lower extremity complication, there are several important concepts. First, given the frequency of examination for patients being treated for a wound, provision of good preventive care, such as RTM, can reduce overall burden to resource-constrained clinics and improve access for patients needing to be seen. Additionally, preventive efforts extend clinical practice into the home and may reduce the need for in-clinic examinations and routine follow-up visits. Finally, there may be a sense of trust established between the clinician and patient with a positive record of adherence with preventive practices. This may translate into more productive communication and less frequent routine visits to better accommodate urgent visits and ensure podiatric care is accessible to veterans.

Conclusions

There is a significant opportunity to shift diabetic foot care from treatment to prevention, improving veteran outcomes and reducing resource utilization. RTM is an evidence-based and recommended but underused telemedicine solution that can catalyze this needed paradigm shift. The VA has been at the forefront of preventive foot care through the PAVE program and more recently through research and clinical application of RTM for veterans. However, as the data presented suggest, more can be done to improve veteran outcomes. More widespread adoption of evidence-based preventive technologies for the diabetic foot, such as RTM, has the potential to dramatically improve the quality of and access to care and reduce costs and burden on resource-constrained clinics.

Diabetic foot ulcers (DFUs) are devastating, common, and costly. This burden is borne disproportionately by veterans who have high prevalence of type 2 diabetes mellitus (T2DM) and other precipitating risk factors.¹ The mortality of veterans following a DFU is sobering, and ulceration is recognized as a significant marker of disease severity.

A 2017 study by Brennan and colleagues reported a 19% mortality rate within 1 year, and only 29% survive past 5 years.² DFUs are often complicated by peripheral arterial disease (PAD) and diabetic immune dysfunction, contributing to chronic wounds and infection.^3,4 About 60% of all foot ulcers become infected, and > 20% of patients with a diabetic foot infection require amputation.^5,6

A 2010 retrospective study reports that > 3,400 veterans have a diabetes-related lower extremity amputation annually, vastly surpassing the rate of amputation secondary to trauma in the Veterans Health Administration (VHA).^7,8 The inpatient costs for each amputation exceeded $60,000 in fiscal year 2010, and these amputation-related costs represent only 1 component of the total expense to the VHA attributable to diabetic foot complications.⁷ A recent systematic review by Chan and colleagues estimated mean annual costs in the year following a foot ulcer to be $44,200 to the public payer.⁹ This implies that direct expenditures for treatment of DFUs within the VHA exceeds $3 billion annually.

Diabetic Foot Ulcer Prevention

Given the dramatic impact of diabetic foot complications to the veteran and the US health care system, the VHA has long recognized the importance of preventive care for those at risk. In 2017 US Department of Veterans Affairs (VA) and Department of Defense issued a clinical practice guideline for the management of T2DM that recommended prophylactic foot care for early identification of any deformity or skin breakdown.¹⁰ The guidelines note that a “person who has had a foot ulcer is at lifelong risk of further ulceration,” reflecting the high rate of recurrence among all patients, including veterans. Multiple studies suggest that as many as 40% of patients experience recidivism in the first year after healing from a wound.^11-16

The VA is well equipped to deliver quality preventive care because of its innovative and long-standing PAVE (Prevention of Amputations for Veterans Everywhere) program.¹⁷ PAVE provides screening, education, appropriate footwear, and stratified care guidelines for veterans at risk for diabetes-related foot complications (Table 1). The practices encouraged by PAVE are evidence-based and synergistic with the objectives of the VA’s patient aligned care team (PACT) delivery approach.¹⁸ The granular data collected through PAVE are used to guide best practices and provide benchmarks for diabetic foot outcomes.

Unfortunately, despite PAVE guidelines requiring annual specialist foot care for at-risk veterans, a 2013 report by the VA Office of the Inspector General (OIG) found that one-third of all patients had no documentation of this minimal requirement of preventive foot care.¹⁹ Although the VA has worked to address this issue, the data hint at the missed opportunities for prevention of complications and the challenges of ensuring that a large at-risk veteran population has systematic and routine screening with access to specialist foot care.

Given the large proportion of veterans at high risk of chronic wound formation and the challenges of ensuring that this cohort receives good preventive foot care, expanding telemedicine has been suggested. Telemedicine solutions have the potential to reduce the impact of chronic wounds on overburdened clinic resources, schedules, and local and federal budgets.²⁰ Interestingly, the only preventive practice for the diabetic foot that has been proven effective through multiple randomized controlled trials and national and international clinical guidance documents is once-daily foot temperature monitoring.^21-26 Daily monitoring has the potential to reduce the burden of DFUs to veterans, improve veteran access to needed preventive care, and reduce costs incurred by the VHA treating diabetic foot complications. Yet despite a recent national guidance document detailing its appropriate use in PAVE 3 veterans, it remains underutilized.²⁷

The purpose of this review is to: (1) discuss the evidence supporting once-daily remote temperature monitoring (RTM), a telemedicine approach critical to improving both veteran access to care and diabetic foot outcomes; (2) summarize a 2017 study that presented an advanced clinical understanding of RTM use among veterans; (3) provide previously unpublished data from this study comparing high-risk VA and non-VA cohorts, highlighting the opportunity for additional focus on foot ulcer prevention within the VA; and (4) report on recent VA utilization of a RTM technology based on this research, emphasizing lessons learned and best practices.

Remote Temperature Monitoring

The objective of daily foot temperature monitoring is to identify impending inflammatory foot conditions, such as DFUs, infection, and acute Charcot neuroarthropathy episodes. The patient and care team then act to resolve the cause of detected inflammation before clinical presentation (prevention) and begin treatment earlier than would otherwise be possible to avoid expensive complications, such as infection (early detection). Preventive therapies are low risk to the patient and inexpensive.

RTM is recommended by multiple clinical practice guidelines, including those of the International Working Group on the Diabetic Foot, the American College of Foot and Ankle Surgeons, and the Wound Healing Society.^24-26 Its use is supported by evidence from 3 National Institutes of Health-funded and well-designed randomized controlled trials, 1 of which was additionally supported by a VA Health Services Research and Development Service Merit Award.^21-23,28 Conducted between 2004 and 2007, these studies demonstrated the potential to reduce foot ulcer incidence by as much as 85% using a dermal thermometer to identify inflammation and prompt decreased ambulation. Investigators established a clinical monitoring protocol comparing the temperatures between 6 matched locations on the left and right feet. Persistent differences in contralateral temperatures exceeding 2.2°C (4.0°F) were used as a marker for elevated risk and to initiate preventive care. Based on the encouraging results from these studies, a 2017 effectiveness review prepared for the Agency for Healthcare Research and Quality concluded that “home monitoring of foot skin temperature is effective for reducing foot ulcer incidence and recurrence.”²⁹

Accuracy of RTM

A 2017 longitudinal study (NCT02647346) has provided novel data to advance understanding of RTM for the prediction and prevention of DFUs.³⁰ This study was the first to systematically analyze the accuracy of RTM over different monitoring thresholds. The results enable practitioners to deliver risk-stratified preventive care. Policy makers can use the data from this study to weigh the cost and benefits of RTM for population health.

The multicenter trials had 129 participants from 4 VA health care systems: VA Long Beach Healthcare System in California, Miami VA Healthcare System in Florida, Phoenix VA Healthcare System in Arizona, and VA West Los Angeles Healthcare System in California. Each participant was followed for 34 weeks under standard preventive foot care and was instructed to step on a telemedicine SmartMat (Podimetrics, Inc) RTM mat for 20 seconds daily. Participants and investigators were blinded to the temperature data so that the accuracy of temperature monitoring could be assessed. All participants had a history of T2DM and healed DFU. Principal exclusion criteria included unhealed plantar wound, history of proximal lower extremity amputation (ie, above ankle), active Charcot foot disease, and comorbidities that could potentially inhibit an inflammatory response, such as end-stage renal disease, active malignancy, and immunosuppressive diseases.

The investigators reported that RTM with the study mat detected 97% of nonacute plantar DFUs using the most commonly studied threshold (sustained 2.2°C temperature difference). The lead time averaged 37 days before clinical identification of the wound under standard care. Although the false-positive rate of 57% was high, corresponding to approximately 3.0 notifications per patient per year on average in the research setting, it is important to note that this study only considered the prediction of plantar DFUs. Thus, detection of foot inflammation secondary to other conditions, such as preulcerative lesion, dorsal wound, Charcot neuroarthropathy, or foot infection, were reported as a false positive per the study’s definitions. Further, Crisologo and Lavery noted in a translational medicine summary of this research, because the intervention is noninvasive and minimally impactful to the patient and the health care system, “the potential to arrest re-ulceration is worth the perceived inconvenience to the patient.”³¹

Secondary outcomes related to adherence and ease of use were encouraging. Eighty-eight percent of participants reported that the mat was “very easy to use,” the highest possible score, and 98% were able to set up the mat for home use without difficulty. At the end of the 34-week study, more than 74% of participants remained engaged in routine use of the mat under a per-protocol assessment of adherence. These results are especially impressive given the documented poor adherence of at-risk patients to routine use of therapeutic footwear, which has been reported to be as low as 15%.³²

New Research

The data collected during this study has led to new research and advancements in RTM. A recent publication by Gordon and colleagues investigated whether RTM is less accurate in cohorts with perceived challenges.³³ They include patients with recently healed wounds and those with a history of partial foot amputation. There was no difference in the accuracy or lead time for either cohort relative to the entire cohort, suggesting that RTM is appropriate for monitoring patients with recently healed DFUs or partial foot amputations.

In another recent study, the data were used to derive a novel approach to monitor a single at-risk foot.³⁴ The practice of RTM has traditionally required comparing temperatures between contralaterally matched plantar locations on the feet, thus limiting its use in patients with a history of major lower extremity amputation and patients being treated for a wound, which may be bandaged or in an off-loading cast or boot. Because the risk factors for DFUs exist in both limbs, these patients are at high risk for developing complications to the contralateral foot and may benefit from preventive once-daily foot temperature monitoring. The investigators empirically derived a novel monitoring approach for patients without a contralateral control. This approach was found to predict 91% of impending plantar DFUs on average 41 days before clinical presentation with a false positive rate of 54%.

Additional Focus on Prevention

Table 2 shows previously unpublished data from a subgroup analysis between veteran and nonveteran participants in the study.²⁵ These descriptive statistics reinforce some widely held assumptions regarding the high-risk veteran population and challenge others. For example, compared with the nonveteran participants, the veteran cohort unsurprisingly had a larger ratio of male participants (P < .01), had a higher rate of cigarette use (P < .01), and was more likely to live alone (although not at a statistically significant level). Veterans in the study had body mass index, rates of alcohol use, frequency of exercise, and glucose control comparable to that of nonveterans.

The potential impact of the PAVE program is clear in several of these comparisons. Although as few as 15% of patients use therapeutic shoes routinely, PAVE ensures that the majority of veterans receive them. Nearly 95% of veterans have therapeutic shoes compared with about 80% of nonveteran participants (P < .05). Veterans also had higher ankle-brachial index results (P < .05), although on average both cohorts were within normal clinical parameters. Veterans had a significantly longer duration since healing from the most recent wound, and fewer veteran participants had a wound that healed in the 3 months prior to the study. Despite this, during the study veterans had annualized DFU incidence equal to that of nonveterans. Furthermore, veterans also had significantly higher rates of amputation prior to participation. That these critical outcomes for veterans are no better than those observed in other care environments despite PAVE suggests that approaches recommended via PAVE alone are insufficient to significantly arrest DFU recurrence, and even more focus on prevention in the VA may be warranted.

From Research to Practice

Since the publication of the 2017 study, the VHA has been at the vanguard of translating the evidence and research underlying RTM into clinical practice. A clinical guidance document governing appropriate use of RTM with the study mat was recently published by the VA Prosthetic and Sensory Aids Service in collaboration with the National Podiatry Program office.²⁷ This guidance document recommends once-daily RTM for at-risk veterans designated PAVE level 3. It defines roles and responsibilities required for the successful implementation of a RTM program with the study device. The document additionally presents various clinical monitoring protocols for veterans, although the protocol and thresholds used are at the discretion of the prescribing clinician and should reflect the risk profile of the veteran in question.

A staged response to inflammation has proven popular, whereby an initial high-sensitivity threshold is chosen for monitoring. The initial response is telephone outreach by a designee supplied by the clinic or device manufacturer, typically a trained registered nurse, to the veteran to collect subjective history and instruct off-loading and reduced ambulation, with a target of 50% baseline reduction in step count. Should the inflammation persist despite off-loading, an examination may be necessary to identify and resolve its cause. For recalcitrant inflammation, more targeted pressure off-loading of the affected area may be accomplished with custom orthotics, accommodative insoles, removable cast walkers, and total contact casting. After 2 to 4 weeks without signs of inflammation, the cause is deemed to have been resolved and lowered the acute risk for developing further diabetic foot complications.

More than 600 veterans have been monitored for > 1,000 patient-years—13 VA medical centers are practicing RTM with the study mat as of this writing. The monitoring program has been integrated into many veteran daily routines as evidenced by > 70% retaining full engagement after having been monitored for > 1 year. The total number of alerts/patient-years across these veterans has been 1.4, significantly lower than the 3.0 alerts/patient-year observed in the study. This is potentially due to successful interventions in response to detected inflammation, resolving inflammation, and avoiding unnecessary alerts occurring in the research setting, which did not employ interventions that resolved inflammation episodes. In the past 6 months, 68% of all inflammation detected resolved via off-loading alone without requiring further clinical intervention. In the cases that required an examination, 76% of patients reported clinically meaningful preventive care (eg, preulcerative callus was debrided, a subungual hemorrhage was treated, a foot ulcer was identified).

Organizational Best Practices

Several best practices have been cultivated related to initiating a RTM program at a new site, for promoting the success of a RTM program, and provisioning excellent preventive care to support the RTM program. Although we advise adhering to the recommendations in the VA guidance document,²⁷ the authors have observed several additional organizational best practices that are not explicitly addressed.

Partnering with PACT. Collaboration between PAVE and PACT has the potential not only to improve outcomes for patients at risk for diabetic foot complications, but also can help identify appropriate high-risk veteran candidates for preventive care with RTM who may not be followed for routine care from a specialty provider, such as a podiatrist, as highlighted by the 2013 OIG report.

Prescreening eligible patients. Several programs have used PAVE data or appointment schedules to identify and target high-risk veterans proactively. This approach has several benefits. It simplifies clinical coordination and streamlines workflow for patient identification and onboarding. It also allows those veterans at highest risk to receive needed and recommended preventive care at their next scheduled appointment. Finally, if PAVE data are used to identify eligible patients, it has the added benefit of ensuring a baseline level of telemedicine preventive foot care for veterans who have become lost to follow-up and have not been seen recently for a routine foot examination.

Implementing foot monitoring during wound treatment. Recent research has expanded the reach of once-daily RTM with the mat to patients being treated for a wound to only 1 foot. This practice has 2 benefits: The patient is able to establish a preventive routine before healing, an important advantage because research strongly suggests that recurrence is most likely in the first months after healing. Second, 48% of patients with a history of DFUs will develop new wounds to the contralateral foot because risk factors, such as neuropathy and peripheral arterial disease, exist in both limbs.³⁵ Furthermore, ongoing treatment for a wound to 1 foot may result in gait deviation and elevated pressure to the sound foot, additionally predisposing the veteran to complications, resulting in a high rate of wounds occurring to the unwounded foot during treatment (0.2 DFU/DFU-year).³⁴ Thus, there is potential benefit in monitoring the sound foot while undergoing treatment for a wound; further, the patient will have immediate access to the device for prevention of recurrence once the wound has resolved.

Utilizing foot monitoring as an extension of telemedicine. Many VA facilities have large geographic catchment areas, making routine follow-up difficult for veterans living in rural areas. RTM serves as an extension of the patient’s daily self-examination and the clinician’s ability to monitor patients with objective information daily. The veterans using the system become more invested and feel as though they are taking an active role in their health care.

Investing in ongoing medical education. Multidisciplinary education sessions reviewing supporting clinical data and resultant clinical practice guidelines raise awareness for those providers and trainees unaware of preventive best practices for the diabetic foot, including those related to foot RTM. These sessions also are helpful for those familiar with foot temperature monitoring or who are responsible for administration of an ongoing program to remain current with contemporary best practices and to discuss improvements for patient care. Familiarity also can help address clinical inertia when benefits and evidence are clearly communicated with health care providers (HCPs).

Clinical Best Practices

Treating preulcerative lesions urgently and aggressively. Callus and other preulcerative lesions often cause progressive tissue damage and poor outcomes. When identified, these lesions should be promptly treated to ensure best outcomes.²⁴

Recognizing the limits of patient self-examinations. Comorbidities such as visual impairment and reduced joint mobility often preclude patients from completing rigorous self-examinations of the foot, which is especially critical while collecting subjective history from the patient during triage of inflammation. A caregiver or spouse can help inspect the foot during outreach and provide additional context.³⁶

Interpreting a benign foot on examination. Because RTM has been demonstrated to detect inflammation preceding a foot ulcer as many as 5 weeks before presentation to the clinic, some veterans may have few signs or symptoms of acute risk during examination. Often, the damage is to subcutaneous tissue resulting from repetitive microtrauma. Research suggests that clinical examination in these cases is often unreliable for identifying the earliest signs of risk, such as palpation to identify subtle temperature changes secondary to inflammation.³⁷ If a patient has refractory inflammation requiring examination and presents with an otherwise unremarkable foot, it is an opportunity to evaluate whether the patient’s shoewear remains appropriate or has worn out, to communicate the veteran’s ongoing elevated risk, and to educate on the importance of diligence in daily foot self-examinations, daily use of the foot temperature monitoring, and continued off-loading until the inflammation resolves.

Communicating the distinction between healing and remission. Although healing is the goal of wound care, patients should be educated that the underlying disease remains after epithelialization. In some cases, tissue deep to the skin has not completed remodeling, and the patient is at acute risk of recurrence. Remission is a powerful metaphor that better describes the patient’s ongoing risk to encourage continued healthy routines and diligent self-care.³⁸Considering the entirety of both feet for recurrence. Critical risk factors for diabetic foot complications, such as peripheral neuropathy and PAD, exist in both limbs, and patients with a history of wounds often develop new complications to different ipsilateral locations, or in as many as 48% of cases, to the contralateral foot.³⁵ For best outcomes, detected inflammation should be treated aggressively independent of whether the location coincides with an area of previous concern.

Encouraging adherence, routine, and empowerment. Advanced diabetes mellitus and neuropathy may impact a patient’s executive function, and multiple studies have reported that patients at risk for inflammatory foot diseases exhibit fatalism toward their foot care and outcomes.^39-41 Consistent education, encouragement, empowerment, and establishment of positive routines are needed to ensure high adherence with all preventive care regimens, including RTM.

Case Presentations

The following case series illustrates many of these clinical best practices and characterizes the potential benefits of RTM to veterans within the VA.

Case 1: Prevention After Healing

A veteran underwent a Chopart amputation and was recommended to use the mat after healing was perceived. Immediately on use of the study mat, the patient was found to have inflammation to the surgical incision (Figure 1). Clinical staff was alerted to the findings, and the patient was instructed to limit further walking and continue off-loading in his removable cast walker, per protocol. The inflammation of the operative foot quickly reduced, and the patient continued healing successfully, potentially avoiding incisional dehiscence and possible postoperative infection.

This case illustrates that patients’ wounds or surgical incisions may not be completely healed on epithelialization. In the immediate phase after closure, HCPs should consider additional protection to avoid complications. This case demonstrates that RTM can provide objective data to help guide care in that critical period.

Case 2: Identifying Preulcerative Lesions

An 88-year-old veteran had a chronic callus under the second metatarsal head. In addition to routine foot care and therapeutic shoes, he was followed with once-daily RTM. Inflammation was noted, and the veteran was seen in the podiatry clinic where debridement of the callus was performed. The difference in temperatures between feet detected by thermography prior to the clinic visits rapidly resolved after callus debridement, indicating that the underlying inflammation had subsided. RTM was used by the clinical staff to determine the appropriate time interval between clinic visits to avoid callus breakdown and subsequent ulceration.

Case 3: Extending the Clinic Into the Home

An 80-year-old veteran with T2DM and neuropathy was deemed a high-risk patient due to recurrent ulcerations to the left great toe. He was issued a RTM mat and was adherent with routine use. After nearly a year without hot-spot development, inflammation was noted (Figure 2).

Unfortunately, the patient had missed several routine foot care visits and likely that was the reason for the noted inflammation. The patient was called and became reengaged in regular visits for routine foot care. On debridement of his callus, a superficial, noninfected ulceration was discovered. Had remote monitoring not detected the inflammation and impending ulceration, the patient likely would not have been seen in the regular clinic and may have developed a wound infection, potentially resulting in a worse and more costly outcome.

Paradigm Shift to Prevention

Given the exceedingly high burden of diabetic foot complications in the VA, a paradigm shift is needed among HCPs from a culture of treatment to one of prevention. Bus and colleagues reported that in Europe, for every euro spent on ulcer prevention, 10 are spent on ulcer healing, and for every randomized clinical trial conducted on prevention, 10 are conducted on treatment.^42-44 Hicks and colleagues showed that the cost of curative care for DFUs is 5 to 30 times greater than the cost of preventive care.⁴⁵ For RTM in high-risk cohorts (ie, PAVE level 3), the number-needed-to-treat for DFU prevention may be as low as 6, assuming that a 70% reduction in incidence is possible, consistent with previous research. In the year following a DFU, costs exceed $44,000.⁹ Thus, it seems natural that future direction in diabetic foot care should emphasize prevention strategies.

Foot ulcers that become infected often lead to hospitalization and result in an increased burden to an already overburdened VA health care system. Research suggests that about two-thirds of all diabetic foot costs are attributable to inpatient management.⁴⁶ The impact of diabetic foot complications on hospital resource utilization is staggering. A 2017 study by Skrepnik analyzed the risk of hospitalization for various diseases.⁴⁷ The investigators found that the inpatient admission odds ratio (OR) for congestive heart failure was 2.6, surpassed only by DFUs (OR, 3.4) and diabetic foot infection (OR, 6.7). A 2019 point-prevalence study found that > 10% of hospital admissions have a foot-related condition as the primary or secondary reason, and the majority of these are due to foot diseases, such as ulcers, infections, and Charcot neuroarthropathy.⁴⁸

It is therefore incumbent on VA HCPs to avert wound recurrence in the interest of avoiding veteran hospitalizations and for administrators to encourage and incentivize best practices for managing the diabetic foot, with an emphasis on prevention therapies. In evaluating the financial impact of prevention with foot RTM, administrators should consider that the cost benefit is likely to be realized across the medical center, with budgets related to inpatient management likely to receive the largest returns.

Prevention has the potential to rein in costs as well as reduce strain on the hospital and clinic by preventing outcomes that require frequent visits for treatment or hospitalization. Wound treatment is very burdensome to the clinic; patients require frequent (in many cases, weekly) examinations, and chronic wounds often require hospitalization, necessitating rounding and additional coordination in care. Thus, preventing wounds or reducing their severity at presentation substantially reduces burden on the clinic, even after accounting for the modest clinical resources needed to administer preventative care. For example, a brief examination may be necessary if the inflammation detected by the study mat is secondary to a callus that must be debrided. However, if the patient was not seen until the callus had progressed to a wound, weekly follow-up and substantial clinical and budgetary resources may be required to heal the wound. Preventive care allows for substantially better patient outcomes, and the minimal time invested prevents the clinical burden of extensive wound treatment.

The success of preventive efforts relies on multidisciplinary management of this high-risk patient cohort. Often, it is the responsibility of the primary care provider to follow diabetic foot clinical reminders and appropriately refer to specialty care. Successful, open communication between PACT, PAVE, and the Podiatry Service has been shown to reduce poor outcomes, including lower extremity amputations. Traditionally, the model of preventive care has included podiatrist-driven interventions, including integrated routine foot care and comprehensive diabetic foot education. Collaboration between routine evaluation and prompt referral of at-risk patients for specialist foot care, therapeutic footwear recommendations, daily self-foot examinations, and in-home temperature monitoring are critically effective when performed consistently.

When trying to translate research science to effective clinical practice for preventing lower extremity complication, there are several important concepts. First, given the frequency of examination for patients being treated for a wound, provision of good preventive care, such as RTM, can reduce overall burden to resource-constrained clinics and improve access for patients needing to be seen. Additionally, preventive efforts extend clinical practice into the home and may reduce the need for in-clinic examinations and routine follow-up visits. Finally, there may be a sense of trust established between the clinician and patient with a positive record of adherence with preventive practices. This may translate into more productive communication and less frequent routine visits to better accommodate urgent visits and ensure podiatric care is accessible to veterans.

Conclusions

There is a significant opportunity to shift diabetic foot care from treatment to prevention, improving veteran outcomes and reducing resource utilization. RTM is an evidence-based and recommended but underused telemedicine solution that can catalyze this needed paradigm shift. The VA has been at the forefront of preventive foot care through the PAVE program and more recently through research and clinical application of RTM for veterans. However, as the data presented suggest, more can be done to improve veteran outcomes. More widespread adoption of evidence-based preventive technologies for the diabetic foot, such as RTM, has the potential to dramatically improve the quality of and access to care and reduce costs and burden on resource-constrained clinics.

Diabetic foot ulcers (DFUs) are devastating, common, and costly. This burden is borne disproportionately by veterans who have high prevalence of type 2 diabetes mellitus (T2DM) and other precipitating risk factors.¹ The mortality of veterans following a DFU is sobering, and ulceration is recognized as a significant marker of disease severity.

A 2017 study by Brennan and colleagues reported a 19% mortality rate within 1 year, and only 29% survive past 5 years.² DFUs are often complicated by peripheral arterial disease (PAD) and diabetic immune dysfunction, contributing to chronic wounds and infection.^3,4 About 60% of all foot ulcers become infected, and > 20% of patients with a diabetic foot infection require amputation.^5,6

A 2010 retrospective study reports that > 3,400 veterans have a diabetes-related lower extremity amputation annually, vastly surpassing the rate of amputation secondary to trauma in the Veterans Health Administration (VHA).^7,8 The inpatient costs for each amputation exceeded $60,000 in fiscal year 2010, and these amputation-related costs represent only 1 component of the total expense to the VHA attributable to diabetic foot complications.⁷ A recent systematic review by Chan and colleagues estimated mean annual costs in the year following a foot ulcer to be $44,200 to the public payer.⁹ This implies that direct expenditures for treatment of DFUs within the VHA exceeds $3 billion annually.

Diabetic Foot Ulcer Prevention

Given the dramatic impact of diabetic foot complications to the veteran and the US health care system, the VHA has long recognized the importance of preventive care for those at risk. In 2017 US Department of Veterans Affairs (VA) and Department of Defense issued a clinical practice guideline for the management of T2DM that recommended prophylactic foot care for early identification of any deformity or skin breakdown.¹⁰ The guidelines note that a “person who has had a foot ulcer is at lifelong risk of further ulceration,” reflecting the high rate of recurrence among all patients, including veterans. Multiple studies suggest that as many as 40% of patients experience recidivism in the first year after healing from a wound.^11-16

The VA is well equipped to deliver quality preventive care because of its innovative and long-standing PAVE (Prevention of Amputations for Veterans Everywhere) program.¹⁷ PAVE provides screening, education, appropriate footwear, and stratified care guidelines for veterans at risk for diabetes-related foot complications (Table 1). The practices encouraged by PAVE are evidence-based and synergistic with the objectives of the VA’s patient aligned care team (PACT) delivery approach.¹⁸ The granular data collected through PAVE are used to guide best practices and provide benchmarks for diabetic foot outcomes.

Unfortunately, despite PAVE guidelines requiring annual specialist foot care for at-risk veterans, a 2013 report by the VA Office of the Inspector General (OIG) found that one-third of all patients had no documentation of this minimal requirement of preventive foot care.¹⁹ Although the VA has worked to address this issue, the data hint at the missed opportunities for prevention of complications and the challenges of ensuring that a large at-risk veteran population has systematic and routine screening with access to specialist foot care.

Given the large proportion of veterans at high risk of chronic wound formation and the challenges of ensuring that this cohort receives good preventive foot care, expanding telemedicine has been suggested. Telemedicine solutions have the potential to reduce the impact of chronic wounds on overburdened clinic resources, schedules, and local and federal budgets.²⁰ Interestingly, the only preventive practice for the diabetic foot that has been proven effective through multiple randomized controlled trials and national and international clinical guidance documents is once-daily foot temperature monitoring.^21-26 Daily monitoring has the potential to reduce the burden of DFUs to veterans, improve veteran access to needed preventive care, and reduce costs incurred by the VHA treating diabetic foot complications. Yet despite a recent national guidance document detailing its appropriate use in PAVE 3 veterans, it remains underutilized.²⁷

The purpose of this review is to: (1) discuss the evidence supporting once-daily remote temperature monitoring (RTM), a telemedicine approach critical to improving both veteran access to care and diabetic foot outcomes; (2) summarize a 2017 study that presented an advanced clinical understanding of RTM use among veterans; (3) provide previously unpublished data from this study comparing high-risk VA and non-VA cohorts, highlighting the opportunity for additional focus on foot ulcer prevention within the VA; and (4) report on recent VA utilization of a RTM technology based on this research, emphasizing lessons learned and best practices.

Remote Temperature Monitoring

The objective of daily foot temperature monitoring is to identify impending inflammatory foot conditions, such as DFUs, infection, and acute Charcot neuroarthropathy episodes. The patient and care team then act to resolve the cause of detected inflammation before clinical presentation (prevention) and begin treatment earlier than would otherwise be possible to avoid expensive complications, such as infection (early detection). Preventive therapies are low risk to the patient and inexpensive.

RTM is recommended by multiple clinical practice guidelines, including those of the International Working Group on the Diabetic Foot, the American College of Foot and Ankle Surgeons, and the Wound Healing Society.^24-26 Its use is supported by evidence from 3 National Institutes of Health-funded and well-designed randomized controlled trials, 1 of which was additionally supported by a VA Health Services Research and Development Service Merit Award.^21-23,28 Conducted between 2004 and 2007, these studies demonstrated the potential to reduce foot ulcer incidence by as much as 85% using a dermal thermometer to identify inflammation and prompt decreased ambulation. Investigators established a clinical monitoring protocol comparing the temperatures between 6 matched locations on the left and right feet. Persistent differences in contralateral temperatures exceeding 2.2°C (4.0°F) were used as a marker for elevated risk and to initiate preventive care. Based on the encouraging results from these studies, a 2017 effectiveness review prepared for the Agency for Healthcare Research and Quality concluded that “home monitoring of foot skin temperature is effective for reducing foot ulcer incidence and recurrence.”²⁹

Accuracy of RTM

A 2017 longitudinal study (NCT02647346) has provided novel data to advance understanding of RTM for the prediction and prevention of DFUs.³⁰ This study was the first to systematically analyze the accuracy of RTM over different monitoring thresholds. The results enable practitioners to deliver risk-stratified preventive care. Policy makers can use the data from this study to weigh the cost and benefits of RTM for population health.

The multicenter trials had 129 participants from 4 VA health care systems: VA Long Beach Healthcare System in California, Miami VA Healthcare System in Florida, Phoenix VA Healthcare System in Arizona, and VA West Los Angeles Healthcare System in California. Each participant was followed for 34 weeks under standard preventive foot care and was instructed to step on a telemedicine SmartMat (Podimetrics, Inc) RTM mat for 20 seconds daily. Participants and investigators were blinded to the temperature data so that the accuracy of temperature monitoring could be assessed. All participants had a history of T2DM and healed DFU. Principal exclusion criteria included unhealed plantar wound, history of proximal lower extremity amputation (ie, above ankle), active Charcot foot disease, and comorbidities that could potentially inhibit an inflammatory response, such as end-stage renal disease, active malignancy, and immunosuppressive diseases.

The investigators reported that RTM with the study mat detected 97% of nonacute plantar DFUs using the most commonly studied threshold (sustained 2.2°C temperature difference). The lead time averaged 37 days before clinical identification of the wound under standard care. Although the false-positive rate of 57% was high, corresponding to approximately 3.0 notifications per patient per year on average in the research setting, it is important to note that this study only considered the prediction of plantar DFUs. Thus, detection of foot inflammation secondary to other conditions, such as preulcerative lesion, dorsal wound, Charcot neuroarthropathy, or foot infection, were reported as a false positive per the study’s definitions. Further, Crisologo and Lavery noted in a translational medicine summary of this research, because the intervention is noninvasive and minimally impactful to the patient and the health care system, “the potential to arrest re-ulceration is worth the perceived inconvenience to the patient.”³¹

Secondary outcomes related to adherence and ease of use were encouraging. Eighty-eight percent of participants reported that the mat was “very easy to use,” the highest possible score, and 98% were able to set up the mat for home use without difficulty. At the end of the 34-week study, more than 74% of participants remained engaged in routine use of the mat under a per-protocol assessment of adherence. These results are especially impressive given the documented poor adherence of at-risk patients to routine use of therapeutic footwear, which has been reported to be as low as 15%.³²

New Research

The data collected during this study has led to new research and advancements in RTM. A recent publication by Gordon and colleagues investigated whether RTM is less accurate in cohorts with perceived challenges.³³ They include patients with recently healed wounds and those with a history of partial foot amputation. There was no difference in the accuracy or lead time for either cohort relative to the entire cohort, suggesting that RTM is appropriate for monitoring patients with recently healed DFUs or partial foot amputations.

In another recent study, the data were used to derive a novel approach to monitor a single at-risk foot.³⁴ The practice of RTM has traditionally required comparing temperatures between contralaterally matched plantar locations on the feet, thus limiting its use in patients with a history of major lower extremity amputation and patients being treated for a wound, which may be bandaged or in an off-loading cast or boot. Because the risk factors for DFUs exist in both limbs, these patients are at high risk for developing complications to the contralateral foot and may benefit from preventive once-daily foot temperature monitoring. The investigators empirically derived a novel monitoring approach for patients without a contralateral control. This approach was found to predict 91% of impending plantar DFUs on average 41 days before clinical presentation with a false positive rate of 54%.

Additional Focus on Prevention

Table 2 shows previously unpublished data from a subgroup analysis between veteran and nonveteran participants in the study.²⁵ These descriptive statistics reinforce some widely held assumptions regarding the high-risk veteran population and challenge others. For example, compared with the nonveteran participants, the veteran cohort unsurprisingly had a larger ratio of male participants (P < .01), had a higher rate of cigarette use (P < .01), and was more likely to live alone (although not at a statistically significant level). Veterans in the study had body mass index, rates of alcohol use, frequency of exercise, and glucose control comparable to that of nonveterans.

The potential impact of the PAVE program is clear in several of these comparisons. Although as few as 15% of patients use therapeutic shoes routinely, PAVE ensures that the majority of veterans receive them. Nearly 95% of veterans have therapeutic shoes compared with about 80% of nonveteran participants (P < .05). Veterans also had higher ankle-brachial index results (P < .05), although on average both cohorts were within normal clinical parameters. Veterans had a significantly longer duration since healing from the most recent wound, and fewer veteran participants had a wound that healed in the 3 months prior to the study. Despite this, during the study veterans had annualized DFU incidence equal to that of nonveterans. Furthermore, veterans also had significantly higher rates of amputation prior to participation. That these critical outcomes for veterans are no better than those observed in other care environments despite PAVE suggests that approaches recommended via PAVE alone are insufficient to significantly arrest DFU recurrence, and even more focus on prevention in the VA may be warranted.

From Research to Practice

Since the publication of the 2017 study, the VHA has been at the vanguard of translating the evidence and research underlying RTM into clinical practice. A clinical guidance document governing appropriate use of RTM with the study mat was recently published by the VA Prosthetic and Sensory Aids Service in collaboration with the National Podiatry Program office.²⁷ This guidance document recommends once-daily RTM for at-risk veterans designated PAVE level 3. It defines roles and responsibilities required for the successful implementation of a RTM program with the study device. The document additionally presents various clinical monitoring protocols for veterans, although the protocol and thresholds used are at the discretion of the prescribing clinician and should reflect the risk profile of the veteran in question.

A staged response to inflammation has proven popular, whereby an initial high-sensitivity threshold is chosen for monitoring. The initial response is telephone outreach by a designee supplied by the clinic or device manufacturer, typically a trained registered nurse, to the veteran to collect subjective history and instruct off-loading and reduced ambulation, with a target of 50% baseline reduction in step count. Should the inflammation persist despite off-loading, an examination may be necessary to identify and resolve its cause. For recalcitrant inflammation, more targeted pressure off-loading of the affected area may be accomplished with custom orthotics, accommodative insoles, removable cast walkers, and total contact casting. After 2 to 4 weeks without signs of inflammation, the cause is deemed to have been resolved and lowered the acute risk for developing further diabetic foot complications.

More than 600 veterans have been monitored for > 1,000 patient-years—13 VA medical centers are practicing RTM with the study mat as of this writing. The monitoring program has been integrated into many veteran daily routines as evidenced by > 70% retaining full engagement after having been monitored for > 1 year. The total number of alerts/patient-years across these veterans has been 1.4, significantly lower than the 3.0 alerts/patient-year observed in the study. This is potentially due to successful interventions in response to detected inflammation, resolving inflammation, and avoiding unnecessary alerts occurring in the research setting, which did not employ interventions that resolved inflammation episodes. In the past 6 months, 68% of all inflammation detected resolved via off-loading alone without requiring further clinical intervention. In the cases that required an examination, 76% of patients reported clinically meaningful preventive care (eg, preulcerative callus was debrided, a subungual hemorrhage was treated, a foot ulcer was identified).

Organizational Best Practices

Several best practices have been cultivated related to initiating a RTM program at a new site, for promoting the success of a RTM program, and provisioning excellent preventive care to support the RTM program. Although we advise adhering to the recommendations in the VA guidance document,²⁷ the authors have observed several additional organizational best practices that are not explicitly addressed.

Partnering with PACT. Collaboration between PAVE and PACT has the potential not only to improve outcomes for patients at risk for diabetic foot complications, but also can help identify appropriate high-risk veteran candidates for preventive care with RTM who may not be followed for routine care from a specialty provider, such as a podiatrist, as highlighted by the 2013 OIG report.

Prescreening eligible patients. Several programs have used PAVE data or appointment schedules to identify and target high-risk veterans proactively. This approach has several benefits. It simplifies clinical coordination and streamlines workflow for patient identification and onboarding. It also allows those veterans at highest risk to receive needed and recommended preventive care at their next scheduled appointment. Finally, if PAVE data are used to identify eligible patients, it has the added benefit of ensuring a baseline level of telemedicine preventive foot care for veterans who have become lost to follow-up and have not been seen recently for a routine foot examination.

Implementing foot monitoring during wound treatment. Recent research has expanded the reach of once-daily RTM with the mat to patients being treated for a wound to only 1 foot. This practice has 2 benefits: The patient is able to establish a preventive routine before healing, an important advantage because research strongly suggests that recurrence is most likely in the first months after healing. Second, 48% of patients with a history of DFUs will develop new wounds to the contralateral foot because risk factors, such as neuropathy and peripheral arterial disease, exist in both limbs.³⁵ Furthermore, ongoing treatment for a wound to 1 foot may result in gait deviation and elevated pressure to the sound foot, additionally predisposing the veteran to complications, resulting in a high rate of wounds occurring to the unwounded foot during treatment (0.2 DFU/DFU-year).³⁴ Thus, there is potential benefit in monitoring the sound foot while undergoing treatment for a wound; further, the patient will have immediate access to the device for prevention of recurrence once the wound has resolved.

Utilizing foot monitoring as an extension of telemedicine. Many VA facilities have large geographic catchment areas, making routine follow-up difficult for veterans living in rural areas. RTM serves as an extension of the patient’s daily self-examination and the clinician’s ability to monitor patients with objective information daily. The veterans using the system become more invested and feel as though they are taking an active role in their health care.

Investing in ongoing medical education. Multidisciplinary education sessions reviewing supporting clinical data and resultant clinical practice guidelines raise awareness for those providers and trainees unaware of preventive best practices for the diabetic foot, including those related to foot RTM. These sessions also are helpful for those familiar with foot temperature monitoring or who are responsible for administration of an ongoing program to remain current with contemporary best practices and to discuss improvements for patient care. Familiarity also can help address clinical inertia when benefits and evidence are clearly communicated with health care providers (HCPs).

Clinical Best Practices

Treating preulcerative lesions urgently and aggressively. Callus and other preulcerative lesions often cause progressive tissue damage and poor outcomes. When identified, these lesions should be promptly treated to ensure best outcomes.²⁴

Recognizing the limits of patient self-examinations. Comorbidities such as visual impairment and reduced joint mobility often preclude patients from completing rigorous self-examinations of the foot, which is especially critical while collecting subjective history from the patient during triage of inflammation. A caregiver or spouse can help inspect the foot during outreach and provide additional context.³⁶

Interpreting a benign foot on examination. Because RTM has been demonstrated to detect inflammation preceding a foot ulcer as many as 5 weeks before presentation to the clinic, some veterans may have few signs or symptoms of acute risk during examination. Often, the damage is to subcutaneous tissue resulting from repetitive microtrauma. Research suggests that clinical examination in these cases is often unreliable for identifying the earliest signs of risk, such as palpation to identify subtle temperature changes secondary to inflammation.³⁷ If a patient has refractory inflammation requiring examination and presents with an otherwise unremarkable foot, it is an opportunity to evaluate whether the patient’s shoewear remains appropriate or has worn out, to communicate the veteran’s ongoing elevated risk, and to educate on the importance of diligence in daily foot self-examinations, daily use of the foot temperature monitoring, and continued off-loading until the inflammation resolves.

Communicating the distinction between healing and remission. Although healing is the goal of wound care, patients should be educated that the underlying disease remains after epithelialization. In some cases, tissue deep to the skin has not completed remodeling, and the patient is at acute risk of recurrence. Remission is a powerful metaphor that better describes the patient’s ongoing risk to encourage continued healthy routines and diligent self-care.³⁸Considering the entirety of both feet for recurrence. Critical risk factors for diabetic foot complications, such as peripheral neuropathy and PAD, exist in both limbs, and patients with a history of wounds often develop new complications to different ipsilateral locations, or in as many as 48% of cases, to the contralateral foot.³⁵ For best outcomes, detected inflammation should be treated aggressively independent of whether the location coincides with an area of previous concern.

Encouraging adherence, routine, and empowerment. Advanced diabetes mellitus and neuropathy may impact a patient’s executive function, and multiple studies have reported that patients at risk for inflammatory foot diseases exhibit fatalism toward their foot care and outcomes.^39-41 Consistent education, encouragement, empowerment, and establishment of positive routines are needed to ensure high adherence with all preventive care regimens, including RTM.

Case Presentations

The following case series illustrates many of these clinical best practices and characterizes the potential benefits of RTM to veterans within the VA.

Case 1: Prevention After Healing

A veteran underwent a Chopart amputation and was recommended to use the mat after healing was perceived. Immediately on use of the study mat, the patient was found to have inflammation to the surgical incision (Figure 1). Clinical staff was alerted to the findings, and the patient was instructed to limit further walking and continue off-loading in his removable cast walker, per protocol. The inflammation of the operative foot quickly reduced, and the patient continued healing successfully, potentially avoiding incisional dehiscence and possible postoperative infection.

This case illustrates that patients’ wounds or surgical incisions may not be completely healed on epithelialization. In the immediate phase after closure, HCPs should consider additional protection to avoid complications. This case demonstrates that RTM can provide objective data to help guide care in that critical period.

Case 2: Identifying Preulcerative Lesions

An 88-year-old veteran had a chronic callus under the second metatarsal head. In addition to routine foot care and therapeutic shoes, he was followed with once-daily RTM. Inflammation was noted, and the veteran was seen in the podiatry clinic where debridement of the callus was performed. The difference in temperatures between feet detected by thermography prior to the clinic visits rapidly resolved after callus debridement, indicating that the underlying inflammation had subsided. RTM was used by the clinical staff to determine the appropriate time interval between clinic visits to avoid callus breakdown and subsequent ulceration.

Case 3: Extending the Clinic Into the Home

An 80-year-old veteran with T2DM and neuropathy was deemed a high-risk patient due to recurrent ulcerations to the left great toe. He was issued a RTM mat and was adherent with routine use. After nearly a year without hot-spot development, inflammation was noted (Figure 2).

Unfortunately, the patient had missed several routine foot care visits and likely that was the reason for the noted inflammation. The patient was called and became reengaged in regular visits for routine foot care. On debridement of his callus, a superficial, noninfected ulceration was discovered. Had remote monitoring not detected the inflammation and impending ulceration, the patient likely would not have been seen in the regular clinic and may have developed a wound infection, potentially resulting in a worse and more costly outcome.

Paradigm Shift to Prevention

Given the exceedingly high burden of diabetic foot complications in the VA, a paradigm shift is needed among HCPs from a culture of treatment to one of prevention. Bus and colleagues reported that in Europe, for every euro spent on ulcer prevention, 10 are spent on ulcer healing, and for every randomized clinical trial conducted on prevention, 10 are conducted on treatment.^42-44 Hicks and colleagues showed that the cost of curative care for DFUs is 5 to 30 times greater than the cost of preventive care.⁴⁵ For RTM in high-risk cohorts (ie, PAVE level 3), the number-needed-to-treat for DFU prevention may be as low as 6, assuming that a 70% reduction in incidence is possible, consistent with previous research. In the year following a DFU, costs exceed $44,000.⁹ Thus, it seems natural that future direction in diabetic foot care should emphasize prevention strategies.

Foot ulcers that become infected often lead to hospitalization and result in an increased burden to an already overburdened VA health care system. Research suggests that about two-thirds of all diabetic foot costs are attributable to inpatient management.⁴⁶ The impact of diabetic foot complications on hospital resource utilization is staggering. A 2017 study by Skrepnik analyzed the risk of hospitalization for various diseases.⁴⁷ The investigators found that the inpatient admission odds ratio (OR) for congestive heart failure was 2.6, surpassed only by DFUs (OR, 3.4) and diabetic foot infection (OR, 6.7). A 2019 point-prevalence study found that > 10% of hospital admissions have a foot-related condition as the primary or secondary reason, and the majority of these are due to foot diseases, such as ulcers, infections, and Charcot neuroarthropathy.⁴⁸

It is therefore incumbent on VA HCPs to avert wound recurrence in the interest of avoiding veteran hospitalizations and for administrators to encourage and incentivize best practices for managing the diabetic foot, with an emphasis on prevention therapies. In evaluating the financial impact of prevention with foot RTM, administrators should consider that the cost benefit is likely to be realized across the medical center, with budgets related to inpatient management likely to receive the largest returns.

Prevention has the potential to rein in costs as well as reduce strain on the hospital and clinic by preventing outcomes that require frequent visits for treatment or hospitalization. Wound treatment is very burdensome to the clinic; patients require frequent (in many cases, weekly) examinations, and chronic wounds often require hospitalization, necessitating rounding and additional coordination in care. Thus, preventing wounds or reducing their severity at presentation substantially reduces burden on the clinic, even after accounting for the modest clinical resources needed to administer preventative care. For example, a brief examination may be necessary if the inflammation detected by the study mat is secondary to a callus that must be debrided. However, if the patient was not seen until the callus had progressed to a wound, weekly follow-up and substantial clinical and budgetary resources may be required to heal the wound. Preventive care allows for substantially better patient outcomes, and the minimal time invested prevents the clinical burden of extensive wound treatment.

The success of preventive efforts relies on multidisciplinary management of this high-risk patient cohort. Often, it is the responsibility of the primary care provider to follow diabetic foot clinical reminders and appropriately refer to specialty care. Successful, open communication between PACT, PAVE, and the Podiatry Service has been shown to reduce poor outcomes, including lower extremity amputations. Traditionally, the model of preventive care has included podiatrist-driven interventions, including integrated routine foot care and comprehensive diabetic foot education. Collaboration between routine evaluation and prompt referral of at-risk patients for specialist foot care, therapeutic footwear recommendations, daily self-foot examinations, and in-home temperature monitoring are critically effective when performed consistently.

When trying to translate research science to effective clinical practice for preventing lower extremity complication, there are several important concepts. First, given the frequency of examination for patients being treated for a wound, provision of good preventive care, such as RTM, can reduce overall burden to resource-constrained clinics and improve access for patients needing to be seen. Additionally, preventive efforts extend clinical practice into the home and may reduce the need for in-clinic examinations and routine follow-up visits. Finally, there may be a sense of trust established between the clinician and patient with a positive record of adherence with preventive practices. This may translate into more productive communication and less frequent routine visits to better accommodate urgent visits and ensure podiatric care is accessible to veterans.

Conclusions

There is a significant opportunity to shift diabetic foot care from treatment to prevention, improving veteran outcomes and reducing resource utilization. RTM is an evidence-based and recommended but underused telemedicine solution that can catalyze this needed paradigm shift. The VA has been at the forefront of preventive foot care through the PAVE program and more recently through research and clinical application of RTM for veterans. However, as the data presented suggest, more can be done to improve veteran outcomes. More widespread adoption of evidence-based preventive technologies for the diabetic foot, such as RTM, has the potential to dramatically improve the quality of and access to care and reduce costs and burden on resource-constrained clinics.