Octavio has prostate cancer. His prostate growth is large but localized.

“What do your doctors suggest?” I asked him.

“They sent me to two specialists at the medical center,” he said. “One does robotic surgery, the other does radiation. Each one told me why they recommend their technique.”

“How will you decide?”

“I’ll do some reading,” he said.

“What about the doctor who sent you to them?”

“He hasn’t discussed the choice with me, just sent me to get opinions. I have to make up own mind.”

Out of training for some time, I gather from students and family medical interactions that patient autonomy is now a reigning principle. Here is one definition:

Patient autonomy: The right of patients to make decisions about their medical care without their health care provider trying to influence the decision. Patient autonomy does allow for health care providers to educate the patient but does not allow the health care provider to make the decision for the patient.


This sounds sensible, even admirable: no more paternalistic physicians talking down to patients and ordering them around. Yet a closer look shows a contradiction:

1. The second sentence says that patient autonomy “does not allow the health care provider to make the decision for the patient.”

2. But the first one says that patients should decide, “without their health care provider trying to influence the decision.”

Is “trying to influence” the same as making the decision for the patient?

Some would argue that it is: The power discrepancy between the parties makes a doctor’s attempt to influence amount to coercion.

Do you agree, esteemed colleagues, those of you who, like me, treat patients all day? If the choice is between freezing an actinic keratosis, burning it, or using topical chemotherapy, do you just lay all three options out there and ask the patient to pick one? What if your patient works in public and doesn’t have 2 weeks to wait while the reaction to topical 5-fluorouracil that makes his skin look like raw lobster subsides? Can you point that out? Or would that be “trying to influence” and thus not allowed?

FatCamera/Getty Images

You and I can think of many other examples, about medical choices large and small, where we could pose similar questions. This is not abstract philosophy; it is what we do all day.

Look up robot-assisted surgery and radiation for prostate cancer. You will find proponents of both, each making claims concerning survival, recurrence, discomfort, complications. Which is more important – a 15% greater chance of living 2 years longer or a 22% lower risk of incontinence? Will reading such statistics make your choice easier? What if other studies show different numbers?

Octavio chose surgery. I asked him how he decided.

“I talked with an internist I know socially,” he said. “He shared his experience with patients he’s referred for my problem and advised surgery as the better choice. I also saw a story online about a lawyer who chose one method, then 5 years later had to do the other.”

Octavio is sophisticated and well read. He lives near Boston, the self-described hub of medical expertise and academic excellence. Yet he makes up his mind the way everybody does: by asking a trusted adviser, by hearing an arresting anecdote. It’s not science. It’s how people think.

You don’t have to be a behavioral psychologist to know how hard it is for patients, especially frightened ones, to interpret statistical variances or compare disparate categories. Which is better – shorter life with less pain or longer life with more? How much less? How much more? There are ways to address such questions, but having an expert, trusted, and sympathetic adviser is a pretty good way to start. Only an abstract ethicist with no practical exposure to (or sympathy with) actual existing patients and their actual existing providers could possibly think otherwise.

“Let’s freeze those actinics off,” I suggest to a patient. “That won’t scar, you won’t need a dozen shots of lidocaine, and you won’t have to hide for 3 weeks.”

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at dermnews@mdedge.com.

Octavio has prostate cancer. His prostate growth is large but localized.

“What do your doctors suggest?” I asked him.

“They sent me to two specialists at the medical center,” he said. “One does robotic surgery, the other does radiation. Each one told me why they recommend their technique.”

“How will you decide?”

“I’ll do some reading,” he said.

“What about the doctor who sent you to them?”

“He hasn’t discussed the choice with me, just sent me to get opinions. I have to make up own mind.”

Out of training for some time, I gather from students and family medical interactions that patient autonomy is now a reigning principle. Here is one definition:

Patient autonomy: The right of patients to make decisions about their medical care without their health care provider trying to influence the decision. Patient autonomy does allow for health care providers to educate the patient but does not allow the health care provider to make the decision for the patient.


This sounds sensible, even admirable: no more paternalistic physicians talking down to patients and ordering them around. Yet a closer look shows a contradiction:

1. The second sentence says that patient autonomy “does not allow the health care provider to make the decision for the patient.”

2. But the first one says that patients should decide, “without their health care provider trying to influence the decision.”

Is “trying to influence” the same as making the decision for the patient?

Some would argue that it is: The power discrepancy between the parties makes a doctor’s attempt to influence amount to coercion.

Do you agree, esteemed colleagues, those of you who, like me, treat patients all day? If the choice is between freezing an actinic keratosis, burning it, or using topical chemotherapy, do you just lay all three options out there and ask the patient to pick one? What if your patient works in public and doesn’t have 2 weeks to wait while the reaction to topical 5-fluorouracil that makes his skin look like raw lobster subsides? Can you point that out? Or would that be “trying to influence” and thus not allowed?

FatCamera/Getty Images

You and I can think of many other examples, about medical choices large and small, where we could pose similar questions. This is not abstract philosophy; it is what we do all day.

Look up robot-assisted surgery and radiation for prostate cancer. You will find proponents of both, each making claims concerning survival, recurrence, discomfort, complications. Which is more important – a 15% greater chance of living 2 years longer or a 22% lower risk of incontinence? Will reading such statistics make your choice easier? What if other studies show different numbers?

Octavio chose surgery. I asked him how he decided.

“I talked with an internist I know socially,” he said. “He shared his experience with patients he’s referred for my problem and advised surgery as the better choice. I also saw a story online about a lawyer who chose one method, then 5 years later had to do the other.”

Octavio is sophisticated and well read. He lives near Boston, the self-described hub of medical expertise and academic excellence. Yet he makes up his mind the way everybody does: by asking a trusted adviser, by hearing an arresting anecdote. It’s not science. It’s how people think.

You don’t have to be a behavioral psychologist to know how hard it is for patients, especially frightened ones, to interpret statistical variances or compare disparate categories. Which is better – shorter life with less pain or longer life with more? How much less? How much more? There are ways to address such questions, but having an expert, trusted, and sympathetic adviser is a pretty good way to start. Only an abstract ethicist with no practical exposure to (or sympathy with) actual existing patients and their actual existing providers could possibly think otherwise.

“Let’s freeze those actinics off,” I suggest to a patient. “That won’t scar, you won’t need a dozen shots of lidocaine, and you won’t have to hide for 3 weeks.”

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at dermnews@mdedge.com.

Octavio has prostate cancer. His prostate growth is large but localized.

“What do your doctors suggest?” I asked him.

“They sent me to two specialists at the medical center,” he said. “One does robotic surgery, the other does radiation. Each one told me why they recommend their technique.”

“How will you decide?”

“I’ll do some reading,” he said.

“What about the doctor who sent you to them?”

“He hasn’t discussed the choice with me, just sent me to get opinions. I have to make up own mind.”

Out of training for some time, I gather from students and family medical interactions that patient autonomy is now a reigning principle. Here is one definition:

Patient autonomy: The right of patients to make decisions about their medical care without their health care provider trying to influence the decision. Patient autonomy does allow for health care providers to educate the patient but does not allow the health care provider to make the decision for the patient.


This sounds sensible, even admirable: no more paternalistic physicians talking down to patients and ordering them around. Yet a closer look shows a contradiction:

1. The second sentence says that patient autonomy “does not allow the health care provider to make the decision for the patient.”

2. But the first one says that patients should decide, “without their health care provider trying to influence the decision.”

Is “trying to influence” the same as making the decision for the patient?

Some would argue that it is: The power discrepancy between the parties makes a doctor’s attempt to influence amount to coercion.

Do you agree, esteemed colleagues, those of you who, like me, treat patients all day? If the choice is between freezing an actinic keratosis, burning it, or using topical chemotherapy, do you just lay all three options out there and ask the patient to pick one? What if your patient works in public and doesn’t have 2 weeks to wait while the reaction to topical 5-fluorouracil that makes his skin look like raw lobster subsides? Can you point that out? Or would that be “trying to influence” and thus not allowed?

FatCamera/Getty Images

You and I can think of many other examples, about medical choices large and small, where we could pose similar questions. This is not abstract philosophy; it is what we do all day.

Look up robot-assisted surgery and radiation for prostate cancer. You will find proponents of both, each making claims concerning survival, recurrence, discomfort, complications. Which is more important – a 15% greater chance of living 2 years longer or a 22% lower risk of incontinence? Will reading such statistics make your choice easier? What if other studies show different numbers?

Octavio chose surgery. I asked him how he decided.

“I talked with an internist I know socially,” he said. “He shared his experience with patients he’s referred for my problem and advised surgery as the better choice. I also saw a story online about a lawyer who chose one method, then 5 years later had to do the other.”

Octavio is sophisticated and well read. He lives near Boston, the self-described hub of medical expertise and academic excellence. Yet he makes up his mind the way everybody does: by asking a trusted adviser, by hearing an arresting anecdote. It’s not science. It’s how people think.

You don’t have to be a behavioral psychologist to know how hard it is for patients, especially frightened ones, to interpret statistical variances or compare disparate categories. Which is better – shorter life with less pain or longer life with more? How much less? How much more? There are ways to address such questions, but having an expert, trusted, and sympathetic adviser is a pretty good way to start. Only an abstract ethicist with no practical exposure to (or sympathy with) actual existing patients and their actual existing providers could possibly think otherwise.

“Let’s freeze those actinics off,” I suggest to a patient. “That won’t scar, you won’t need a dozen shots of lidocaine, and you won’t have to hide for 3 weeks.”

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at dermnews@mdedge.com.

DALLAS – Stem cell tourism – the unethical practice of offering unproven cellular preparations to patients for a variety of conditions – is increasingly sought by patients with incurable conditions such as multiple sclerosis and amyotrophic lateral sclerosis, results from a novel survey suggest.

Doug Brunk/MDedge News

In fact, most academic neurologists have been approached by patients with incurable conditions who ask them about stem cell therapy, while about two-thirds have had at least one patient who has undergone stem cell therapy.

“It’s really scary,” Wijdan Rai, MBBS, the study’s first author, said in an interview at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “This is a more prevalent issue than we think, and the complication rates are higher than we think.”

According to the study’s senior author, Jaime Imitola, MD, who directs the Progressive Multiple Sclerosis Multidisciplinary Clinic and Translational Research Program at the Ohio State University Wexner Medical Center, Columbus, the results “call for the creation of a nationwide registry where neurologists can document adverse reactions to stem cell procedures and further support dedicated patient and neurologist education as we have proposed before” (See Semin Neurol. 2018; 38[2]:176-81 and JAMA Neurol. 2015;72[11]:1342-5).


In an effort to understand the experiences and attitudes of academic neurologists regarding stem cell tourism and patient-reported complications, the researchers developed a 25-question survey disseminated via Synapse, a web tool from the American Academy of Neurology. Respondents were asked about demographic information, frequency of patient questioning, perception of physician competence, patient complications and experiences, and attitudes toward increased physician education.

Dr. Rai, who is a senior neurology resident at the medical center, presented findings from 204 neurologist respondents, of whom 31% identified themselves as MS specialists. Nearly all respondents (91%) said they have been approached by patients with incurable conditions seeking information about stem cells (37% of whom had diagnosis of MS). In addition, 65% have had at least one patient that has undergone “stem cell therapy,” and 73% said it would be “helpful” or “very helpful” to have an evidence-based patient education tool on the topic. “Patients most often wanted general information,” Dr. Rai said. “However, 50% requested permission to undergo a stem cell procedure, and 31% approached their neurologist after the procedure.”

Survey respondents reported that 33% of the stem cell interventions were performed in the United States and 22% abroad, while 37% reported both in the U.S. and abroad. Patients underwent the procedures in China, Germany, the Bahamas, Mexico, Russia, and Costa Rica. Three-quarters of respondents (75%) indicated no patient experiencing complications from the stem cell interventions. However, 25% reported patients experiencing a variety of complications from the procedures, including strokes, meningoencephalitis, quadriparesis, MS deterioration, sepsis, hepatitis C, seizures, meningitis from intrathecal cell injections, infections, and spinal cord tumors. “At least three respondents had a patient who died as a direct complication from stem cell therapy,” Dr. Rai said.

In their poster, the researchers recommended a “multipronged approach to improve education of MS patients from exploitation and engaging multiple stakeholders in the field, including MS academic societies, licensing boards, and legislative bodies. Specifically, we call for creation of evidence-based education for both neurologists and patients, including physical resources that neurologists can use when discussing stem cell interventions with patients and videos on proper counseling during these visits.”

Colleagues from OSU’s Laboratory for Neural Stem Cells and Functional Neurogenetics contributed to this work. The researchers reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Rai W et al. ACTRIMS Forum 2019, Poster 237.

DALLAS – Stem cell tourism – the unethical practice of offering unproven cellular preparations to patients for a variety of conditions – is increasingly sought by patients with incurable conditions such as multiple sclerosis and amyotrophic lateral sclerosis, results from a novel survey suggest.

Doug Brunk/MDedge News

In fact, most academic neurologists have been approached by patients with incurable conditions who ask them about stem cell therapy, while about two-thirds have had at least one patient who has undergone stem cell therapy.

“It’s really scary,” Wijdan Rai, MBBS, the study’s first author, said in an interview at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “This is a more prevalent issue than we think, and the complication rates are higher than we think.”

According to the study’s senior author, Jaime Imitola, MD, who directs the Progressive Multiple Sclerosis Multidisciplinary Clinic and Translational Research Program at the Ohio State University Wexner Medical Center, Columbus, the results “call for the creation of a nationwide registry where neurologists can document adverse reactions to stem cell procedures and further support dedicated patient and neurologist education as we have proposed before” (See Semin Neurol. 2018; 38[2]:176-81 and JAMA Neurol. 2015;72[11]:1342-5).


In an effort to understand the experiences and attitudes of academic neurologists regarding stem cell tourism and patient-reported complications, the researchers developed a 25-question survey disseminated via Synapse, a web tool from the American Academy of Neurology. Respondents were asked about demographic information, frequency of patient questioning, perception of physician competence, patient complications and experiences, and attitudes toward increased physician education.

Dr. Rai, who is a senior neurology resident at the medical center, presented findings from 204 neurologist respondents, of whom 31% identified themselves as MS specialists. Nearly all respondents (91%) said they have been approached by patients with incurable conditions seeking information about stem cells (37% of whom had diagnosis of MS). In addition, 65% have had at least one patient that has undergone “stem cell therapy,” and 73% said it would be “helpful” or “very helpful” to have an evidence-based patient education tool on the topic. “Patients most often wanted general information,” Dr. Rai said. “However, 50% requested permission to undergo a stem cell procedure, and 31% approached their neurologist after the procedure.”

Survey respondents reported that 33% of the stem cell interventions were performed in the United States and 22% abroad, while 37% reported both in the U.S. and abroad. Patients underwent the procedures in China, Germany, the Bahamas, Mexico, Russia, and Costa Rica. Three-quarters of respondents (75%) indicated no patient experiencing complications from the stem cell interventions. However, 25% reported patients experiencing a variety of complications from the procedures, including strokes, meningoencephalitis, quadriparesis, MS deterioration, sepsis, hepatitis C, seizures, meningitis from intrathecal cell injections, infections, and spinal cord tumors. “At least three respondents had a patient who died as a direct complication from stem cell therapy,” Dr. Rai said.

In their poster, the researchers recommended a “multipronged approach to improve education of MS patients from exploitation and engaging multiple stakeholders in the field, including MS academic societies, licensing boards, and legislative bodies. Specifically, we call for creation of evidence-based education for both neurologists and patients, including physical resources that neurologists can use when discussing stem cell interventions with patients and videos on proper counseling during these visits.”

Colleagues from OSU’s Laboratory for Neural Stem Cells and Functional Neurogenetics contributed to this work. The researchers reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Rai W et al. ACTRIMS Forum 2019, Poster 237.

DALLAS – Stem cell tourism – the unethical practice of offering unproven cellular preparations to patients for a variety of conditions – is increasingly sought by patients with incurable conditions such as multiple sclerosis and amyotrophic lateral sclerosis, results from a novel survey suggest.

Doug Brunk/MDedge News

In fact, most academic neurologists have been approached by patients with incurable conditions who ask them about stem cell therapy, while about two-thirds have had at least one patient who has undergone stem cell therapy.

“It’s really scary,” Wijdan Rai, MBBS, the study’s first author, said in an interview at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “This is a more prevalent issue than we think, and the complication rates are higher than we think.”

According to the study’s senior author, Jaime Imitola, MD, who directs the Progressive Multiple Sclerosis Multidisciplinary Clinic and Translational Research Program at the Ohio State University Wexner Medical Center, Columbus, the results “call for the creation of a nationwide registry where neurologists can document adverse reactions to stem cell procedures and further support dedicated patient and neurologist education as we have proposed before” (See Semin Neurol. 2018; 38[2]:176-81 and JAMA Neurol. 2015;72[11]:1342-5).


In an effort to understand the experiences and attitudes of academic neurologists regarding stem cell tourism and patient-reported complications, the researchers developed a 25-question survey disseminated via Synapse, a web tool from the American Academy of Neurology. Respondents were asked about demographic information, frequency of patient questioning, perception of physician competence, patient complications and experiences, and attitudes toward increased physician education.

Dr. Rai, who is a senior neurology resident at the medical center, presented findings from 204 neurologist respondents, of whom 31% identified themselves as MS specialists. Nearly all respondents (91%) said they have been approached by patients with incurable conditions seeking information about stem cells (37% of whom had diagnosis of MS). In addition, 65% have had at least one patient that has undergone “stem cell therapy,” and 73% said it would be “helpful” or “very helpful” to have an evidence-based patient education tool on the topic. “Patients most often wanted general information,” Dr. Rai said. “However, 50% requested permission to undergo a stem cell procedure, and 31% approached their neurologist after the procedure.”

Survey respondents reported that 33% of the stem cell interventions were performed in the United States and 22% abroad, while 37% reported both in the U.S. and abroad. Patients underwent the procedures in China, Germany, the Bahamas, Mexico, Russia, and Costa Rica. Three-quarters of respondents (75%) indicated no patient experiencing complications from the stem cell interventions. However, 25% reported patients experiencing a variety of complications from the procedures, including strokes, meningoencephalitis, quadriparesis, MS deterioration, sepsis, hepatitis C, seizures, meningitis from intrathecal cell injections, infections, and spinal cord tumors. “At least three respondents had a patient who died as a direct complication from stem cell therapy,” Dr. Rai said.

In their poster, the researchers recommended a “multipronged approach to improve education of MS patients from exploitation and engaging multiple stakeholders in the field, including MS academic societies, licensing boards, and legislative bodies. Specifically, we call for creation of evidence-based education for both neurologists and patients, including physical resources that neurologists can use when discussing stem cell interventions with patients and videos on proper counseling during these visits.”

Colleagues from OSU’s Laboratory for Neural Stem Cells and Functional Neurogenetics contributed to this work. The researchers reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Rai W et al. ACTRIMS Forum 2019, Poster 237.

WASHINGTON – The “therapeutic drought” in available therapies for atopic dermatitis (AD) is “finally ending,” in part because understanding of the pathogenesis of the disease has grown, Emma Guttman-Yassky, MD, PhD, said during a presentation at the annual meeting of the American Academy of Dermatology.

“It’s due to the increased understanding we now have in atopic dermatitis,” Dr. Guttman-Yassky, professor and vice chair for research in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, said in her presentation.

According to Dr. Guttman-Yassky, therapeutic development was prevented in AD because of the abnormalities present in the disease immune responses and barrier abnormalities. “Frankly, pharma[ceutical] companies didn’t know what they should go after,” she said. “Should they go after the immune abnormalities, or should they go after the barrier? I think that’s why we’re so far behind psoriasis – but don’t worry, we are catching up quite fast because now ... we understand what we need to go after.”


It was when researchers began to look at AD in the same way as psoriasis that they realized the two were “polar” immune diseases, with psoriasis having Th17/interleukin-17 involvement while atopic dermatitis had Th2/IL-13 involvement. The same approach of “bedside-to-bench pathogenic dissection and translational testing of therapeutics” that led to successful advancements in therapies for psoriasis can also be applied to AD, Dr. Guttman-Yassky said.

To create a translational approach to AD, researchers need to have a well-defined molecular phenotype and understanding of inflammatory pathways, good baseline biomarkers of disease activity and treatment responses, and drugs that would selectively target the immune system. Th2-type cytokines such as IL-4 and IL-13 could help link the barrier and immune defects in AD. In addition, all variations of AD subtypes across white, black, Asian, and pediatric populations have “robust Th2 activation” but differ in other areas. “We’ll need to stratify biomarkers specific to different atopic dermatitis phenotypes to really develop a personalized medicine approach in atopic dermatitis,” she said.

High-level systemic immune activation shows that AD is emerging as a systemic disease that leads to atopic comorbidities such as allergy and asthma, as well as cardiovascular and infectious comorbidities. “We need to think about it when we treat our patients, because we really need to give them systemic treatment approaches when they have this moderate to severe disease,” Dr. Guttman-Yassky said. “When adult patients have moderate to severe disease, what is nonlesional today may be lesional tomorrow, and to treat them effectively, you have to offer them some systemic approaches.”

There is evidence that dupilumab, a human monoclonal antibody that targets IL-4 receptor alpha, is “proving the immune hypothesis” of AD, Dr. Guttman-Yassky said. She cited a recent study from her own group that found use of dupilumab to inhibit IL-4/IL-13 signaling improved disease activity for patients with AD, including reducing the expression of genes that caused type 2 inflammation, epidermal hyperplasia, T cells, dendritic cells, and Th17/Th22 activity (J Allergy Clin Immunol. 2019 Jan;143(1):155-72).

“We could postulate it before, but we couldn’t prove it,” she said. “Basically, this opened the door to all the therapy that we now have in atopic dermatitis.”

According to Dr. Guttman-Yassky, the future of AD will be in creating personalized treatments for patients by stratifying biomarkers specific to different AD phenotypes.

“It’s a very hopeful time in atopic dermatitis with this growing knowledge that we have of the biology of [the disease],” she said. “We have many more agents to treat our patients, and I think the future will be about personalized medicine so we really are treating the disease very well.”

Dr. Guttman-Yassky reported relationships with AbbVie, Allergan, Almirall, Anacor Pharmaceuticals, Asana BioSciences, Celgene, Dermira, Eli Lilly, Escalier Biosciences, Galderma Research & Development, Glenmark Generics, Janssen, Kyowa Hakko Kirin, Leo Pharma, Medimmune, Novartis, Pfizer, Regeneron, Sanofi-Aventis, Sanofi/Regeneron, Stiefel, Theravance Biopharma, and Vitae Pharmaceuticals.

WASHINGTON – The “therapeutic drought” in available therapies for atopic dermatitis (AD) is “finally ending,” in part because understanding of the pathogenesis of the disease has grown, Emma Guttman-Yassky, MD, PhD, said during a presentation at the annual meeting of the American Academy of Dermatology.

“It’s due to the increased understanding we now have in atopic dermatitis,” Dr. Guttman-Yassky, professor and vice chair for research in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, said in her presentation.

According to Dr. Guttman-Yassky, therapeutic development was prevented in AD because of the abnormalities present in the disease immune responses and barrier abnormalities. “Frankly, pharma[ceutical] companies didn’t know what they should go after,” she said. “Should they go after the immune abnormalities, or should they go after the barrier? I think that’s why we’re so far behind psoriasis – but don’t worry, we are catching up quite fast because now ... we understand what we need to go after.”


It was when researchers began to look at AD in the same way as psoriasis that they realized the two were “polar” immune diseases, with psoriasis having Th17/interleukin-17 involvement while atopic dermatitis had Th2/IL-13 involvement. The same approach of “bedside-to-bench pathogenic dissection and translational testing of therapeutics” that led to successful advancements in therapies for psoriasis can also be applied to AD, Dr. Guttman-Yassky said.

To create a translational approach to AD, researchers need to have a well-defined molecular phenotype and understanding of inflammatory pathways, good baseline biomarkers of disease activity and treatment responses, and drugs that would selectively target the immune system. Th2-type cytokines such as IL-4 and IL-13 could help link the barrier and immune defects in AD. In addition, all variations of AD subtypes across white, black, Asian, and pediatric populations have “robust Th2 activation” but differ in other areas. “We’ll need to stratify biomarkers specific to different atopic dermatitis phenotypes to really develop a personalized medicine approach in atopic dermatitis,” she said.

High-level systemic immune activation shows that AD is emerging as a systemic disease that leads to atopic comorbidities such as allergy and asthma, as well as cardiovascular and infectious comorbidities. “We need to think about it when we treat our patients, because we really need to give them systemic treatment approaches when they have this moderate to severe disease,” Dr. Guttman-Yassky said. “When adult patients have moderate to severe disease, what is nonlesional today may be lesional tomorrow, and to treat them effectively, you have to offer them some systemic approaches.”

There is evidence that dupilumab, a human monoclonal antibody that targets IL-4 receptor alpha, is “proving the immune hypothesis” of AD, Dr. Guttman-Yassky said. She cited a recent study from her own group that found use of dupilumab to inhibit IL-4/IL-13 signaling improved disease activity for patients with AD, including reducing the expression of genes that caused type 2 inflammation, epidermal hyperplasia, T cells, dendritic cells, and Th17/Th22 activity (J Allergy Clin Immunol. 2019 Jan;143(1):155-72).

“We could postulate it before, but we couldn’t prove it,” she said. “Basically, this opened the door to all the therapy that we now have in atopic dermatitis.”

According to Dr. Guttman-Yassky, the future of AD will be in creating personalized treatments for patients by stratifying biomarkers specific to different AD phenotypes.

“It’s a very hopeful time in atopic dermatitis with this growing knowledge that we have of the biology of [the disease],” she said. “We have many more agents to treat our patients, and I think the future will be about personalized medicine so we really are treating the disease very well.”

Dr. Guttman-Yassky reported relationships with AbbVie, Allergan, Almirall, Anacor Pharmaceuticals, Asana BioSciences, Celgene, Dermira, Eli Lilly, Escalier Biosciences, Galderma Research & Development, Glenmark Generics, Janssen, Kyowa Hakko Kirin, Leo Pharma, Medimmune, Novartis, Pfizer, Regeneron, Sanofi-Aventis, Sanofi/Regeneron, Stiefel, Theravance Biopharma, and Vitae Pharmaceuticals.

WASHINGTON – The “therapeutic drought” in available therapies for atopic dermatitis (AD) is “finally ending,” in part because understanding of the pathogenesis of the disease has grown, Emma Guttman-Yassky, MD, PhD, said during a presentation at the annual meeting of the American Academy of Dermatology.

“It’s due to the increased understanding we now have in atopic dermatitis,” Dr. Guttman-Yassky, professor and vice chair for research in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, said in her presentation.

According to Dr. Guttman-Yassky, therapeutic development was prevented in AD because of the abnormalities present in the disease immune responses and barrier abnormalities. “Frankly, pharma[ceutical] companies didn’t know what they should go after,” she said. “Should they go after the immune abnormalities, or should they go after the barrier? I think that’s why we’re so far behind psoriasis – but don’t worry, we are catching up quite fast because now ... we understand what we need to go after.”


It was when researchers began to look at AD in the same way as psoriasis that they realized the two were “polar” immune diseases, with psoriasis having Th17/interleukin-17 involvement while atopic dermatitis had Th2/IL-13 involvement. The same approach of “bedside-to-bench pathogenic dissection and translational testing of therapeutics” that led to successful advancements in therapies for psoriasis can also be applied to AD, Dr. Guttman-Yassky said.

To create a translational approach to AD, researchers need to have a well-defined molecular phenotype and understanding of inflammatory pathways, good baseline biomarkers of disease activity and treatment responses, and drugs that would selectively target the immune system. Th2-type cytokines such as IL-4 and IL-13 could help link the barrier and immune defects in AD. In addition, all variations of AD subtypes across white, black, Asian, and pediatric populations have “robust Th2 activation” but differ in other areas. “We’ll need to stratify biomarkers specific to different atopic dermatitis phenotypes to really develop a personalized medicine approach in atopic dermatitis,” she said.

High-level systemic immune activation shows that AD is emerging as a systemic disease that leads to atopic comorbidities such as allergy and asthma, as well as cardiovascular and infectious comorbidities. “We need to think about it when we treat our patients, because we really need to give them systemic treatment approaches when they have this moderate to severe disease,” Dr. Guttman-Yassky said. “When adult patients have moderate to severe disease, what is nonlesional today may be lesional tomorrow, and to treat them effectively, you have to offer them some systemic approaches.”

There is evidence that dupilumab, a human monoclonal antibody that targets IL-4 receptor alpha, is “proving the immune hypothesis” of AD, Dr. Guttman-Yassky said. She cited a recent study from her own group that found use of dupilumab to inhibit IL-4/IL-13 signaling improved disease activity for patients with AD, including reducing the expression of genes that caused type 2 inflammation, epidermal hyperplasia, T cells, dendritic cells, and Th17/Th22 activity (J Allergy Clin Immunol. 2019 Jan;143(1):155-72).

“We could postulate it before, but we couldn’t prove it,” she said. “Basically, this opened the door to all the therapy that we now have in atopic dermatitis.”

According to Dr. Guttman-Yassky, the future of AD will be in creating personalized treatments for patients by stratifying biomarkers specific to different AD phenotypes.

“It’s a very hopeful time in atopic dermatitis with this growing knowledge that we have of the biology of [the disease],” she said. “We have many more agents to treat our patients, and I think the future will be about personalized medicine so we really are treating the disease very well.”

Dr. Guttman-Yassky reported relationships with AbbVie, Allergan, Almirall, Anacor Pharmaceuticals, Asana BioSciences, Celgene, Dermira, Eli Lilly, Escalier Biosciences, Galderma Research & Development, Glenmark Generics, Janssen, Kyowa Hakko Kirin, Leo Pharma, Medimmune, Novartis, Pfizer, Regeneron, Sanofi-Aventis, Sanofi/Regeneron, Stiefel, Theravance Biopharma, and Vitae Pharmaceuticals.

Odds of sudden unexpected infant death (SUID) more than doubled with maternal prenatal smoking and increased linearly with each additional cigarette mothers smoked during pregnancy, but quitting smoking during pregnancy cut SUID risk, according to a new study in Pediatrics.

Jasmin Merdan/fotolia

“As prevalence of prone sleeping has declined, the relative contribution of prenatal maternal smoking to the risk of sudden infant death has increased,” Tatiana M. Anderson, PhD, of the Seattle Children’s Research Institute and her associates reported. When the researchers considered causality, they estimated that approximately 800 infants (22% of all SUID cases) per year in the United States could be attributed to maternal smoking during pregnancy.

The researchers analyzed 19,127 SUID cases among 20,685,463 births included in the Centers for Disease Control and Prevention Birth Cohort Linked Birth/Infant Death Data Set for 2007-2011. A SUID diagnosis included sudden infant death syndrome, infant death from ill-defined or unknown cause, and accidental suffocation or strangulation in bed for any infants under 1 year old.

When the authors calculated odds related to prenatal maternal smoking and SUID, they adjusted for infant sex and birth weight, gestational length of pregnancy, delivery method (vaginal or cesarean), total prenatal visits, live birth order, maternal marital status and education, and maternal and paternal age and race/ethnicity.

Any maternal smoking at all during pregnancy was associated with more than twice the odds of SUID (adjusted odds ratio, 2.44). Odds of SUID also doubled for smoking one cigarette daily during pregnancy versus smoking none. For each additional cigarette smoked daily during pregnancy, odds of SUID increased by 0.07 up until 20 cigarettes, when the risk evened out, which suggests “that smoking cessation efforts may have greater impact on decreasing SUID rates when directed toward those who smoke fewer than 1 pack per day versus the more traditionally targeted heavy ([more than] 20 cigarettes per day) smokers,” the authors wrote.

Odds of SUID dropped 12% when mothers cut down on smoking during pregnancy and dropped 23% when they quit altogether (aORs, 0.88 and 0.77, respectively). “However, there may be some selection bias because the group who reduced smoking started at a higher average number of cigarettes in the first trimester, whereas those who successfully quit smoked fewer cigarettes in the first trimester,” the authors noted.

Among the 11.6% of mothers who said in 2011 that they smoked in the 3 months leading up to pregnancy, only a quarter quit while pregnant, the authors wrote. Quitting after having smoked before pregnancy was linked to a 47% increased risk of SUID, although the researchers noted that second- and third-hand smoke may have played a role since mothers who smoke may begin smoking again post partum and/or often have a partner who smokes.

“This group may have also included women who stopped smoking as soon as they knew they were pregnant and thus reported that they were nonsmokers in the first trimester, but the fetus had been exposed to maternal smoking during the period before pregnancy was diagnosed,” the authors wrote. They also acknowledged the possibility of residual confounding, particularly from socioeconomic factors or alcohol consumption during pregnancy.

The research was funded by the National Institutes of Health, Microsoft, and the Aaron Matthew Sudden Infant Death Syndrome Research Guild. One author has testified as a paid expert in a SUID case. No other authors reported conflicts of interest.

SOURCE: Anderson TM et al. Pediatrics. 2019 March 11. doi: 10.1542/peds.2018-3325.

Odds of sudden unexpected infant death (SUID) more than doubled with maternal prenatal smoking and increased linearly with each additional cigarette mothers smoked during pregnancy, but quitting smoking during pregnancy cut SUID risk, according to a new study in Pediatrics.

Jasmin Merdan/fotolia

“As prevalence of prone sleeping has declined, the relative contribution of prenatal maternal smoking to the risk of sudden infant death has increased,” Tatiana M. Anderson, PhD, of the Seattle Children’s Research Institute and her associates reported. When the researchers considered causality, they estimated that approximately 800 infants (22% of all SUID cases) per year in the United States could be attributed to maternal smoking during pregnancy.

The researchers analyzed 19,127 SUID cases among 20,685,463 births included in the Centers for Disease Control and Prevention Birth Cohort Linked Birth/Infant Death Data Set for 2007-2011. A SUID diagnosis included sudden infant death syndrome, infant death from ill-defined or unknown cause, and accidental suffocation or strangulation in bed for any infants under 1 year old.

When the authors calculated odds related to prenatal maternal smoking and SUID, they adjusted for infant sex and birth weight, gestational length of pregnancy, delivery method (vaginal or cesarean), total prenatal visits, live birth order, maternal marital status and education, and maternal and paternal age and race/ethnicity.

Any maternal smoking at all during pregnancy was associated with more than twice the odds of SUID (adjusted odds ratio, 2.44). Odds of SUID also doubled for smoking one cigarette daily during pregnancy versus smoking none. For each additional cigarette smoked daily during pregnancy, odds of SUID increased by 0.07 up until 20 cigarettes, when the risk evened out, which suggests “that smoking cessation efforts may have greater impact on decreasing SUID rates when directed toward those who smoke fewer than 1 pack per day versus the more traditionally targeted heavy ([more than] 20 cigarettes per day) smokers,” the authors wrote.

Odds of SUID dropped 12% when mothers cut down on smoking during pregnancy and dropped 23% when they quit altogether (aORs, 0.88 and 0.77, respectively). “However, there may be some selection bias because the group who reduced smoking started at a higher average number of cigarettes in the first trimester, whereas those who successfully quit smoked fewer cigarettes in the first trimester,” the authors noted.

Among the 11.6% of mothers who said in 2011 that they smoked in the 3 months leading up to pregnancy, only a quarter quit while pregnant, the authors wrote. Quitting after having smoked before pregnancy was linked to a 47% increased risk of SUID, although the researchers noted that second- and third-hand smoke may have played a role since mothers who smoke may begin smoking again post partum and/or often have a partner who smokes.

“This group may have also included women who stopped smoking as soon as they knew they were pregnant and thus reported that they were nonsmokers in the first trimester, but the fetus had been exposed to maternal smoking during the period before pregnancy was diagnosed,” the authors wrote. They also acknowledged the possibility of residual confounding, particularly from socioeconomic factors or alcohol consumption during pregnancy.

The research was funded by the National Institutes of Health, Microsoft, and the Aaron Matthew Sudden Infant Death Syndrome Research Guild. One author has testified as a paid expert in a SUID case. No other authors reported conflicts of interest.

SOURCE: Anderson TM et al. Pediatrics. 2019 March 11. doi: 10.1542/peds.2018-3325.

Odds of sudden unexpected infant death (SUID) more than doubled with maternal prenatal smoking and increased linearly with each additional cigarette mothers smoked during pregnancy, but quitting smoking during pregnancy cut SUID risk, according to a new study in Pediatrics.

Jasmin Merdan/fotolia

“As prevalence of prone sleeping has declined, the relative contribution of prenatal maternal smoking to the risk of sudden infant death has increased,” Tatiana M. Anderson, PhD, of the Seattle Children’s Research Institute and her associates reported. When the researchers considered causality, they estimated that approximately 800 infants (22% of all SUID cases) per year in the United States could be attributed to maternal smoking during pregnancy.

The researchers analyzed 19,127 SUID cases among 20,685,463 births included in the Centers for Disease Control and Prevention Birth Cohort Linked Birth/Infant Death Data Set for 2007-2011. A SUID diagnosis included sudden infant death syndrome, infant death from ill-defined or unknown cause, and accidental suffocation or strangulation in bed for any infants under 1 year old.

When the authors calculated odds related to prenatal maternal smoking and SUID, they adjusted for infant sex and birth weight, gestational length of pregnancy, delivery method (vaginal or cesarean), total prenatal visits, live birth order, maternal marital status and education, and maternal and paternal age and race/ethnicity.

Any maternal smoking at all during pregnancy was associated with more than twice the odds of SUID (adjusted odds ratio, 2.44). Odds of SUID also doubled for smoking one cigarette daily during pregnancy versus smoking none. For each additional cigarette smoked daily during pregnancy, odds of SUID increased by 0.07 up until 20 cigarettes, when the risk evened out, which suggests “that smoking cessation efforts may have greater impact on decreasing SUID rates when directed toward those who smoke fewer than 1 pack per day versus the more traditionally targeted heavy ([more than] 20 cigarettes per day) smokers,” the authors wrote.

Odds of SUID dropped 12% when mothers cut down on smoking during pregnancy and dropped 23% when they quit altogether (aORs, 0.88 and 0.77, respectively). “However, there may be some selection bias because the group who reduced smoking started at a higher average number of cigarettes in the first trimester, whereas those who successfully quit smoked fewer cigarettes in the first trimester,” the authors noted.

Among the 11.6% of mothers who said in 2011 that they smoked in the 3 months leading up to pregnancy, only a quarter quit while pregnant, the authors wrote. Quitting after having smoked before pregnancy was linked to a 47% increased risk of SUID, although the researchers noted that second- and third-hand smoke may have played a role since mothers who smoke may begin smoking again post partum and/or often have a partner who smokes.

“This group may have also included women who stopped smoking as soon as they knew they were pregnant and thus reported that they were nonsmokers in the first trimester, but the fetus had been exposed to maternal smoking during the period before pregnancy was diagnosed,” the authors wrote. They also acknowledged the possibility of residual confounding, particularly from socioeconomic factors or alcohol consumption during pregnancy.

The research was funded by the National Institutes of Health, Microsoft, and the Aaron Matthew Sudden Infant Death Syndrome Research Guild. One author has testified as a paid expert in a SUID case. No other authors reported conflicts of interest.

SOURCE: Anderson TM et al. Pediatrics. 2019 March 11. doi: 10.1542/peds.2018-3325.

CASE A 53-year-old woman you are seeing for the first time has been taking 10 mg of prednisone daily for a month, prescribed by another practitioner for polymyalgia rheumatica. Testing is negative for hepatitis B surface antigen but is positive for hepatitis B core antibody total, indicating a resolved hepatitis B infection. The absence of hepatitis B DNA is confirmed.

How would you proceed with this patient?

Patients with resolved hepatitis B virus (HBV) or chronic hepatitis B (CHB) infections are at risk for HBV reactivation (HBVr) if they undergo immunosuppressive therapy for a condition such as cancer. HBVr can in turn lead to delays in treatment and increased morbidity and mortality.

HBVr is a well-documented adverse outcome in patients treated with rituximab and in those undergoing stem cell transplantation. Current oncology guidelines recommend screening for HBV prior to initiating these treatments.^1,2 More recent evidence shows that many other immunosuppressive therapies can also lead to HBVr.³ Such treatments are now used across a multitude of specialties and conditions. For many of these conditions, there are no consistent guidelines regarding HBV screening.

In 2013, the US Food and Drug Administration (FDA) announced the requirement of a Boxed Warning for the immunosuppressive drugs ofatumumab and rituximab. In 2016, the FDA announced the same requirement for certain direct-acting antiviral medicines for hepatitis C virus.

Among patients who are positive for hepatitis-B surface antigen (HBsAg) and who are treated with immunosuppression, the frequency of HBVr has ranged from 0% to 39%.^4,5

As the list of immunosuppressive therapies that can cause HBVr grows, specialty guidelines are evolving to address the risk that HBVr poses.

Continue to: An underrecognized problem

An underrecognized problem. CHB affects an estimated 350 million people worldwide⁶ but remains underrecognized and underdiagnosed. An estimated 1.4 million Americans⁶ have CHB, but only a minority of them are aware of their positive status and are followed by a hepatologist or receive medical care for their disease.⁷ Compared with the natural-born US population, a higher prevalence of CHB exists among immigrants to this country from the Asian Pacific and Eastern Mediterranean regions, sub-Saharan Africa, and certain parts of South America.^8-10 In 2008, the Centers for Disease Control and Prevention (CDC) updated its recommendations on screening for HBV to include immigrants to the United States from intermediate and high endemic areas.⁶ Unfortunately, data published on physicians’ adherence to the CDC guidelines for screening show that only 60% correctly screened at-risk patients.¹¹

Individuals with CHB are at risk and rely on a robust immune system to keep their disease from becoming active. During infection, the virus gains entry into the hepatocytes and the double-stranded viral genome is imported into the nucleus of the cell, where it is repaired into covalently closed circular DNA (cccDNA). Research has demonstrated the stability of cccDNA and its persistence as a latent reservoir for HBV reactivation, even decades after recovery from infection.¹²

Also at risk are individuals who have unrecovered from HBV infection and are HBsAg negative and anti-HBc positive. To avert reverse seroconversion, they also rely on a robust immune system.¹³ Reverse seroconversion is defined as a reappearance of HBV DNA and HBsAg positivity in individuals who were previously negative.¹³ In these individuals, HBV DNA may not be quantifiable in circulation, but trace amounts of viral DNA found in the liver are enough to pose a reactivation risk in the setting of immune suppression.¹⁴

Moreover, often overlooked is the fact that reactivation or reverse seroconversion can necessitate disruptions and delays in immunosuppressive treatment for other life-threatening disease processes.^14,15

Universal screening reduces risk for HBVr. Patients with CHB are at risk for reactivation, as are patients with resolved HBV infection. Many patients, however, do not know their status. By screening all patients before beginning immunosuppressive therapy, physicians can provide effective prophylaxis, which has been shown to significantly reduce the risk for HBVr.^8.15

Continue to: Recognizing the onset of HBVr

Recognizing the onset of HBVr

In patients with CHB, HBVr is defined as at least a 3-fold increase in aspart aminotransferase (AST) and alanine aminotransferase (ALT) and at least a 10-fold increase from baseline in HBV DNA. In patients with resolved HBV infection, there may be reverse seroconversion from HbsAg-negative to HBsAg-positive status (TABLE 1^13,16).

Not all elevations in AST/ALT in patients undergoing chemotherapy or immunosuppressive therapy indicate HBVr. Very often, derangements in AST/ALT may be related to the toxic effects of therapy or to the underlying disease process. However, as immunosuppressive therapy is now used for a wide array of medical conditions, consider HBVr as a potential cause of abnormal liver function in all patients receiving such therapy.

A patient is at risk for HBVr when starting immunosuppression and up to a year following the completion of therapy. With suppression of the immune system, HBV replication increases and serum AST/ALT concentrations may rise. HBVr may also present with the appearance of HBV DNA in patients with previously undetectable levels.^12,17

Most patients remain asymptomatic, and abnormal AST/ALT levels eventually resolve after completion of immunosuppression. However, some patients' liver enzymes may rise, indicating a more severe hepatic flare. These patients may present with right upper-quadrant tenderness, jaundice, or fatigue. In these cases, recognizing HBVr and starting antivirals may reduce hepatitis flare.

Unfortunately, despite early recognition of HBVr and initiation of appropriate therapy, some patients can progress to hepatic decompensation and even fulminant hepatic failure that may have been prevented with prophylaxis.

Continue to: The justification for universal screening

 

 

The justification for universal screening

Although nongastroenterology societies differ in their recommendations on screening for HBV, universal screening before implementing prolonged immunosuppressive treatment is recommended by the CDC,⁶ the American Association for the Study of Liver Diseases,¹⁸ the Asian Pacific Association for the Study of the Liver,¹⁹ the European Association for the Study of the Liver,²⁰ and the American Gastroenterological Association (AGA).²¹

Older guidelines recommended screening only high-risk populations. But such screening has downfalls. It requires that patients or their physicians recognize that they are at high risk. In one study, nearly 65% of an infected Asian-American population was unaware of their positive HBV status.²² Risk-based screening also requires that physicians ask the appropriate questions and that patients admit to high-risk behavior. Screening patients based only on risk factors may easily overlook patients who need prophylaxis against HBVr.

Common arguments against universal screening include the cost of testing, the possibility of false-positive results, and the implications of a new diagnosis of hepatitis B. However, the potential benefits of screening are significant, and HBV screening in the general population has been shown to be cost effective when the prevalence of HBV is 0.3%.²¹ In the United States, conservative estimates are a prevalence of HBsAg positivity of 0.4% and past infection of 3%, making screening a cost-effective recommendation.¹⁶ It is therefore prudent to screen all patients before starting immunosuppressive therapy.

How to screen

All guidelines agree on how to test for HBV. Measuring levels of HBsAg and hepatitis B core antibody (anti-HBc total) allows the clinician to ascertain whether the patient’s HBV infection status is acute, chronic, or resolved (TABLE 2²³) and to perform HBVr risk stratification (discussed later).

Patients with acute infections should be referred to a hepatologist. With chronic or resolved HBV, stratify patients into a prophylaxis group or monitoring group (FIGURE¹⁴). Stratification involves identifying HBV status (chronic or resolved) and selecting a type of immunosuppressive therapy. Whether the patient falls into prophylaxis or monitoring, obtain a baseline level of viral DNA, as this has proven to be the best predictor of HBV reactivation.¹⁶

Continue to: In screening, be sure the appropriate...

In screening, be sure the appropriate anti-HBc testing is covered. Common usage of the term anti-HBc may refer to immunoglobulin G (IgG) or immunoglobulin M (IgM)or total core antibody, containing both IgG and IgM. But in this context, accurate screening requires either total core antibody or anti-HBc IgG. Anti-IgM alone is inadequate. Many commercial laboratories offer acute hepatitis panels or hepatitis profiles (TABLE 3^24,25), and it is important to confirm that such order sets contain the tests necessary to allow for risk stratification.

Testing for hepatitis B surface antibody (anti-HBs) is not useful in screening. Although it was hypothesized that the presence of this antibody lowered risk, recent studies have proven no change in risk based on this value.²¹

How to assess HBVr risk

Assessing risk for HBVr takes into account both the patient’s serology and intended treatment. Reddy et al delineated patient groups into high, moderate, and low risk (TABLES 4 and 5).²¹ The high-risk group was defined by anticipated incidence of HBVr in > 10% of cases; the moderate-risk group had an anticipated incidence of 1% to 10%; and the low-risk group had an anticipated incidence of <1%.²¹ Evidence was strongest in the high-risk group.

Patients with CHB (HBsAg positive and anti-HBc positive) are considered high risk for reactivation with a wide variety of immunosuppressive therapies. Such patients are 5 to 8 times more likely to develop HBVr than patients with an HBsAg-negative status signifying a resolved infection.¹⁶

Immunosuppressive agents and associated risks. The AGA guidelines consider treatment with B-cell-depleting agents, such as rituximab and ofatumumab, to be high risk, regardless of a patient’s surface antigen status. Additionally, for patients who are HBsAg positive, high-risk treatments include anthracycline derivatives, such as doxorubicin and epirubicin, or high- or moderate-dose steroids. These treatments are considered moderate risk when used in patients who have resolved HBV infection (HBsAg negative/anti-HBc positive). Moderate-risk modalities also include tumor necrosis factor inhibitors and tyrosine kinase inhibitors, regardless of surface antigen status; and low-dose steroids or cytokine or integrin inhibitors in HbsAg-positive individuals.²¹

Continue to: Other immunosuppression modalities...

Other immunosuppression modalities considered to be moderate risk independent of HBV serology include proteasome inhibitors, such as bortezomib, used for multiple myeloma treatment, and histone deacetylase inhibitors, such as romidepsin, used to treat T-cell lymphoma.¹³ Low-dose steroids or cytokine or integrin inhibitors are considered to be low risk in surface antigen-negative individuals; azathioprine, mercaptopurine, or methotrexate are low risk regardless of HBsAg status.²¹ Intra-articular steroid injections are considered extremely low risk in HbsAg-positive individuals, and are unclassified for HbsAg-negative individuals.¹³

More recent evidence has implicated other medication classes in triggering HBVr — (eg, direct-acting antivirals.)²⁶

Prophylaxis options: High to moderate risk vs low risk

The consensus of major guideline issuers is to offer prophylaxis to high-risk patients and to monitor low-risk patients. The AGA additionally recommends prophylaxis for patients at moderate risk.

Controversy surrounding the moderate-risk group. Some authors argue that monitoring HBV DNA in the moderate-risk group is preferable to committing patients to long periods of prophylaxis, and that rescue treatment could be initiated as needed. However, the ideal monitoring period has not been determined, and the effectiveness of prophylaxis over monitoring is so significant that monitoring is losing favor.

Perrillo et al performed a meta-analysis of 5 randomized controlled trials evaluating antiviral agents vs no prophylaxis.¹⁶ The analysis included 139 patients receiving prophylaxis and 137 controls. The pooled results demonstrated an 87% relative risk reduction with prophylaxis, supporting the trend toward treating patients with moderate risk.¹⁶

Continue to: Prophylactic treatment options are safe...

Prophylactic treatment options are safe and well tolerated. For this reason, committing a high- or moderate-risk patient to a course of treatment should be less of a concern than the risk for HBVr.

A recent meta-analysis demonstrated that tenofovir and entecavir are preferable to lamivudine in preventing HBVr.

In the early randomized controlled trials for HBVr prophylaxis, lamivudine, although effective, unfortunately led to a high incidence of viral resistance after prolonged use, thus diminishing its desirability.¹⁸ Newer agents, such as entecavir and tenofovir, have proven just as effective as lamivudine and are largely unaffected by viral resistance.²⁷

In retrospective and prospective studies on HBVr prophylaxis, patients treated with entecavir had less HBV-related hepatitis, less delay in chemotherapy, and a lower rate of HBVr when compared with lamivudine.^28,29 Tenofovir is recommended, however, if patients were previously treated with lamivudine.³⁰

A recent meta-analysis demonstrated that tenofovir and entecavir are preferable to lamivudine in preventing HBVr.³¹

Looking ahead

Screening for HBsAg and anti-HBc total before starting immunosuppressive therapy can reduce morbidity and mortality in patients undergoing such treatment. The AGA recommends screening all patients about to begin high- or moderate-risk therapy or patients in populations with a prevalence of CHB ≥2%, per the CDC.^6,21

Continue to: Classes of medications...

Classes of medications other than immunosuppressants may also trigger HBVr. The FDA has issued a warning regarding direct-acting antivirals, but optimal management of these patients is still evolving.

Once HBV status is established, a patient’s risk for HBVr can be specified as high, moderate, or low using their HBV status and the type of therapy being initiated. The AGA recommends prophylactic treatment with well-tolerated and effective agents for patients classified as high or moderate risk. If a patient’s risk is low, regular monitoring of HBV DNA and AST and ALT levels is sufficient. Recommendations of monitoring intervals span from monthly to every 3 months.^13,14

CASE Given the patient’s status of resolved HBV infection and her current moderate-dose regimen of prednisone, her risk for HBV reactivation is moderate. She could either receive antiviral prophylaxis or undergo regular monitoring. Following a discussion of the options, she opts for referral to a hepatologist to discuss possible prophylactic treatment.

Increased awareness of HBVr risk associated with immunosuppressive therapy, coupled with a planned approach to appropriate screening and risk stratification, can help health care providers prevent the reactivation of HBV or initiate early intervention for CHB.

CORRESPONDENCE
Ronan Farrell, MD, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903; ronan_farrell@brown.edu.

CASE A 53-year-old woman you are seeing for the first time has been taking 10 mg of prednisone daily for a month, prescribed by another practitioner for polymyalgia rheumatica. Testing is negative for hepatitis B surface antigen but is positive for hepatitis B core antibody total, indicating a resolved hepatitis B infection. The absence of hepatitis B DNA is confirmed.

How would you proceed with this patient?

Patients with resolved hepatitis B virus (HBV) or chronic hepatitis B (CHB) infections are at risk for HBV reactivation (HBVr) if they undergo immunosuppressive therapy for a condition such as cancer. HBVr can in turn lead to delays in treatment and increased morbidity and mortality.

HBVr is a well-documented adverse outcome in patients treated with rituximab and in those undergoing stem cell transplantation. Current oncology guidelines recommend screening for HBV prior to initiating these treatments.^1,2 More recent evidence shows that many other immunosuppressive therapies can also lead to HBVr.³ Such treatments are now used across a multitude of specialties and conditions. For many of these conditions, there are no consistent guidelines regarding HBV screening.

In 2013, the US Food and Drug Administration (FDA) announced the requirement of a Boxed Warning for the immunosuppressive drugs ofatumumab and rituximab. In 2016, the FDA announced the same requirement for certain direct-acting antiviral medicines for hepatitis C virus.

Among patients who are positive for hepatitis-B surface antigen (HBsAg) and who are treated with immunosuppression, the frequency of HBVr has ranged from 0% to 39%.^4,5

As the list of immunosuppressive therapies that can cause HBVr grows, specialty guidelines are evolving to address the risk that HBVr poses.

Continue to: An underrecognized problem

An underrecognized problem. CHB affects an estimated 350 million people worldwide⁶ but remains underrecognized and underdiagnosed. An estimated 1.4 million Americans⁶ have CHB, but only a minority of them are aware of their positive status and are followed by a hepatologist or receive medical care for their disease.⁷ Compared with the natural-born US population, a higher prevalence of CHB exists among immigrants to this country from the Asian Pacific and Eastern Mediterranean regions, sub-Saharan Africa, and certain parts of South America.^8-10 In 2008, the Centers for Disease Control and Prevention (CDC) updated its recommendations on screening for HBV to include immigrants to the United States from intermediate and high endemic areas.⁶ Unfortunately, data published on physicians’ adherence to the CDC guidelines for screening show that only 60% correctly screened at-risk patients.¹¹

Individuals with CHB are at risk and rely on a robust immune system to keep their disease from becoming active. During infection, the virus gains entry into the hepatocytes and the double-stranded viral genome is imported into the nucleus of the cell, where it is repaired into covalently closed circular DNA (cccDNA). Research has demonstrated the stability of cccDNA and its persistence as a latent reservoir for HBV reactivation, even decades after recovery from infection.¹²

Also at risk are individuals who have unrecovered from HBV infection and are HBsAg negative and anti-HBc positive. To avert reverse seroconversion, they also rely on a robust immune system.¹³ Reverse seroconversion is defined as a reappearance of HBV DNA and HBsAg positivity in individuals who were previously negative.¹³ In these individuals, HBV DNA may not be quantifiable in circulation, but trace amounts of viral DNA found in the liver are enough to pose a reactivation risk in the setting of immune suppression.¹⁴

Moreover, often overlooked is the fact that reactivation or reverse seroconversion can necessitate disruptions and delays in immunosuppressive treatment for other life-threatening disease processes.^14,15

Universal screening reduces risk for HBVr. Patients with CHB are at risk for reactivation, as are patients with resolved HBV infection. Many patients, however, do not know their status. By screening all patients before beginning immunosuppressive therapy, physicians can provide effective prophylaxis, which has been shown to significantly reduce the risk for HBVr.^8.15

Continue to: Recognizing the onset of HBVr

Recognizing the onset of HBVr

In patients with CHB, HBVr is defined as at least a 3-fold increase in aspart aminotransferase (AST) and alanine aminotransferase (ALT) and at least a 10-fold increase from baseline in HBV DNA. In patients with resolved HBV infection, there may be reverse seroconversion from HbsAg-negative to HBsAg-positive status (TABLE 1^13,16).

Not all elevations in AST/ALT in patients undergoing chemotherapy or immunosuppressive therapy indicate HBVr. Very often, derangements in AST/ALT may be related to the toxic effects of therapy or to the underlying disease process. However, as immunosuppressive therapy is now used for a wide array of medical conditions, consider HBVr as a potential cause of abnormal liver function in all patients receiving such therapy.

A patient is at risk for HBVr when starting immunosuppression and up to a year following the completion of therapy. With suppression of the immune system, HBV replication increases and serum AST/ALT concentrations may rise. HBVr may also present with the appearance of HBV DNA in patients with previously undetectable levels.^12,17

Most patients remain asymptomatic, and abnormal AST/ALT levels eventually resolve after completion of immunosuppression. However, some patients' liver enzymes may rise, indicating a more severe hepatic flare. These patients may present with right upper-quadrant tenderness, jaundice, or fatigue. In these cases, recognizing HBVr and starting antivirals may reduce hepatitis flare.

Unfortunately, despite early recognition of HBVr and initiation of appropriate therapy, some patients can progress to hepatic decompensation and even fulminant hepatic failure that may have been prevented with prophylaxis.

Continue to: The justification for universal screening

 

 

The justification for universal screening

Although nongastroenterology societies differ in their recommendations on screening for HBV, universal screening before implementing prolonged immunosuppressive treatment is recommended by the CDC,⁶ the American Association for the Study of Liver Diseases,¹⁸ the Asian Pacific Association for the Study of the Liver,¹⁹ the European Association for the Study of the Liver,²⁰ and the American Gastroenterological Association (AGA).²¹

Older guidelines recommended screening only high-risk populations. But such screening has downfalls. It requires that patients or their physicians recognize that they are at high risk. In one study, nearly 65% of an infected Asian-American population was unaware of their positive HBV status.²² Risk-based screening also requires that physicians ask the appropriate questions and that patients admit to high-risk behavior. Screening patients based only on risk factors may easily overlook patients who need prophylaxis against HBVr.

Common arguments against universal screening include the cost of testing, the possibility of false-positive results, and the implications of a new diagnosis of hepatitis B. However, the potential benefits of screening are significant, and HBV screening in the general population has been shown to be cost effective when the prevalence of HBV is 0.3%.²¹ In the United States, conservative estimates are a prevalence of HBsAg positivity of 0.4% and past infection of 3%, making screening a cost-effective recommendation.¹⁶ It is therefore prudent to screen all patients before starting immunosuppressive therapy.

How to screen

All guidelines agree on how to test for HBV. Measuring levels of HBsAg and hepatitis B core antibody (anti-HBc total) allows the clinician to ascertain whether the patient’s HBV infection status is acute, chronic, or resolved (TABLE 2²³) and to perform HBVr risk stratification (discussed later).

Patients with acute infections should be referred to a hepatologist. With chronic or resolved HBV, stratify patients into a prophylaxis group or monitoring group (FIGURE¹⁴). Stratification involves identifying HBV status (chronic or resolved) and selecting a type of immunosuppressive therapy. Whether the patient falls into prophylaxis or monitoring, obtain a baseline level of viral DNA, as this has proven to be the best predictor of HBV reactivation.¹⁶

Continue to: In screening, be sure the appropriate...

In screening, be sure the appropriate anti-HBc testing is covered. Common usage of the term anti-HBc may refer to immunoglobulin G (IgG) or immunoglobulin M (IgM)or total core antibody, containing both IgG and IgM. But in this context, accurate screening requires either total core antibody or anti-HBc IgG. Anti-IgM alone is inadequate. Many commercial laboratories offer acute hepatitis panels or hepatitis profiles (TABLE 3^24,25), and it is important to confirm that such order sets contain the tests necessary to allow for risk stratification.

Testing for hepatitis B surface antibody (anti-HBs) is not useful in screening. Although it was hypothesized that the presence of this antibody lowered risk, recent studies have proven no change in risk based on this value.²¹

How to assess HBVr risk

Assessing risk for HBVr takes into account both the patient’s serology and intended treatment. Reddy et al delineated patient groups into high, moderate, and low risk (TABLES 4 and 5).²¹ The high-risk group was defined by anticipated incidence of HBVr in > 10% of cases; the moderate-risk group had an anticipated incidence of 1% to 10%; and the low-risk group had an anticipated incidence of <1%.²¹ Evidence was strongest in the high-risk group.

Patients with CHB (HBsAg positive and anti-HBc positive) are considered high risk for reactivation with a wide variety of immunosuppressive therapies. Such patients are 5 to 8 times more likely to develop HBVr than patients with an HBsAg-negative status signifying a resolved infection.¹⁶

Immunosuppressive agents and associated risks. The AGA guidelines consider treatment with B-cell-depleting agents, such as rituximab and ofatumumab, to be high risk, regardless of a patient’s surface antigen status. Additionally, for patients who are HBsAg positive, high-risk treatments include anthracycline derivatives, such as doxorubicin and epirubicin, or high- or moderate-dose steroids. These treatments are considered moderate risk when used in patients who have resolved HBV infection (HBsAg negative/anti-HBc positive). Moderate-risk modalities also include tumor necrosis factor inhibitors and tyrosine kinase inhibitors, regardless of surface antigen status; and low-dose steroids or cytokine or integrin inhibitors in HbsAg-positive individuals.²¹

Continue to: Other immunosuppression modalities...

Other immunosuppression modalities considered to be moderate risk independent of HBV serology include proteasome inhibitors, such as bortezomib, used for multiple myeloma treatment, and histone deacetylase inhibitors, such as romidepsin, used to treat T-cell lymphoma.¹³ Low-dose steroids or cytokine or integrin inhibitors are considered to be low risk in surface antigen-negative individuals; azathioprine, mercaptopurine, or methotrexate are low risk regardless of HBsAg status.²¹ Intra-articular steroid injections are considered extremely low risk in HbsAg-positive individuals, and are unclassified for HbsAg-negative individuals.¹³

More recent evidence has implicated other medication classes in triggering HBVr — (eg, direct-acting antivirals.)²⁶

Prophylaxis options: High to moderate risk vs low risk

The consensus of major guideline issuers is to offer prophylaxis to high-risk patients and to monitor low-risk patients. The AGA additionally recommends prophylaxis for patients at moderate risk.

Controversy surrounding the moderate-risk group. Some authors argue that monitoring HBV DNA in the moderate-risk group is preferable to committing patients to long periods of prophylaxis, and that rescue treatment could be initiated as needed. However, the ideal monitoring period has not been determined, and the effectiveness of prophylaxis over monitoring is so significant that monitoring is losing favor.

Perrillo et al performed a meta-analysis of 5 randomized controlled trials evaluating antiviral agents vs no prophylaxis.¹⁶ The analysis included 139 patients receiving prophylaxis and 137 controls. The pooled results demonstrated an 87% relative risk reduction with prophylaxis, supporting the trend toward treating patients with moderate risk.¹⁶

Continue to: Prophylactic treatment options are safe...

Prophylactic treatment options are safe and well tolerated. For this reason, committing a high- or moderate-risk patient to a course of treatment should be less of a concern than the risk for HBVr.

A recent meta-analysis demonstrated that tenofovir and entecavir are preferable to lamivudine in preventing HBVr.

In the early randomized controlled trials for HBVr prophylaxis, lamivudine, although effective, unfortunately led to a high incidence of viral resistance after prolonged use, thus diminishing its desirability.¹⁸ Newer agents, such as entecavir and tenofovir, have proven just as effective as lamivudine and are largely unaffected by viral resistance.²⁷

In retrospective and prospective studies on HBVr prophylaxis, patients treated with entecavir had less HBV-related hepatitis, less delay in chemotherapy, and a lower rate of HBVr when compared with lamivudine.^28,29 Tenofovir is recommended, however, if patients were previously treated with lamivudine.³⁰

A recent meta-analysis demonstrated that tenofovir and entecavir are preferable to lamivudine in preventing HBVr.³¹

Looking ahead

Screening for HBsAg and anti-HBc total before starting immunosuppressive therapy can reduce morbidity and mortality in patients undergoing such treatment. The AGA recommends screening all patients about to begin high- or moderate-risk therapy or patients in populations with a prevalence of CHB ≥2%, per the CDC.^6,21

Continue to: Classes of medications...

Classes of medications other than immunosuppressants may also trigger HBVr. The FDA has issued a warning regarding direct-acting antivirals, but optimal management of these patients is still evolving.

Once HBV status is established, a patient’s risk for HBVr can be specified as high, moderate, or low using their HBV status and the type of therapy being initiated. The AGA recommends prophylactic treatment with well-tolerated and effective agents for patients classified as high or moderate risk. If a patient’s risk is low, regular monitoring of HBV DNA and AST and ALT levels is sufficient. Recommendations of monitoring intervals span from monthly to every 3 months.^13,14

CASE Given the patient’s status of resolved HBV infection and her current moderate-dose regimen of prednisone, her risk for HBV reactivation is moderate. She could either receive antiviral prophylaxis or undergo regular monitoring. Following a discussion of the options, she opts for referral to a hepatologist to discuss possible prophylactic treatment.

Increased awareness of HBVr risk associated with immunosuppressive therapy, coupled with a planned approach to appropriate screening and risk stratification, can help health care providers prevent the reactivation of HBV or initiate early intervention for CHB.

CORRESPONDENCE
Ronan Farrell, MD, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903; ronan_farrell@brown.edu.

CASE A 53-year-old woman you are seeing for the first time has been taking 10 mg of prednisone daily for a month, prescribed by another practitioner for polymyalgia rheumatica. Testing is negative for hepatitis B surface antigen but is positive for hepatitis B core antibody total, indicating a resolved hepatitis B infection. The absence of hepatitis B DNA is confirmed.

How would you proceed with this patient?

Patients with resolved hepatitis B virus (HBV) or chronic hepatitis B (CHB) infections are at risk for HBV reactivation (HBVr) if they undergo immunosuppressive therapy for a condition such as cancer. HBVr can in turn lead to delays in treatment and increased morbidity and mortality.

HBVr is a well-documented adverse outcome in patients treated with rituximab and in those undergoing stem cell transplantation. Current oncology guidelines recommend screening for HBV prior to initiating these treatments.^1,2 More recent evidence shows that many other immunosuppressive therapies can also lead to HBVr.³ Such treatments are now used across a multitude of specialties and conditions. For many of these conditions, there are no consistent guidelines regarding HBV screening.

In 2013, the US Food and Drug Administration (FDA) announced the requirement of a Boxed Warning for the immunosuppressive drugs ofatumumab and rituximab. In 2016, the FDA announced the same requirement for certain direct-acting antiviral medicines for hepatitis C virus.

Among patients who are positive for hepatitis-B surface antigen (HBsAg) and who are treated with immunosuppression, the frequency of HBVr has ranged from 0% to 39%.^4,5

As the list of immunosuppressive therapies that can cause HBVr grows, specialty guidelines are evolving to address the risk that HBVr poses.

Continue to: An underrecognized problem

An underrecognized problem. CHB affects an estimated 350 million people worldwide⁶ but remains underrecognized and underdiagnosed. An estimated 1.4 million Americans⁶ have CHB, but only a minority of them are aware of their positive status and are followed by a hepatologist or receive medical care for their disease.⁷ Compared with the natural-born US population, a higher prevalence of CHB exists among immigrants to this country from the Asian Pacific and Eastern Mediterranean regions, sub-Saharan Africa, and certain parts of South America.^8-10 In 2008, the Centers for Disease Control and Prevention (CDC) updated its recommendations on screening for HBV to include immigrants to the United States from intermediate and high endemic areas.⁶ Unfortunately, data published on physicians’ adherence to the CDC guidelines for screening show that only 60% correctly screened at-risk patients.¹¹

Individuals with CHB are at risk and rely on a robust immune system to keep their disease from becoming active. During infection, the virus gains entry into the hepatocytes and the double-stranded viral genome is imported into the nucleus of the cell, where it is repaired into covalently closed circular DNA (cccDNA). Research has demonstrated the stability of cccDNA and its persistence as a latent reservoir for HBV reactivation, even decades after recovery from infection.¹²

Also at risk are individuals who have unrecovered from HBV infection and are HBsAg negative and anti-HBc positive. To avert reverse seroconversion, they also rely on a robust immune system.¹³ Reverse seroconversion is defined as a reappearance of HBV DNA and HBsAg positivity in individuals who were previously negative.¹³ In these individuals, HBV DNA may not be quantifiable in circulation, but trace amounts of viral DNA found in the liver are enough to pose a reactivation risk in the setting of immune suppression.¹⁴

Moreover, often overlooked is the fact that reactivation or reverse seroconversion can necessitate disruptions and delays in immunosuppressive treatment for other life-threatening disease processes.^14,15

Universal screening reduces risk for HBVr. Patients with CHB are at risk for reactivation, as are patients with resolved HBV infection. Many patients, however, do not know their status. By screening all patients before beginning immunosuppressive therapy, physicians can provide effective prophylaxis, which has been shown to significantly reduce the risk for HBVr.^8.15

Continue to: Recognizing the onset of HBVr

Recognizing the onset of HBVr

In patients with CHB, HBVr is defined as at least a 3-fold increase in aspart aminotransferase (AST) and alanine aminotransferase (ALT) and at least a 10-fold increase from baseline in HBV DNA. In patients with resolved HBV infection, there may be reverse seroconversion from HbsAg-negative to HBsAg-positive status (TABLE 1^13,16).

Not all elevations in AST/ALT in patients undergoing chemotherapy or immunosuppressive therapy indicate HBVr. Very often, derangements in AST/ALT may be related to the toxic effects of therapy or to the underlying disease process. However, as immunosuppressive therapy is now used for a wide array of medical conditions, consider HBVr as a potential cause of abnormal liver function in all patients receiving such therapy.

A patient is at risk for HBVr when starting immunosuppression and up to a year following the completion of therapy. With suppression of the immune system, HBV replication increases and serum AST/ALT concentrations may rise. HBVr may also present with the appearance of HBV DNA in patients with previously undetectable levels.^12,17

Most patients remain asymptomatic, and abnormal AST/ALT levels eventually resolve after completion of immunosuppression. However, some patients' liver enzymes may rise, indicating a more severe hepatic flare. These patients may present with right upper-quadrant tenderness, jaundice, or fatigue. In these cases, recognizing HBVr and starting antivirals may reduce hepatitis flare.

Unfortunately, despite early recognition of HBVr and initiation of appropriate therapy, some patients can progress to hepatic decompensation and even fulminant hepatic failure that may have been prevented with prophylaxis.

Continue to: The justification for universal screening

 

 

The justification for universal screening

Although nongastroenterology societies differ in their recommendations on screening for HBV, universal screening before implementing prolonged immunosuppressive treatment is recommended by the CDC,⁶ the American Association for the Study of Liver Diseases,¹⁸ the Asian Pacific Association for the Study of the Liver,¹⁹ the European Association for the Study of the Liver,²⁰ and the American Gastroenterological Association (AGA).²¹

Older guidelines recommended screening only high-risk populations. But such screening has downfalls. It requires that patients or their physicians recognize that they are at high risk. In one study, nearly 65% of an infected Asian-American population was unaware of their positive HBV status.²² Risk-based screening also requires that physicians ask the appropriate questions and that patients admit to high-risk behavior. Screening patients based only on risk factors may easily overlook patients who need prophylaxis against HBVr.

Common arguments against universal screening include the cost of testing, the possibility of false-positive results, and the implications of a new diagnosis of hepatitis B. However, the potential benefits of screening are significant, and HBV screening in the general population has been shown to be cost effective when the prevalence of HBV is 0.3%.²¹ In the United States, conservative estimates are a prevalence of HBsAg positivity of 0.4% and past infection of 3%, making screening a cost-effective recommendation.¹⁶ It is therefore prudent to screen all patients before starting immunosuppressive therapy.

How to screen

All guidelines agree on how to test for HBV. Measuring levels of HBsAg and hepatitis B core antibody (anti-HBc total) allows the clinician to ascertain whether the patient’s HBV infection status is acute, chronic, or resolved (TABLE 2²³) and to perform HBVr risk stratification (discussed later).

Patients with acute infections should be referred to a hepatologist. With chronic or resolved HBV, stratify patients into a prophylaxis group or monitoring group (FIGURE¹⁴). Stratification involves identifying HBV status (chronic or resolved) and selecting a type of immunosuppressive therapy. Whether the patient falls into prophylaxis or monitoring, obtain a baseline level of viral DNA, as this has proven to be the best predictor of HBV reactivation.¹⁶

Continue to: In screening, be sure the appropriate...

In screening, be sure the appropriate anti-HBc testing is covered. Common usage of the term anti-HBc may refer to immunoglobulin G (IgG) or immunoglobulin M (IgM)or total core antibody, containing both IgG and IgM. But in this context, accurate screening requires either total core antibody or anti-HBc IgG. Anti-IgM alone is inadequate. Many commercial laboratories offer acute hepatitis panels or hepatitis profiles (TABLE 3^24,25), and it is important to confirm that such order sets contain the tests necessary to allow for risk stratification.

Testing for hepatitis B surface antibody (anti-HBs) is not useful in screening. Although it was hypothesized that the presence of this antibody lowered risk, recent studies have proven no change in risk based on this value.²¹

How to assess HBVr risk

Assessing risk for HBVr takes into account both the patient’s serology and intended treatment. Reddy et al delineated patient groups into high, moderate, and low risk (TABLES 4 and 5).²¹ The high-risk group was defined by anticipated incidence of HBVr in > 10% of cases; the moderate-risk group had an anticipated incidence of 1% to 10%; and the low-risk group had an anticipated incidence of <1%.²¹ Evidence was strongest in the high-risk group.

Patients with CHB (HBsAg positive and anti-HBc positive) are considered high risk for reactivation with a wide variety of immunosuppressive therapies. Such patients are 5 to 8 times more likely to develop HBVr than patients with an HBsAg-negative status signifying a resolved infection.¹⁶

Immunosuppressive agents and associated risks. The AGA guidelines consider treatment with B-cell-depleting agents, such as rituximab and ofatumumab, to be high risk, regardless of a patient’s surface antigen status. Additionally, for patients who are HBsAg positive, high-risk treatments include anthracycline derivatives, such as doxorubicin and epirubicin, or high- or moderate-dose steroids. These treatments are considered moderate risk when used in patients who have resolved HBV infection (HBsAg negative/anti-HBc positive). Moderate-risk modalities also include tumor necrosis factor inhibitors and tyrosine kinase inhibitors, regardless of surface antigen status; and low-dose steroids or cytokine or integrin inhibitors in HbsAg-positive individuals.²¹

Continue to: Other immunosuppression modalities...

Other immunosuppression modalities considered to be moderate risk independent of HBV serology include proteasome inhibitors, such as bortezomib, used for multiple myeloma treatment, and histone deacetylase inhibitors, such as romidepsin, used to treat T-cell lymphoma.¹³ Low-dose steroids or cytokine or integrin inhibitors are considered to be low risk in surface antigen-negative individuals; azathioprine, mercaptopurine, or methotrexate are low risk regardless of HBsAg status.²¹ Intra-articular steroid injections are considered extremely low risk in HbsAg-positive individuals, and are unclassified for HbsAg-negative individuals.¹³

More recent evidence has implicated other medication classes in triggering HBVr — (eg, direct-acting antivirals.)²⁶

Prophylaxis options: High to moderate risk vs low risk

The consensus of major guideline issuers is to offer prophylaxis to high-risk patients and to monitor low-risk patients. The AGA additionally recommends prophylaxis for patients at moderate risk.

Controversy surrounding the moderate-risk group. Some authors argue that monitoring HBV DNA in the moderate-risk group is preferable to committing patients to long periods of prophylaxis, and that rescue treatment could be initiated as needed. However, the ideal monitoring period has not been determined, and the effectiveness of prophylaxis over monitoring is so significant that monitoring is losing favor.

Perrillo et al performed a meta-analysis of 5 randomized controlled trials evaluating antiviral agents vs no prophylaxis.¹⁶ The analysis included 139 patients receiving prophylaxis and 137 controls. The pooled results demonstrated an 87% relative risk reduction with prophylaxis, supporting the trend toward treating patients with moderate risk.¹⁶

Continue to: Prophylactic treatment options are safe...

Prophylactic treatment options are safe and well tolerated. For this reason, committing a high- or moderate-risk patient to a course of treatment should be less of a concern than the risk for HBVr.

A recent meta-analysis demonstrated that tenofovir and entecavir are preferable to lamivudine in preventing HBVr.

In the early randomized controlled trials for HBVr prophylaxis, lamivudine, although effective, unfortunately led to a high incidence of viral resistance after prolonged use, thus diminishing its desirability.¹⁸ Newer agents, such as entecavir and tenofovir, have proven just as effective as lamivudine and are largely unaffected by viral resistance.²⁷

In retrospective and prospective studies on HBVr prophylaxis, patients treated with entecavir had less HBV-related hepatitis, less delay in chemotherapy, and a lower rate of HBVr when compared with lamivudine.^28,29 Tenofovir is recommended, however, if patients were previously treated with lamivudine.³⁰

A recent meta-analysis demonstrated that tenofovir and entecavir are preferable to lamivudine in preventing HBVr.³¹

Looking ahead

Screening for HBsAg and anti-HBc total before starting immunosuppressive therapy can reduce morbidity and mortality in patients undergoing such treatment. The AGA recommends screening all patients about to begin high- or moderate-risk therapy or patients in populations with a prevalence of CHB ≥2%, per the CDC.^6,21

Continue to: Classes of medications...

Classes of medications other than immunosuppressants may also trigger HBVr. The FDA has issued a warning regarding direct-acting antivirals, but optimal management of these patients is still evolving.

Once HBV status is established, a patient’s risk for HBVr can be specified as high, moderate, or low using their HBV status and the type of therapy being initiated. The AGA recommends prophylactic treatment with well-tolerated and effective agents for patients classified as high or moderate risk. If a patient’s risk is low, regular monitoring of HBV DNA and AST and ALT levels is sufficient. Recommendations of monitoring intervals span from monthly to every 3 months.^13,14

CASE Given the patient’s status of resolved HBV infection and her current moderate-dose regimen of prednisone, her risk for HBV reactivation is moderate. She could either receive antiviral prophylaxis or undergo regular monitoring. Following a discussion of the options, she opts for referral to a hepatologist to discuss possible prophylactic treatment.

Increased awareness of HBVr risk associated with immunosuppressive therapy, coupled with a planned approach to appropriate screening and risk stratification, can help health care providers prevent the reactivation of HBV or initiate early intervention for CHB.

CORRESPONDENCE
Ronan Farrell, MD, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903; ronan_farrell@brown.edu.

To the Editor: Even one death by suicide is too many. Suicide is complex and a serious national public health issue that affects people from all walks of life—not just veterans—for a variety of reasons. While there is still a lot we can learn about suicide, we know that suicide is preventable, treatment works, and there is hope.

At the US Department of Veterans Affairs (VA), our suicide prevention efforts are guided by the National Strategy for Preventing Veteran Suicide.¹ Published in 2018, this long-term strategy expands beyond crisis intervention and provides a framework for identifying priorities, organizing efforts, and focusing national attention and community resources to prevent suicide among veterans through a broad public health approach with an emphasis on comprehensive, community-based engagement.

This approach is grounded in 4 key areas: Primary prevention focuses on preventing suicidal behavior before it occurs; whole health considers factors beyond mental health, such as physical health, alcohol or substance misuse, and life events; application of data and research emphasizes evidence-based approaches that can be tailored to the needs of veterans in local communities; and collaboration educates and empowers diverse communities to participate in suicide prevention efforts through coordination.

A recent article by Russell Lemle, PhD, noted that the National Strategy does not emphasize the work of the VA, and he is correct.² Rather than perpetuate the myth that VA can address suicide alone, the strategy was intended to guide veteran suicide prevention efforts across the entire nation, not just within VA’s walls. It is a plan for how we can ALL work together to prevent veteran suicide. The National Strategy does not minimize VA’s role in suicide prevention. It enhances VA’s ability and expectation to engage in collaborative efforts across the nation.

Every year, about 6,000 veterans die by suicide, the majority of whom have not received recent VA care. We are mindful that some veterans may not receive any or all of their health care services from the VA, for various reasons, and want to be respectful and cognizant of those choices. To save lives, VA needs the support of partners across sectors. We need to ensure that multiple systems are working in a coordinated way to reach veterans where they live, work, and thrive.

Our philosophy is that there is no wrong door to care. That is why we focused on universal, non-VA community interventions. Preventing suicide among all of the nation’s 20 million veterans cannot be the sole responsibility of VA—it requires a nationwide effort. As there is no single cause of suicide, no single organization can tackle suicide prevention alone. Put simply, VA must ensure suicide prevention is a part of every aspect of veterans’ lives, not just their VA interactions. At VA, we know that the care and support that veterans need often comes before a mental health crisis occurs, and communities and families may be better equipped to provide these types of supports.

Activities or special interest groups can boost protective factors against suicide and combat risk factors. Communities can foster an environment where veterans can find connection and camaraderie, achieve a sense of purpose, bolster their coping skills, and live healthily. And partners like the National Shooting Sports Foundation help VA to address sensitive issues, such as lethal means safety, while correcting misconceptions about how VA handles gun ownership.

Data also are an integral piece of our public health approach, driving how VA defines the problem, targets its programs, and delivers and implements interventions. VA was one of the first institutions to implement comprehensive suicide analysis and predictive analytics, and VA has continuously improved data surveillance related to veteran suicide.

We began comprehensive suicide monitoring for the entire VA patient population in 2006, and in 2012, VA released its first report of suicide surveillance among all veterans in select partnering states. Though we are able to share data, we acknowledge the limitations Dr. Lemle highlighted in implementing predictive analytics program outside the VA. However, VA continues to improve reporting and surveillance efforts, especially to better understand the 20 veterans and service members who die by suicide each day.

As Lemle noted, little was previously known about the 14 of 20 veterans who die by suicide every day who weren’t recent users of VA health services. Since the September 2018 release of the National Strategy, VA has obtained additional data. In addition to sharing data, VA will focus on helping non-VA entities understand the problem so that they can help reach veterans who may never go to VA for care. Efforts are underway to better understand specific groups that are at elevated risk, such as veterans aged 18 to 34 years, women veterans, never federally activated guardsmen and reservists, recently separated veterans, and former service members with Other Than Honorable discharges.

To end veteran suicide, VA is relentlessly working to make improvements to existing suicide prevention programs, develop VA-specific plans to advance the National Strategy, find innovative ways to get people into care, and educate veterans and family members about VA care. Through Executive Order 13822, for example, VA has partnered with the Departments of Defense and Homeland Security, which allows us to educate service members about VA offerings before they become veterans. We also are making it easier for them to quickly find information online about VA mental health services.

We acknowledge VA is not a perfect organization, and a negative image can turn away veterans. VA is actively working with the media to get more good news stories published. We have many exciting things to talk about, such as a newly implemented Comprehensive Suicide Risk Assessment, and it is important for people to know that VA is providing the gold standard of care. Sometimes, those stories are better messaged and amplified by partners and non-VA entities, and this is a key part of our approach.

Lemle also raised a concern around funding this new public health initiative. While we recognize the challenges in advancing this new public health approach without additional funding, we are hopeful we can energize communities to work with us to find a solution.

The National Strategy is not the end of the conversation. It is a starting point. We are thankful for Lemle’s thoughtful questions and are actively pursuing and investigating solutions regarding veteran suicide studies, peer support, and community care guidelines for partners as we seek to improve our services. We also are putting pen to paper on a plan to strengthen family involvement and integrate suicide prevention within VA’s whole health and social services strategies.

The National Strategy is a call to action to every organization, system, and institution interested in preventing veteran suicide to help do this work where we cannot. For our part, VA will continue to energize communities to increase local involvement to reach all veterans, and we will continue to empower and equip ALL veterans with the resources and care they need to thrive.

To learn about the resources available for veterans and how you can #BeThere as a VA employee, family member, friend, community partner, or clinician, visit www.mentalhealth.va.gov/suicide_prevention/resources.asp. If you or someone you know is having thoughts of suicide, contact the Veterans Crisis Line to receive free, confidential support and crisis intervention available 24 hours a day, 7 days a week, 365 days a year. Call 800-273-8255 and press 1, text to 838255, or chat online at VeteransCrisisLine.net/Chat.

- Keita Franklin, LCSD, PhD

Author affiliations: Executive Director, Suicide Prevention VA Office of Mental Health and Suicide Prevention.

Author disclosures: Keita Franklin participated in the development of the National Strategy for Preventing Veteran Suicide .

Disclaimer: The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner , Frontline Medical Communications Inc., the US Government, or any of its agencies.

Author Response: Keita Franklin, PhD, offers a valuable response to my December critique of the VA National Strategy to Prevent Veteran Suicide. Dr. Franklin thoughtfully articulates why public health approaches to prevent suicide must be a core component of a multifaceted strategy. She is right about that.

While I see considerable overlap between our statements, there are 2 important points where we diverge: (1) Unless Congress appropriates sufficient funds for extensive public health outreach, there is a danger that funds to implement it would be diverted from VA’s extant effective VA suicide prevention programs. (2) A prospective suicide prevention plan requires 3 prongs of universal, group, and individually focused strategies, because suicide cannot be prevented by any single strategy. The VA National Strategy as well as the March 2019 Executive Order on a National Roadmap to Empower Veterans and End Suicide, focus predominantly on universal strategies, and I believe its overall approach would be improved by also explicitly supporting VA’s targeted programs for at-risk veterans.

- Russell B. Lemle, PhD

Author affiliations: Policy Analyst at the Veterans Healthcare Policy Institute in Oakland, California.

To the Editor: Even one death by suicide is too many. Suicide is complex and a serious national public health issue that affects people from all walks of life—not just veterans—for a variety of reasons. While there is still a lot we can learn about suicide, we know that suicide is preventable, treatment works, and there is hope.

At the US Department of Veterans Affairs (VA), our suicide prevention efforts are guided by the National Strategy for Preventing Veteran Suicide.¹ Published in 2018, this long-term strategy expands beyond crisis intervention and provides a framework for identifying priorities, organizing efforts, and focusing national attention and community resources to prevent suicide among veterans through a broad public health approach with an emphasis on comprehensive, community-based engagement.

This approach is grounded in 4 key areas: Primary prevention focuses on preventing suicidal behavior before it occurs; whole health considers factors beyond mental health, such as physical health, alcohol or substance misuse, and life events; application of data and research emphasizes evidence-based approaches that can be tailored to the needs of veterans in local communities; and collaboration educates and empowers diverse communities to participate in suicide prevention efforts through coordination.

A recent article by Russell Lemle, PhD, noted that the National Strategy does not emphasize the work of the VA, and he is correct.² Rather than perpetuate the myth that VA can address suicide alone, the strategy was intended to guide veteran suicide prevention efforts across the entire nation, not just within VA’s walls. It is a plan for how we can ALL work together to prevent veteran suicide. The National Strategy does not minimize VA’s role in suicide prevention. It enhances VA’s ability and expectation to engage in collaborative efforts across the nation.

Every year, about 6,000 veterans die by suicide, the majority of whom have not received recent VA care. We are mindful that some veterans may not receive any or all of their health care services from the VA, for various reasons, and want to be respectful and cognizant of those choices. To save lives, VA needs the support of partners across sectors. We need to ensure that multiple systems are working in a coordinated way to reach veterans where they live, work, and thrive.

Our philosophy is that there is no wrong door to care. That is why we focused on universal, non-VA community interventions. Preventing suicide among all of the nation’s 20 million veterans cannot be the sole responsibility of VA—it requires a nationwide effort. As there is no single cause of suicide, no single organization can tackle suicide prevention alone. Put simply, VA must ensure suicide prevention is a part of every aspect of veterans’ lives, not just their VA interactions. At VA, we know that the care and support that veterans need often comes before a mental health crisis occurs, and communities and families may be better equipped to provide these types of supports.

Activities or special interest groups can boost protective factors against suicide and combat risk factors. Communities can foster an environment where veterans can find connection and camaraderie, achieve a sense of purpose, bolster their coping skills, and live healthily. And partners like the National Shooting Sports Foundation help VA to address sensitive issues, such as lethal means safety, while correcting misconceptions about how VA handles gun ownership.

Data also are an integral piece of our public health approach, driving how VA defines the problem, targets its programs, and delivers and implements interventions. VA was one of the first institutions to implement comprehensive suicide analysis and predictive analytics, and VA has continuously improved data surveillance related to veteran suicide.

We began comprehensive suicide monitoring for the entire VA patient population in 2006, and in 2012, VA released its first report of suicide surveillance among all veterans in select partnering states. Though we are able to share data, we acknowledge the limitations Dr. Lemle highlighted in implementing predictive analytics program outside the VA. However, VA continues to improve reporting and surveillance efforts, especially to better understand the 20 veterans and service members who die by suicide each day.

As Lemle noted, little was previously known about the 14 of 20 veterans who die by suicide every day who weren’t recent users of VA health services. Since the September 2018 release of the National Strategy, VA has obtained additional data. In addition to sharing data, VA will focus on helping non-VA entities understand the problem so that they can help reach veterans who may never go to VA for care. Efforts are underway to better understand specific groups that are at elevated risk, such as veterans aged 18 to 34 years, women veterans, never federally activated guardsmen and reservists, recently separated veterans, and former service members with Other Than Honorable discharges.

To end veteran suicide, VA is relentlessly working to make improvements to existing suicide prevention programs, develop VA-specific plans to advance the National Strategy, find innovative ways to get people into care, and educate veterans and family members about VA care. Through Executive Order 13822, for example, VA has partnered with the Departments of Defense and Homeland Security, which allows us to educate service members about VA offerings before they become veterans. We also are making it easier for them to quickly find information online about VA mental health services.

We acknowledge VA is not a perfect organization, and a negative image can turn away veterans. VA is actively working with the media to get more good news stories published. We have many exciting things to talk about, such as a newly implemented Comprehensive Suicide Risk Assessment, and it is important for people to know that VA is providing the gold standard of care. Sometimes, those stories are better messaged and amplified by partners and non-VA entities, and this is a key part of our approach.

Lemle also raised a concern around funding this new public health initiative. While we recognize the challenges in advancing this new public health approach without additional funding, we are hopeful we can energize communities to work with us to find a solution.

The National Strategy is not the end of the conversation. It is a starting point. We are thankful for Lemle’s thoughtful questions and are actively pursuing and investigating solutions regarding veteran suicide studies, peer support, and community care guidelines for partners as we seek to improve our services. We also are putting pen to paper on a plan to strengthen family involvement and integrate suicide prevention within VA’s whole health and social services strategies.

The National Strategy is a call to action to every organization, system, and institution interested in preventing veteran suicide to help do this work where we cannot. For our part, VA will continue to energize communities to increase local involvement to reach all veterans, and we will continue to empower and equip ALL veterans with the resources and care they need to thrive.

To learn about the resources available for veterans and how you can #BeThere as a VA employee, family member, friend, community partner, or clinician, visit www.mentalhealth.va.gov/suicide_prevention/resources.asp. If you or someone you know is having thoughts of suicide, contact the Veterans Crisis Line to receive free, confidential support and crisis intervention available 24 hours a day, 7 days a week, 365 days a year. Call 800-273-8255 and press 1, text to 838255, or chat online at VeteransCrisisLine.net/Chat.

- Keita Franklin, LCSD, PhD

Author affiliations: Executive Director, Suicide Prevention VA Office of Mental Health and Suicide Prevention.

Author disclosures: Keita Franklin participated in the development of the National Strategy for Preventing Veteran Suicide .

Disclaimer: The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner , Frontline Medical Communications Inc., the US Government, or any of its agencies.

Author Response: Keita Franklin, PhD, offers a valuable response to my December critique of the VA National Strategy to Prevent Veteran Suicide. Dr. Franklin thoughtfully articulates why public health approaches to prevent suicide must be a core component of a multifaceted strategy. She is right about that.

While I see considerable overlap between our statements, there are 2 important points where we diverge: (1) Unless Congress appropriates sufficient funds for extensive public health outreach, there is a danger that funds to implement it would be diverted from VA’s extant effective VA suicide prevention programs. (2) A prospective suicide prevention plan requires 3 prongs of universal, group, and individually focused strategies, because suicide cannot be prevented by any single strategy. The VA National Strategy as well as the March 2019 Executive Order on a National Roadmap to Empower Veterans and End Suicide, focus predominantly on universal strategies, and I believe its overall approach would be improved by also explicitly supporting VA’s targeted programs for at-risk veterans.

- Russell B. Lemle, PhD

Author affiliations: Policy Analyst at the Veterans Healthcare Policy Institute in Oakland, California.

To the Editor: Even one death by suicide is too many. Suicide is complex and a serious national public health issue that affects people from all walks of life—not just veterans—for a variety of reasons. While there is still a lot we can learn about suicide, we know that suicide is preventable, treatment works, and there is hope.

At the US Department of Veterans Affairs (VA), our suicide prevention efforts are guided by the National Strategy for Preventing Veteran Suicide.¹ Published in 2018, this long-term strategy expands beyond crisis intervention and provides a framework for identifying priorities, organizing efforts, and focusing national attention and community resources to prevent suicide among veterans through a broad public health approach with an emphasis on comprehensive, community-based engagement.

This approach is grounded in 4 key areas: Primary prevention focuses on preventing suicidal behavior before it occurs; whole health considers factors beyond mental health, such as physical health, alcohol or substance misuse, and life events; application of data and research emphasizes evidence-based approaches that can be tailored to the needs of veterans in local communities; and collaboration educates and empowers diverse communities to participate in suicide prevention efforts through coordination.

A recent article by Russell Lemle, PhD, noted that the National Strategy does not emphasize the work of the VA, and he is correct.² Rather than perpetuate the myth that VA can address suicide alone, the strategy was intended to guide veteran suicide prevention efforts across the entire nation, not just within VA’s walls. It is a plan for how we can ALL work together to prevent veteran suicide. The National Strategy does not minimize VA’s role in suicide prevention. It enhances VA’s ability and expectation to engage in collaborative efforts across the nation.

Every year, about 6,000 veterans die by suicide, the majority of whom have not received recent VA care. We are mindful that some veterans may not receive any or all of their health care services from the VA, for various reasons, and want to be respectful and cognizant of those choices. To save lives, VA needs the support of partners across sectors. We need to ensure that multiple systems are working in a coordinated way to reach veterans where they live, work, and thrive.

Our philosophy is that there is no wrong door to care. That is why we focused on universal, non-VA community interventions. Preventing suicide among all of the nation’s 20 million veterans cannot be the sole responsibility of VA—it requires a nationwide effort. As there is no single cause of suicide, no single organization can tackle suicide prevention alone. Put simply, VA must ensure suicide prevention is a part of every aspect of veterans’ lives, not just their VA interactions. At VA, we know that the care and support that veterans need often comes before a mental health crisis occurs, and communities and families may be better equipped to provide these types of supports.

Activities or special interest groups can boost protective factors against suicide and combat risk factors. Communities can foster an environment where veterans can find connection and camaraderie, achieve a sense of purpose, bolster their coping skills, and live healthily. And partners like the National Shooting Sports Foundation help VA to address sensitive issues, such as lethal means safety, while correcting misconceptions about how VA handles gun ownership.

Data also are an integral piece of our public health approach, driving how VA defines the problem, targets its programs, and delivers and implements interventions. VA was one of the first institutions to implement comprehensive suicide analysis and predictive analytics, and VA has continuously improved data surveillance related to veteran suicide.

We began comprehensive suicide monitoring for the entire VA patient population in 2006, and in 2012, VA released its first report of suicide surveillance among all veterans in select partnering states. Though we are able to share data, we acknowledge the limitations Dr. Lemle highlighted in implementing predictive analytics program outside the VA. However, VA continues to improve reporting and surveillance efforts, especially to better understand the 20 veterans and service members who die by suicide each day.

As Lemle noted, little was previously known about the 14 of 20 veterans who die by suicide every day who weren’t recent users of VA health services. Since the September 2018 release of the National Strategy, VA has obtained additional data. In addition to sharing data, VA will focus on helping non-VA entities understand the problem so that they can help reach veterans who may never go to VA for care. Efforts are underway to better understand specific groups that are at elevated risk, such as veterans aged 18 to 34 years, women veterans, never federally activated guardsmen and reservists, recently separated veterans, and former service members with Other Than Honorable discharges.

To end veteran suicide, VA is relentlessly working to make improvements to existing suicide prevention programs, develop VA-specific plans to advance the National Strategy, find innovative ways to get people into care, and educate veterans and family members about VA care. Through Executive Order 13822, for example, VA has partnered with the Departments of Defense and Homeland Security, which allows us to educate service members about VA offerings before they become veterans. We also are making it easier for them to quickly find information online about VA mental health services.

We acknowledge VA is not a perfect organization, and a negative image can turn away veterans. VA is actively working with the media to get more good news stories published. We have many exciting things to talk about, such as a newly implemented Comprehensive Suicide Risk Assessment, and it is important for people to know that VA is providing the gold standard of care. Sometimes, those stories are better messaged and amplified by partners and non-VA entities, and this is a key part of our approach.

Lemle also raised a concern around funding this new public health initiative. While we recognize the challenges in advancing this new public health approach without additional funding, we are hopeful we can energize communities to work with us to find a solution.

The National Strategy is not the end of the conversation. It is a starting point. We are thankful for Lemle’s thoughtful questions and are actively pursuing and investigating solutions regarding veteran suicide studies, peer support, and community care guidelines for partners as we seek to improve our services. We also are putting pen to paper on a plan to strengthen family involvement and integrate suicide prevention within VA’s whole health and social services strategies.

The National Strategy is a call to action to every organization, system, and institution interested in preventing veteran suicide to help do this work where we cannot. For our part, VA will continue to energize communities to increase local involvement to reach all veterans, and we will continue to empower and equip ALL veterans with the resources and care they need to thrive.

To learn about the resources available for veterans and how you can #BeThere as a VA employee, family member, friend, community partner, or clinician, visit www.mentalhealth.va.gov/suicide_prevention/resources.asp. If you or someone you know is having thoughts of suicide, contact the Veterans Crisis Line to receive free, confidential support and crisis intervention available 24 hours a day, 7 days a week, 365 days a year. Call 800-273-8255 and press 1, text to 838255, or chat online at VeteransCrisisLine.net/Chat.

- Keita Franklin, LCSD, PhD

Author affiliations: Executive Director, Suicide Prevention VA Office of Mental Health and Suicide Prevention.

Author disclosures: Keita Franklin participated in the development of the National Strategy for Preventing Veteran Suicide .

Disclaimer: The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner , Frontline Medical Communications Inc., the US Government, or any of its agencies.

Author Response: Keita Franklin, PhD, offers a valuable response to my December critique of the VA National Strategy to Prevent Veteran Suicide. Dr. Franklin thoughtfully articulates why public health approaches to prevent suicide must be a core component of a multifaceted strategy. She is right about that.

While I see considerable overlap between our statements, there are 2 important points where we diverge: (1) Unless Congress appropriates sufficient funds for extensive public health outreach, there is a danger that funds to implement it would be diverted from VA’s extant effective VA suicide prevention programs. (2) A prospective suicide prevention plan requires 3 prongs of universal, group, and individually focused strategies, because suicide cannot be prevented by any single strategy. The VA National Strategy as well as the March 2019 Executive Order on a National Roadmap to Empower Veterans and End Suicide, focus predominantly on universal strategies, and I believe its overall approach would be improved by also explicitly supporting VA’s targeted programs for at-risk veterans.

- Russell B. Lemle, PhD

Author affiliations: Policy Analyst at the Veterans Healthcare Policy Institute in Oakland, California.

Necrotizing infection of the extremity is a rare but potentially lethal diagnosis with a mortality rate in the range of 17% to 35%.^1-4 The plastic surgery service at the Malcom Randall Veterans Affairs Medical Center (MRVAMC) treats all hand emergencies, including upper extremity infection, in the North Florida/South Georgia Veterans Heath System. There has been a well-coordinated emergency hand care system in place for several years that includes specialty templates on the electronic health record, pre-existing urgent clinic appointments, and single service surgical specialty care.⁵ This facilitates a fluid line of communication between primary care, emergency department (ED) providers, and surgical specialties. The objective of the study was to evaluate our identification, treatment, and outcome of these serious infections.

Methods

The MRVAMC Institutional Review Board approved a retrospective review of necrotizing infection of the upper extremity treated at the facility by the plastic surgery service. Surgical cases over a 9-year period (June 5, 2008-June 5, 2017) were identified by CPT (current procedural technology) codes for amputation and/or debridement of the upper extremity. The charts were reviewed for evidence of necrotizing infection by clinical description or pathology report. The patients’ age, sex, etiology, comorbidities from their problem list, vitals, and laboratory results were recorded upon arrival at the hospital. Time from presentation to surgery, treatment, and outcomes were recorded.

Results

Ten patients were treated for necrotizing infection of the upper extremity over a 9-year period; all were men with an average age of 64 years. Etiologies included nail biting, “bug bites,” crush injuries, burns, suspected IV drug use, and unknown. Nine of 10 patients had diabetes mellitus (DM). Most did not show evidence of hemodynamic instability on hospital arrival (Table). One patient was hypotensive with a mean arterial blood pressure < 65 mm Hg, 2 had heart rates > 100 beats/min, 1 patient had a temperature > 38° C, and 7 had elevated white blood cell (WBC) counts ranging from 11 to 24 k/cmm. Two undiagnosed patients with DM (patients 1 and 8) expressed no complaints of pain and presented with blood glucose > 450 mg/dL with hemoglobin A_1c levels > 12%.

Infectious disease and critical care services were involved in the treatment of several cases when requested. A computed tomography (CT) scan was used in 2 of the patients (patients 1 and 4) to assist in the diagnosis (Figure 1). 

Antibiotics were managed by critical care, hospitalist, or infectious disease services and adjusted once final cultures were returned (Table). 

Discussion

Necrotizing infection of the upper extremity is a rare pathology with a substantial risk of amputation and mortality that requires a high index of suspicion and expeditious referral to a hand surgeon. It is well accepted that the key to survival is prompt surgical debridement of all necrotic tissue, ideally within 24 hours of hospital arrival.^2-4,6 Death is usually secondary to sepsis.³ The classic presentation of pain out of proportion to exam, hypotension, erythema, skin necrosis, elevated WBC count, and fever may not be present and can delay diagnosis.^1-4,6

DM is the most common comorbidity, and reviews have found the disease occurs more often in males, both which are consistent with our study.^1-3 Diabetic infections have been found to be more likely to present as necrotizing infection than are nondiabetic infections and be at a higher risk for amputation.⁷ The patients with the wrist disarticulations and forearm amputation had DM. A minor trauma can be a portal for infection, which can be monomicrobial or polymicrobial.^1,4 Once the diagnosis is suspected, prompt resuscitation, surgical debridement, IV antibiotics, and early intensive care are lifesaving. Hyperbaric oxygen is not available at MRVAMC and was not pursued as a transfer request due to its controversial benefit.⁶

There were no perioperative 30-day mortalities over a 9-year period in patients identified as having necrotizing infection of the upper extremity. This is attributed to an aggressive and well-coordinated, multisystem approach involving emergency, surgical, anesthesia, intensive care, and infectious disease services.

The hand trauma triage system in place at MRVAMC was started in 2008 and presented at the 38th Annual VA Surgeons Meeting in New Haven, Connecticut. The process starts at the level of the ED, urgent care or primary care provider and facilitates rapid access to subspecialty care by reducing unnecessary phone calls and appointment wait times.

All hand emergencies are covered by the plastic surgery service rather than the traditional split coverage between orthopedics and plastic surgery. This provides consistency and continuity for the patients and staff. The electronic health record consult template gives specific instructions to contact the on-call plastic surgeon. The resident/fellow gets called if patient is in-house, and faculty is called if the patient is outside the main hospital. The requesting provider gets instructions on treatment and follow-up. Clinic profiles have appointments reserved for urgent consults during the first hour so that patients can be sent to pre-anesthesia clinic or hand therapy, depending on the diagnosis. This triage system increased our hand trauma volume by a multiple of 6 between 2008 and 2012 but cut the appointment wait time > 1 week by half, as a percentage of consults, and did not significantly increase after-hour use of the operating room. The number of faculty and trainees stayed the same.

We did find that speed to diagnosis for necrotizing infection is an area that can be improved on with a higher clinical suspicion. There is a learning curve to the diagnosis and treatment, which can be prolonged when the index cases do not present themselves often and the patients do not appear in distress. This argues for consistency in hand-specific trauma coverage. The patients were most often initially seen by the resident and examined by a faculty member within hours. There were 4 different plastic surgery faculty involved in these cases, and they all included resident participation before, during, and after surgery. Debridement consists of wide local excision to bleeding tissue. Author review of the operative notes found the numbers of trips to the operating room for debridement can be reduced as the surgeon becomes more confident in the diagnosis and management, resulting in less “whittling” and a more definitive debridement, resulting in a faster recovery.

The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) is a tool that helps to distinguish necrotizing infection from other forms of soft tissue infection by using a point system for laboratory values that include C-reactive protein (CRP), white blood count, hemoglobin, sodium, creatinine, and glucose values.⁸ We do not routinely request CRP results, but 1 of the 2 patients (patient 9) who had the full complement of laboratory tests would have met high-risk criteria. The diagnostic accuracy of this tool has been questioned⁹; however, the authors welcome any method that can rapidly and noninvasively assist in getting the patient proper attention.

The patients were not seen for long-term follow-up, but some did return to the main hospital or clinic for other pathology and were pleased to show off their grip strength after a 3-ray amputation (patient 1) and aesthetics after upper arm and forearm debridement and skin graft reconstruction (patient 4, Figure 4).

A single-ray amputation can be expected to result in a loss of grip and pinch strength, about 43.3% and 33.6%, respectively; however, given the alternative of further loss of life or limb, this was considered a reasonable trade-off.¹⁰ One wrist disarticulation and the forearm amputation were seen by amputee clinic for prosthetic fitting many months after the amputations once the wounds were healed and edema had subsided.

Conclusion

A well-coordinated multidisciplinary effort was the key to successful identification and treatment of this serious life- and limb-threatening infection at our institution. We did identify room for improvement in making an earlier diagnosis and performing a more aggressive first debridement.

Acknowledgments
This project is the result of work supported with resources and use of facilities at the Malcom Randall VA Medical Center in Gainesville, Florida.

Necrotizing infection of the extremity is a rare but potentially lethal diagnosis with a mortality rate in the range of 17% to 35%.^1-4 The plastic surgery service at the Malcom Randall Veterans Affairs Medical Center (MRVAMC) treats all hand emergencies, including upper extremity infection, in the North Florida/South Georgia Veterans Heath System. There has been a well-coordinated emergency hand care system in place for several years that includes specialty templates on the electronic health record, pre-existing urgent clinic appointments, and single service surgical specialty care.⁵ This facilitates a fluid line of communication between primary care, emergency department (ED) providers, and surgical specialties. The objective of the study was to evaluate our identification, treatment, and outcome of these serious infections.

Methods

The MRVAMC Institutional Review Board approved a retrospective review of necrotizing infection of the upper extremity treated at the facility by the plastic surgery service. Surgical cases over a 9-year period (June 5, 2008-June 5, 2017) were identified by CPT (current procedural technology) codes for amputation and/or debridement of the upper extremity. The charts were reviewed for evidence of necrotizing infection by clinical description or pathology report. The patients’ age, sex, etiology, comorbidities from their problem list, vitals, and laboratory results were recorded upon arrival at the hospital. Time from presentation to surgery, treatment, and outcomes were recorded.

Results

Ten patients were treated for necrotizing infection of the upper extremity over a 9-year period; all were men with an average age of 64 years. Etiologies included nail biting, “bug bites,” crush injuries, burns, suspected IV drug use, and unknown. Nine of 10 patients had diabetes mellitus (DM). Most did not show evidence of hemodynamic instability on hospital arrival (Table). One patient was hypotensive with a mean arterial blood pressure < 65 mm Hg, 2 had heart rates > 100 beats/min, 1 patient had a temperature > 38° C, and 7 had elevated white blood cell (WBC) counts ranging from 11 to 24 k/cmm. Two undiagnosed patients with DM (patients 1 and 8) expressed no complaints of pain and presented with blood glucose > 450 mg/dL with hemoglobin A_1c levels > 12%.

Infectious disease and critical care services were involved in the treatment of several cases when requested. A computed tomography (CT) scan was used in 2 of the patients (patients 1 and 4) to assist in the diagnosis (Figure 1). 

Antibiotics were managed by critical care, hospitalist, or infectious disease services and adjusted once final cultures were returned (Table). 

Discussion

Necrotizing infection of the upper extremity is a rare pathology with a substantial risk of amputation and mortality that requires a high index of suspicion and expeditious referral to a hand surgeon. It is well accepted that the key to survival is prompt surgical debridement of all necrotic tissue, ideally within 24 hours of hospital arrival.^2-4,6 Death is usually secondary to sepsis.³ The classic presentation of pain out of proportion to exam, hypotension, erythema, skin necrosis, elevated WBC count, and fever may not be present and can delay diagnosis.^1-4,6

DM is the most common comorbidity, and reviews have found the disease occurs more often in males, both which are consistent with our study.^1-3 Diabetic infections have been found to be more likely to present as necrotizing infection than are nondiabetic infections and be at a higher risk for amputation.⁷ The patients with the wrist disarticulations and forearm amputation had DM. A minor trauma can be a portal for infection, which can be monomicrobial or polymicrobial.^1,4 Once the diagnosis is suspected, prompt resuscitation, surgical debridement, IV antibiotics, and early intensive care are lifesaving. Hyperbaric oxygen is not available at MRVAMC and was not pursued as a transfer request due to its controversial benefit.⁶

There were no perioperative 30-day mortalities over a 9-year period in patients identified as having necrotizing infection of the upper extremity. This is attributed to an aggressive and well-coordinated, multisystem approach involving emergency, surgical, anesthesia, intensive care, and infectious disease services.

The hand trauma triage system in place at MRVAMC was started in 2008 and presented at the 38th Annual VA Surgeons Meeting in New Haven, Connecticut. The process starts at the level of the ED, urgent care or primary care provider and facilitates rapid access to subspecialty care by reducing unnecessary phone calls and appointment wait times.

All hand emergencies are covered by the plastic surgery service rather than the traditional split coverage between orthopedics and plastic surgery. This provides consistency and continuity for the patients and staff. The electronic health record consult template gives specific instructions to contact the on-call plastic surgeon. The resident/fellow gets called if patient is in-house, and faculty is called if the patient is outside the main hospital. The requesting provider gets instructions on treatment and follow-up. Clinic profiles have appointments reserved for urgent consults during the first hour so that patients can be sent to pre-anesthesia clinic or hand therapy, depending on the diagnosis. This triage system increased our hand trauma volume by a multiple of 6 between 2008 and 2012 but cut the appointment wait time > 1 week by half, as a percentage of consults, and did not significantly increase after-hour use of the operating room. The number of faculty and trainees stayed the same.

We did find that speed to diagnosis for necrotizing infection is an area that can be improved on with a higher clinical suspicion. There is a learning curve to the diagnosis and treatment, which can be prolonged when the index cases do not present themselves often and the patients do not appear in distress. This argues for consistency in hand-specific trauma coverage. The patients were most often initially seen by the resident and examined by a faculty member within hours. There were 4 different plastic surgery faculty involved in these cases, and they all included resident participation before, during, and after surgery. Debridement consists of wide local excision to bleeding tissue. Author review of the operative notes found the numbers of trips to the operating room for debridement can be reduced as the surgeon becomes more confident in the diagnosis and management, resulting in less “whittling” and a more definitive debridement, resulting in a faster recovery.

The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) is a tool that helps to distinguish necrotizing infection from other forms of soft tissue infection by using a point system for laboratory values that include C-reactive protein (CRP), white blood count, hemoglobin, sodium, creatinine, and glucose values.⁸ We do not routinely request CRP results, but 1 of the 2 patients (patient 9) who had the full complement of laboratory tests would have met high-risk criteria. The diagnostic accuracy of this tool has been questioned⁹; however, the authors welcome any method that can rapidly and noninvasively assist in getting the patient proper attention.

The patients were not seen for long-term follow-up, but some did return to the main hospital or clinic for other pathology and were pleased to show off their grip strength after a 3-ray amputation (patient 1) and aesthetics after upper arm and forearm debridement and skin graft reconstruction (patient 4, Figure 4).

A single-ray amputation can be expected to result in a loss of grip and pinch strength, about 43.3% and 33.6%, respectively; however, given the alternative of further loss of life or limb, this was considered a reasonable trade-off.¹⁰ One wrist disarticulation and the forearm amputation were seen by amputee clinic for prosthetic fitting many months after the amputations once the wounds were healed and edema had subsided.

Conclusion

A well-coordinated multidisciplinary effort was the key to successful identification and treatment of this serious life- and limb-threatening infection at our institution. We did identify room for improvement in making an earlier diagnosis and performing a more aggressive first debridement.

Acknowledgments
This project is the result of work supported with resources and use of facilities at the Malcom Randall VA Medical Center in Gainesville, Florida.

Necrotizing infection of the extremity is a rare but potentially lethal diagnosis with a mortality rate in the range of 17% to 35%.^1-4 The plastic surgery service at the Malcom Randall Veterans Affairs Medical Center (MRVAMC) treats all hand emergencies, including upper extremity infection, in the North Florida/South Georgia Veterans Heath System. There has been a well-coordinated emergency hand care system in place for several years that includes specialty templates on the electronic health record, pre-existing urgent clinic appointments, and single service surgical specialty care.⁵ This facilitates a fluid line of communication between primary care, emergency department (ED) providers, and surgical specialties. The objective of the study was to evaluate our identification, treatment, and outcome of these serious infections.

Methods

The MRVAMC Institutional Review Board approved a retrospective review of necrotizing infection of the upper extremity treated at the facility by the plastic surgery service. Surgical cases over a 9-year period (June 5, 2008-June 5, 2017) were identified by CPT (current procedural technology) codes for amputation and/or debridement of the upper extremity. The charts were reviewed for evidence of necrotizing infection by clinical description or pathology report. The patients’ age, sex, etiology, comorbidities from their problem list, vitals, and laboratory results were recorded upon arrival at the hospital. Time from presentation to surgery, treatment, and outcomes were recorded.

Results

Ten patients were treated for necrotizing infection of the upper extremity over a 9-year period; all were men with an average age of 64 years. Etiologies included nail biting, “bug bites,” crush injuries, burns, suspected IV drug use, and unknown. Nine of 10 patients had diabetes mellitus (DM). Most did not show evidence of hemodynamic instability on hospital arrival (Table). One patient was hypotensive with a mean arterial blood pressure < 65 mm Hg, 2 had heart rates > 100 beats/min, 1 patient had a temperature > 38° C, and 7 had elevated white blood cell (WBC) counts ranging from 11 to 24 k/cmm. Two undiagnosed patients with DM (patients 1 and 8) expressed no complaints of pain and presented with blood glucose > 450 mg/dL with hemoglobin A_1c levels > 12%.

Infectious disease and critical care services were involved in the treatment of several cases when requested. A computed tomography (CT) scan was used in 2 of the patients (patients 1 and 4) to assist in the diagnosis (Figure 1). 

Antibiotics were managed by critical care, hospitalist, or infectious disease services and adjusted once final cultures were returned (Table). 

Discussion

Necrotizing infection of the upper extremity is a rare pathology with a substantial risk of amputation and mortality that requires a high index of suspicion and expeditious referral to a hand surgeon. It is well accepted that the key to survival is prompt surgical debridement of all necrotic tissue, ideally within 24 hours of hospital arrival.^2-4,6 Death is usually secondary to sepsis.³ The classic presentation of pain out of proportion to exam, hypotension, erythema, skin necrosis, elevated WBC count, and fever may not be present and can delay diagnosis.^1-4,6

DM is the most common comorbidity, and reviews have found the disease occurs more often in males, both which are consistent with our study.^1-3 Diabetic infections have been found to be more likely to present as necrotizing infection than are nondiabetic infections and be at a higher risk for amputation.⁷ The patients with the wrist disarticulations and forearm amputation had DM. A minor trauma can be a portal for infection, which can be monomicrobial or polymicrobial.^1,4 Once the diagnosis is suspected, prompt resuscitation, surgical debridement, IV antibiotics, and early intensive care are lifesaving. Hyperbaric oxygen is not available at MRVAMC and was not pursued as a transfer request due to its controversial benefit.⁶

There were no perioperative 30-day mortalities over a 9-year period in patients identified as having necrotizing infection of the upper extremity. This is attributed to an aggressive and well-coordinated, multisystem approach involving emergency, surgical, anesthesia, intensive care, and infectious disease services.

The hand trauma triage system in place at MRVAMC was started in 2008 and presented at the 38th Annual VA Surgeons Meeting in New Haven, Connecticut. The process starts at the level of the ED, urgent care or primary care provider and facilitates rapid access to subspecialty care by reducing unnecessary phone calls and appointment wait times.

All hand emergencies are covered by the plastic surgery service rather than the traditional split coverage between orthopedics and plastic surgery. This provides consistency and continuity for the patients and staff. The electronic health record consult template gives specific instructions to contact the on-call plastic surgeon. The resident/fellow gets called if patient is in-house, and faculty is called if the patient is outside the main hospital. The requesting provider gets instructions on treatment and follow-up. Clinic profiles have appointments reserved for urgent consults during the first hour so that patients can be sent to pre-anesthesia clinic or hand therapy, depending on the diagnosis. This triage system increased our hand trauma volume by a multiple of 6 between 2008 and 2012 but cut the appointment wait time > 1 week by half, as a percentage of consults, and did not significantly increase after-hour use of the operating room. The number of faculty and trainees stayed the same.

We did find that speed to diagnosis for necrotizing infection is an area that can be improved on with a higher clinical suspicion. There is a learning curve to the diagnosis and treatment, which can be prolonged when the index cases do not present themselves often and the patients do not appear in distress. This argues for consistency in hand-specific trauma coverage. The patients were most often initially seen by the resident and examined by a faculty member within hours. There were 4 different plastic surgery faculty involved in these cases, and they all included resident participation before, during, and after surgery. Debridement consists of wide local excision to bleeding tissue. Author review of the operative notes found the numbers of trips to the operating room for debridement can be reduced as the surgeon becomes more confident in the diagnosis and management, resulting in less “whittling” and a more definitive debridement, resulting in a faster recovery.

The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) is a tool that helps to distinguish necrotizing infection from other forms of soft tissue infection by using a point system for laboratory values that include C-reactive protein (CRP), white blood count, hemoglobin, sodium, creatinine, and glucose values.⁸ We do not routinely request CRP results, but 1 of the 2 patients (patient 9) who had the full complement of laboratory tests would have met high-risk criteria. The diagnostic accuracy of this tool has been questioned⁹; however, the authors welcome any method that can rapidly and noninvasively assist in getting the patient proper attention.

The patients were not seen for long-term follow-up, but some did return to the main hospital or clinic for other pathology and were pleased to show off their grip strength after a 3-ray amputation (patient 1) and aesthetics after upper arm and forearm debridement and skin graft reconstruction (patient 4, Figure 4).

A single-ray amputation can be expected to result in a loss of grip and pinch strength, about 43.3% and 33.6%, respectively; however, given the alternative of further loss of life or limb, this was considered a reasonable trade-off.¹⁰ One wrist disarticulation and the forearm amputation were seen by amputee clinic for prosthetic fitting many months after the amputations once the wounds were healed and edema had subsided.

Conclusion

A well-coordinated multidisciplinary effort was the key to successful identification and treatment of this serious life- and limb-threatening infection at our institution. We did identify room for improvement in making an earlier diagnosis and performing a more aggressive first debridement.

Acknowledgments
This project is the result of work supported with resources and use of facilities at the Malcom Randall VA Medical Center in Gainesville, Florida.

Continuous positive airway pressure therapy (CPAP) is the first-line treatment for obstructive sleep apnea (OSA) recommended by the American College of Physicians and the American Academy of Sleep Medicine.^1,2 CPAP reduces the apnea hypopnea index (AHI), improves oxyhemoglobin desaturation, and reduces cortical arousals associated with apneic/hypopneic events.³ Despite being an effective treatment for OSA, a significant limitation of CPAP is treatment adherence. Factors associated with CPAP adherence include disease and patient characteristics, perceived self-efficacy, treatment titration procedure, device technology factors, adverse effects, and psychosocial factors.⁴

Recent studies suggest that insomnia and depression may be associated with OSA. According to a review by Luyster and colleagues, insomnia is present in 39% to 58% of patients with OSA.⁵ Since OSA may disturb sleep by the number of nightly awakenings, OSA may cause or worsen insomnia. Furthermore, insomnia may exacerbate sleep apnea thus impeding the effectiveness of sleep apnea treatment.

In some studies, the presence of insomnia symptoms prior to initiating CPAP treatment has been found to be associated with reduced CPAP adherence. For example, in 2010, Wickwire and colleagues found that there was a negative association with the average nightly minutes of CPAP use for those patients with OSA that reported symptoms of sleep maintenance insomnia.⁶ This was not found for those patients with OSA who reported symptoms of sleep onset insomnia or reported no insomnia at all. In another study by Pieh and colleagues, self-reported insomnia symptoms were predictive of CPAP adherence (defined as < 4 hours use/night) at a 6-month follow-up.⁷ However, results from a separate study indicated that insomnia was not associated with 6-month CPAP adherence.⁸

Depressive symptoms are commonly reported by patients with OSA, and higher rates of depressive symptomatology in patients with OSA have been observed in a number of prevalence studies when compared with the general population.^9,10 Between 15% and 56% of patients with OSA are diagnosed with a depressive disorder compared with 6.6% of the general population.¹¹ OSA may be causally related with depression or coexist as a separate disorder. Apnea severity has been shown to exacerbate depressive symptoms, and treatment with CPAP can improve depressive symptoms.^12,13 Unfortunately, depression has been found to reduce CPAP adherence. For example, Law and colleagues found that depression was independently associated with poorer adherence during home-based auto-PAP titration.¹⁴ Furthermore, in a study by Gurlanick and colleagues, depressive symptoms were independently associated with reduced CPAP adherence in surgical patients with OSA.¹⁵

To the best of our knowledge, the combined impact of both insomnia and depression on CPAP adherence has not been investigated. In military populations this may be especially important as CPAP adherence has been reported to be worse in military patients with posttraumatic stress disorder (PTSD) and other psychiatric disorders, and there are increasing rates of insomnia and OSA in the military.^16,17 We hypothesize that active-duty and retired military patients with self-reported insomnia and depression will have reduced short and long-term CPAP adherence.

Methods

This is a retrospective cohort study that reviewed charts of active-duty and retired military members diagnosed with OSA by the Sleep Medicine Clinic at Naval Medical Center San Diego in California using a home sleep test (HST). The HSTs were interpreted by board-certified physicians in sleep medicine. Prior to the HST, all patients completed a sleep questionnaire that included self-reports of daytime sleepiness, using the Epworth Sleepiness Scale (ESS), depression using the Center for Epidemiologic Studies Depression Scale (CES-D) and insomnia using the Insomnia Severity Index (ISI).

The study population included active-duty and veteran patients diagnosed with OSA who chose treatment with a CPAP and attended the sleep clinic’s OSA educational class, which discussed the diagnosis and treatment of OSA. Inclusion criteria were patients aged > 18 years and diagnosed with OSA at the Naval Medical Center San Diego sleep lab between June 2014 and June 2015.

The study population was stratified into 4 groups: (1) those with OSA but no self-reported depression or insomnia; (2) those with OSA and self-reported depression but no insomnia; (3) those with OSA and insomnia but no depression; and (4) those with OSA and self-reported depression and insomnia. Charts were excluded from the review if there were incomplete data or if the patient selected an alternative treatment for OSA, such as an oral appliance. A total of 120 charts were included in the final review. This study was approved by the Naval Medical Center San Diego Institutional Review Board.

Data Collection

Data collected included the individual’s age, sex, minimum oxygen saturation during sleep, body mass index (BMI), height, weight, ESS score at time of diagnosis, date of HST, and date of attendance at the clinic’s OSA group treatment class. Diagnosis of OSA was based on the patient’s ≥ 5 AHI. OSA severity was divided into mild (AHI 5-14), moderate (AHI 15-29), or severe (AHI ≥ 30). A patient with a CES-D score > 14 was considered to have clinically significant depression, and a patient with an ISI score of > 14 was considered to have clinically significant insomnia. ISI is a reliable and valid instrument to quantify perceived insomnia severity.¹⁸ The CES-D was used only as an indicator of symptoms relating to depression, not to clinically diagnose depression. It also has been used extensively to investigate levels of depression without a psychiatric diagnosis.¹⁹

Follow-up CPAP adherence was collected at 3- and 12-month intervals after the date of the patient’s OSA treatment group class and included AHI, median pressure setting, median days used, average time used per night, and percentage of days used for more than 4 hours for the previous 30 days. Data were obtained through Sleep Data and ResMed websites, which receive patient adherence data directly from the patient’s CPAP device. Patients were considered to be adherent with CPAP usage based on the Medicare definition: Use of the CPAP device > 4 hours per night for at least 70% of nights during a 30-day period). The 3-month time frame was used as a short interval because that is when patients are seen in the pulmonary clinic for their initial follow-up appointment. Patients are seen again at 12 months because durable medical equipment supplies must be reordered after 12 months, which requires a patient visit.

Statistical Analysis

Linear regression methods were used to characterize any potential relationships between the predictor variables and the target outcome variables associated with CPAP adherence at 3 and 12 months. Scatterplots were produced to assess whether linear structure was sufficient to characterize any detectable relationships, or whether there existed more complex, nonlinear relationships. The best-fitting linear regression line was examined in relation to the confidence bands of the corresponding LOESS line to determine whether a more complicated model structure was needed to capture the relationship.

Standard tests of assumptions required for these methods were also carried out: QQ plots of residuals to test for normality, the Durbin-Watson test for independence of residuals, and the nonconstant variance score test for heteroskedasticity (ie, Breusch-Pagan test). The results of these assumptions tests are reported only in cases in which the assumptions were revealed to be untenable. In cases in which suspicious outlying observations may have biased analyses, robust versions of the corresponding models were constructed. In no cases did the resulting conclusions change; only the results of the original analysis are reported. All analyses were carried out in R (R Foundation, r-project.org). Statistical significance was defined as P < .05.

Results

Our study population was predominately male (90%) with a median age of 41 years (range 22-65) and BMI of 29.8 (range 7.7-57.2)(Table 1). 

Predictors of CPAP Adherence

OSA severity, as measured by the AHI, was the only promising predictor of CPAP use at 3 months (b, 2.128; t₈₀, 2.854; P = .005; adjusted R², 0.081). The severity of self-reported daytime sleepiness prior to a diagnosis of OSA, as measured by the ESS, did not predict 3-month CPAP adherence (b, 0.688; t₇₇, 0.300; P = .765; adjusted R², -0.012). Self-reported depression as measured by the CES-D also did not predict CPAP use at 3 months (b, -0.078; t₈₀, -0.014; P = .941; adjusted R², -0.012). Similarly, self-reported insomnia, as measured by the ISI, did not predict 3-month CPAP adherence (b, 1.765; t₈₀, 0.939; P = .350; adjusted R², -0.001). Furthermore, a model that incorporated both depression and insomnia proved no better at accounting for variation in 3-month CPAP use (R², -0.012). Demographic variables, such as age, sex, or BMI did not predict 3-month CPAP adherence (all Ps > .20). Finally, median CPAP pressure approached statistical significance as a predictor of 3-month CPAP adherence (b, 9.493; t₆₆, 1.881; P = .064; adjusted R², 0.037) (Figure 1).

CPAP Use at 12 months

The results for CPAP use at 12 months mirrored the results for 3 months with one main exception: OSA severity, as measured by the AHI, did not predict CPAP use at 12 months (b, 1.158; t₅₂, 1.245; P = .219; adjusted R², 0.010). Neither adding a quadratic predictor nor log transforming the AHI values produced a better model (R², -0.0007 vs R², 0.0089, respectively). The severity of self-reported daytime sleepiness, as measured by the ESS, did not predict 12-month CPAP adherence (b, -2.201; t₅₀, -0.752; P = .456; adjusted R² = -0.0086). Self-reported depression as measured by the CES-D also did not predict CPAP use at 12 months (b, 0.034, t₅₂, 0.022; P = .983; adjusted R², -0.092). Self-reported insomnia, as measured by the ISI, also did not predict 12-month CPAP adherence (b, 1.765; t₈₀, 0.939; P = .350; adjusted R² = -0.001). Furthermore, a model that incorporated both depression and insomnia proved no better at accounting for variation in 12-month CPAP use, (R², -0.0298). 

Discussion

Our study did not provide evidence that self-reported depressive and insomnia symptoms, as measured by the CES-D and ISI, can serve as useful predictors of short and long-term CPAP adherence in a sample of active-duty and retired military. OSA severity, as measured by the AHI, was the only promising predictor of CPAP adherence at 3 months.

Insomnia has been shown to improve with the use of CPAP. In a pilot study, Krakow and colleagues investigated the use of CPAP, oral appliances, or bilateral turbinectomy on patients with OSA and chronic insomnia.²⁰ Objective measures of insomnia improved with 1 night of CPAP titration. Björnsdóttir and colleagues evaluated the long-term effects of positive airway pressure (PAP) treatment on 705 adults with middle insomnia.²¹ They found after 2 years of PAP treatment combined with cognitive behavioral therapy for insomnia, patients had reduced symptoms of middle insomnia. It is possible that persistent insomnia is associated with more severe OSA which was not studied in our population.²²

As reported in other studies, it is possible that patients with depressive symptoms can improve with CPAP use, suggesting that depression and CPAP use are not totally unrelated. Edwards and colleagues studied the impact of CPAP on depressive symptoms in men and woman. They found that depressive symptoms are common in OSA and markedly improve with CPAP.²³ Bopparaju and colleagues found a high prevalence of anxiety and depression in patients with OSA but did not influence CPAP adherence.²⁴

The results of this study differ from some previous findings where depression was found to predict CPAP adherence.¹⁰ This may be due in part to differences in the type of instrument used to assess depression. Wells and colleagues found that baseline depressive symptoms did not correlate with CPAP adherence and that patients with greater CPAP adherence had improvement in OSA and depressive symptoms.²⁵ Furthermore, patients with residual OSA symptoms using CPAP had more depressive symptoms, suggesting that it is the improvement in OSA symptoms that may be correlated with the improvement in depressive symptoms. Although soldiers with PTSD may have reduced CPAP adherence, use of CPAP is associated with improvement in PTSD symptoms.^11,26

Limitations

This study had several limitations, including a small sample size. Study patients were also from a single institution, and the majority of patients had mild-to-moderate OSA. A multicenter prospective study with a larger sample size that included more severe patients with OSA may have shown different results. The participants in this study were limited to members from the active-duty and retired military population. The findings in this population may not be transferrable to the general public. Another study limitation was that the ISI and the CES-D were only administered prior to the initiation of CPAP. If the CES-D and ISI were administered at the 3- and 12-month follow-up visits, we could determine whether short and long-term CPAP improved these symptoms or whether there was no association between CPAP adherence with insomnia and depressive symptoms. Another limitation is that we did not have access to information about potential PTSD symptomatology, which has been associated with reduced CPAP adherence and is more common in a military and veteran population.¹¹

Conclusion

This study found little evidence that symptoms of depression and insomnia are useful predictors of CPAP adherence, in either short- or long-term use, in an active-duty and retired military sample. Although these were not found to be predictors of CPAP adherence, further research will be necessary to determine whether CPAP adherence improves symptoms of depression and insomnia in military and veteran populations. Apnea severity did predict CPAP adherence in the short term, but not for any length of time beyond 3 months. More research is needed to explore strategies to improve CPAP adherence in military populations.

Continuous positive airway pressure therapy (CPAP) is the first-line treatment for obstructive sleep apnea (OSA) recommended by the American College of Physicians and the American Academy of Sleep Medicine.^1,2 CPAP reduces the apnea hypopnea index (AHI), improves oxyhemoglobin desaturation, and reduces cortical arousals associated with apneic/hypopneic events.³ Despite being an effective treatment for OSA, a significant limitation of CPAP is treatment adherence. Factors associated with CPAP adherence include disease and patient characteristics, perceived self-efficacy, treatment titration procedure, device technology factors, adverse effects, and psychosocial factors.⁴

Recent studies suggest that insomnia and depression may be associated with OSA. According to a review by Luyster and colleagues, insomnia is present in 39% to 58% of patients with OSA.⁵ Since OSA may disturb sleep by the number of nightly awakenings, OSA may cause or worsen insomnia. Furthermore, insomnia may exacerbate sleep apnea thus impeding the effectiveness of sleep apnea treatment.

In some studies, the presence of insomnia symptoms prior to initiating CPAP treatment has been found to be associated with reduced CPAP adherence. For example, in 2010, Wickwire and colleagues found that there was a negative association with the average nightly minutes of CPAP use for those patients with OSA that reported symptoms of sleep maintenance insomnia.⁶ This was not found for those patients with OSA who reported symptoms of sleep onset insomnia or reported no insomnia at all. In another study by Pieh and colleagues, self-reported insomnia symptoms were predictive of CPAP adherence (defined as < 4 hours use/night) at a 6-month follow-up.⁷ However, results from a separate study indicated that insomnia was not associated with 6-month CPAP adherence.⁸

Depressive symptoms are commonly reported by patients with OSA, and higher rates of depressive symptomatology in patients with OSA have been observed in a number of prevalence studies when compared with the general population.^9,10 Between 15% and 56% of patients with OSA are diagnosed with a depressive disorder compared with 6.6% of the general population.¹¹ OSA may be causally related with depression or coexist as a separate disorder. Apnea severity has been shown to exacerbate depressive symptoms, and treatment with CPAP can improve depressive symptoms.^12,13 Unfortunately, depression has been found to reduce CPAP adherence. For example, Law and colleagues found that depression was independently associated with poorer adherence during home-based auto-PAP titration.¹⁴ Furthermore, in a study by Gurlanick and colleagues, depressive symptoms were independently associated with reduced CPAP adherence in surgical patients with OSA.¹⁵

To the best of our knowledge, the combined impact of both insomnia and depression on CPAP adherence has not been investigated. In military populations this may be especially important as CPAP adherence has been reported to be worse in military patients with posttraumatic stress disorder (PTSD) and other psychiatric disorders, and there are increasing rates of insomnia and OSA in the military.^16,17 We hypothesize that active-duty and retired military patients with self-reported insomnia and depression will have reduced short and long-term CPAP adherence.

Methods

This is a retrospective cohort study that reviewed charts of active-duty and retired military members diagnosed with OSA by the Sleep Medicine Clinic at Naval Medical Center San Diego in California using a home sleep test (HST). The HSTs were interpreted by board-certified physicians in sleep medicine. Prior to the HST, all patients completed a sleep questionnaire that included self-reports of daytime sleepiness, using the Epworth Sleepiness Scale (ESS), depression using the Center for Epidemiologic Studies Depression Scale (CES-D) and insomnia using the Insomnia Severity Index (ISI).

The study population included active-duty and veteran patients diagnosed with OSA who chose treatment with a CPAP and attended the sleep clinic’s OSA educational class, which discussed the diagnosis and treatment of OSA. Inclusion criteria were patients aged > 18 years and diagnosed with OSA at the Naval Medical Center San Diego sleep lab between June 2014 and June 2015.

The study population was stratified into 4 groups: (1) those with OSA but no self-reported depression or insomnia; (2) those with OSA and self-reported depression but no insomnia; (3) those with OSA and insomnia but no depression; and (4) those with OSA and self-reported depression and insomnia. Charts were excluded from the review if there were incomplete data or if the patient selected an alternative treatment for OSA, such as an oral appliance. A total of 120 charts were included in the final review. This study was approved by the Naval Medical Center San Diego Institutional Review Board.

Data Collection

Data collected included the individual’s age, sex, minimum oxygen saturation during sleep, body mass index (BMI), height, weight, ESS score at time of diagnosis, date of HST, and date of attendance at the clinic’s OSA group treatment class. Diagnosis of OSA was based on the patient’s ≥ 5 AHI. OSA severity was divided into mild (AHI 5-14), moderate (AHI 15-29), or severe (AHI ≥ 30). A patient with a CES-D score > 14 was considered to have clinically significant depression, and a patient with an ISI score of > 14 was considered to have clinically significant insomnia. ISI is a reliable and valid instrument to quantify perceived insomnia severity.¹⁸ The CES-D was used only as an indicator of symptoms relating to depression, not to clinically diagnose depression. It also has been used extensively to investigate levels of depression without a psychiatric diagnosis.¹⁹

Follow-up CPAP adherence was collected at 3- and 12-month intervals after the date of the patient’s OSA treatment group class and included AHI, median pressure setting, median days used, average time used per night, and percentage of days used for more than 4 hours for the previous 30 days. Data were obtained through Sleep Data and ResMed websites, which receive patient adherence data directly from the patient’s CPAP device. Patients were considered to be adherent with CPAP usage based on the Medicare definition: Use of the CPAP device > 4 hours per night for at least 70% of nights during a 30-day period). The 3-month time frame was used as a short interval because that is when patients are seen in the pulmonary clinic for their initial follow-up appointment. Patients are seen again at 12 months because durable medical equipment supplies must be reordered after 12 months, which requires a patient visit.

Statistical Analysis

Linear regression methods were used to characterize any potential relationships between the predictor variables and the target outcome variables associated with CPAP adherence at 3 and 12 months. Scatterplots were produced to assess whether linear structure was sufficient to characterize any detectable relationships, or whether there existed more complex, nonlinear relationships. The best-fitting linear regression line was examined in relation to the confidence bands of the corresponding LOESS line to determine whether a more complicated model structure was needed to capture the relationship.

Standard tests of assumptions required for these methods were also carried out: QQ plots of residuals to test for normality, the Durbin-Watson test for independence of residuals, and the nonconstant variance score test for heteroskedasticity (ie, Breusch-Pagan test). The results of these assumptions tests are reported only in cases in which the assumptions were revealed to be untenable. In cases in which suspicious outlying observations may have biased analyses, robust versions of the corresponding models were constructed. In no cases did the resulting conclusions change; only the results of the original analysis are reported. All analyses were carried out in R (R Foundation, r-project.org). Statistical significance was defined as P < .05.

Results

Our study population was predominately male (90%) with a median age of 41 years (range 22-65) and BMI of 29.8 (range 7.7-57.2)(Table 1). 

Predictors of CPAP Adherence

OSA severity, as measured by the AHI, was the only promising predictor of CPAP use at 3 months (b, 2.128; t₈₀, 2.854; P = .005; adjusted R², 0.081). The severity of self-reported daytime sleepiness prior to a diagnosis of OSA, as measured by the ESS, did not predict 3-month CPAP adherence (b, 0.688; t₇₇, 0.300; P = .765; adjusted R², -0.012). Self-reported depression as measured by the CES-D also did not predict CPAP use at 3 months (b, -0.078; t₈₀, -0.014; P = .941; adjusted R², -0.012). Similarly, self-reported insomnia, as measured by the ISI, did not predict 3-month CPAP adherence (b, 1.765; t₈₀, 0.939; P = .350; adjusted R², -0.001). Furthermore, a model that incorporated both depression and insomnia proved no better at accounting for variation in 3-month CPAP use (R², -0.012). Demographic variables, such as age, sex, or BMI did not predict 3-month CPAP adherence (all Ps > .20). Finally, median CPAP pressure approached statistical significance as a predictor of 3-month CPAP adherence (b, 9.493; t₆₆, 1.881; P = .064; adjusted R², 0.037) (Figure 1).

CPAP Use at 12 months

The results for CPAP use at 12 months mirrored the results for 3 months with one main exception: OSA severity, as measured by the AHI, did not predict CPAP use at 12 months (b, 1.158; t₅₂, 1.245; P = .219; adjusted R², 0.010). Neither adding a quadratic predictor nor log transforming the AHI values produced a better model (R², -0.0007 vs R², 0.0089, respectively). The severity of self-reported daytime sleepiness, as measured by the ESS, did not predict 12-month CPAP adherence (b, -2.201; t₅₀, -0.752; P = .456; adjusted R² = -0.0086). Self-reported depression as measured by the CES-D also did not predict CPAP use at 12 months (b, 0.034, t₅₂, 0.022; P = .983; adjusted R², -0.092). Self-reported insomnia, as measured by the ISI, also did not predict 12-month CPAP adherence (b, 1.765; t₈₀, 0.939; P = .350; adjusted R² = -0.001). Furthermore, a model that incorporated both depression and insomnia proved no better at accounting for variation in 12-month CPAP use, (R², -0.0298). 

Discussion

Our study did not provide evidence that self-reported depressive and insomnia symptoms, as measured by the CES-D and ISI, can serve as useful predictors of short and long-term CPAP adherence in a sample of active-duty and retired military. OSA severity, as measured by the AHI, was the only promising predictor of CPAP adherence at 3 months.

Insomnia has been shown to improve with the use of CPAP. In a pilot study, Krakow and colleagues investigated the use of CPAP, oral appliances, or bilateral turbinectomy on patients with OSA and chronic insomnia.²⁰ Objective measures of insomnia improved with 1 night of CPAP titration. Björnsdóttir and colleagues evaluated the long-term effects of positive airway pressure (PAP) treatment on 705 adults with middle insomnia.²¹ They found after 2 years of PAP treatment combined with cognitive behavioral therapy for insomnia, patients had reduced symptoms of middle insomnia. It is possible that persistent insomnia is associated with more severe OSA which was not studied in our population.²²

As reported in other studies, it is possible that patients with depressive symptoms can improve with CPAP use, suggesting that depression and CPAP use are not totally unrelated. Edwards and colleagues studied the impact of CPAP on depressive symptoms in men and woman. They found that depressive symptoms are common in OSA and markedly improve with CPAP.²³ Bopparaju and colleagues found a high prevalence of anxiety and depression in patients with OSA but did not influence CPAP adherence.²⁴

The results of this study differ from some previous findings where depression was found to predict CPAP adherence.¹⁰ This may be due in part to differences in the type of instrument used to assess depression. Wells and colleagues found that baseline depressive symptoms did not correlate with CPAP adherence and that patients with greater CPAP adherence had improvement in OSA and depressive symptoms.²⁵ Furthermore, patients with residual OSA symptoms using CPAP had more depressive symptoms, suggesting that it is the improvement in OSA symptoms that may be correlated with the improvement in depressive symptoms. Although soldiers with PTSD may have reduced CPAP adherence, use of CPAP is associated with improvement in PTSD symptoms.^11,26

Limitations

This study had several limitations, including a small sample size. Study patients were also from a single institution, and the majority of patients had mild-to-moderate OSA. A multicenter prospective study with a larger sample size that included more severe patients with OSA may have shown different results. The participants in this study were limited to members from the active-duty and retired military population. The findings in this population may not be transferrable to the general public. Another study limitation was that the ISI and the CES-D were only administered prior to the initiation of CPAP. If the CES-D and ISI were administered at the 3- and 12-month follow-up visits, we could determine whether short and long-term CPAP improved these symptoms or whether there was no association between CPAP adherence with insomnia and depressive symptoms. Another limitation is that we did not have access to information about potential PTSD symptomatology, which has been associated with reduced CPAP adherence and is more common in a military and veteran population.¹¹

Conclusion

This study found little evidence that symptoms of depression and insomnia are useful predictors of CPAP adherence, in either short- or long-term use, in an active-duty and retired military sample. Although these were not found to be predictors of CPAP adherence, further research will be necessary to determine whether CPAP adherence improves symptoms of depression and insomnia in military and veteran populations. Apnea severity did predict CPAP adherence in the short term, but not for any length of time beyond 3 months. More research is needed to explore strategies to improve CPAP adherence in military populations.

Continuous positive airway pressure therapy (CPAP) is the first-line treatment for obstructive sleep apnea (OSA) recommended by the American College of Physicians and the American Academy of Sleep Medicine.^1,2 CPAP reduces the apnea hypopnea index (AHI), improves oxyhemoglobin desaturation, and reduces cortical arousals associated with apneic/hypopneic events.³ Despite being an effective treatment for OSA, a significant limitation of CPAP is treatment adherence. Factors associated with CPAP adherence include disease and patient characteristics, perceived self-efficacy, treatment titration procedure, device technology factors, adverse effects, and psychosocial factors.⁴

Recent studies suggest that insomnia and depression may be associated with OSA. According to a review by Luyster and colleagues, insomnia is present in 39% to 58% of patients with OSA.⁵ Since OSA may disturb sleep by the number of nightly awakenings, OSA may cause or worsen insomnia. Furthermore, insomnia may exacerbate sleep apnea thus impeding the effectiveness of sleep apnea treatment.

In some studies, the presence of insomnia symptoms prior to initiating CPAP treatment has been found to be associated with reduced CPAP adherence. For example, in 2010, Wickwire and colleagues found that there was a negative association with the average nightly minutes of CPAP use for those patients with OSA that reported symptoms of sleep maintenance insomnia.⁶ This was not found for those patients with OSA who reported symptoms of sleep onset insomnia or reported no insomnia at all. In another study by Pieh and colleagues, self-reported insomnia symptoms were predictive of CPAP adherence (defined as < 4 hours use/night) at a 6-month follow-up.⁷ However, results from a separate study indicated that insomnia was not associated with 6-month CPAP adherence.⁸

Depressive symptoms are commonly reported by patients with OSA, and higher rates of depressive symptomatology in patients with OSA have been observed in a number of prevalence studies when compared with the general population.^9,10 Between 15% and 56% of patients with OSA are diagnosed with a depressive disorder compared with 6.6% of the general population.¹¹ OSA may be causally related with depression or coexist as a separate disorder. Apnea severity has been shown to exacerbate depressive symptoms, and treatment with CPAP can improve depressive symptoms.^12,13 Unfortunately, depression has been found to reduce CPAP adherence. For example, Law and colleagues found that depression was independently associated with poorer adherence during home-based auto-PAP titration.¹⁴ Furthermore, in a study by Gurlanick and colleagues, depressive symptoms were independently associated with reduced CPAP adherence in surgical patients with OSA.¹⁵

To the best of our knowledge, the combined impact of both insomnia and depression on CPAP adherence has not been investigated. In military populations this may be especially important as CPAP adherence has been reported to be worse in military patients with posttraumatic stress disorder (PTSD) and other psychiatric disorders, and there are increasing rates of insomnia and OSA in the military.^16,17 We hypothesize that active-duty and retired military patients with self-reported insomnia and depression will have reduced short and long-term CPAP adherence.

Methods

This is a retrospective cohort study that reviewed charts of active-duty and retired military members diagnosed with OSA by the Sleep Medicine Clinic at Naval Medical Center San Diego in California using a home sleep test (HST). The HSTs were interpreted by board-certified physicians in sleep medicine. Prior to the HST, all patients completed a sleep questionnaire that included self-reports of daytime sleepiness, using the Epworth Sleepiness Scale (ESS), depression using the Center for Epidemiologic Studies Depression Scale (CES-D) and insomnia using the Insomnia Severity Index (ISI).

The study population included active-duty and veteran patients diagnosed with OSA who chose treatment with a CPAP and attended the sleep clinic’s OSA educational class, which discussed the diagnosis and treatment of OSA. Inclusion criteria were patients aged > 18 years and diagnosed with OSA at the Naval Medical Center San Diego sleep lab between June 2014 and June 2015.

The study population was stratified into 4 groups: (1) those with OSA but no self-reported depression or insomnia; (2) those with OSA and self-reported depression but no insomnia; (3) those with OSA and insomnia but no depression; and (4) those with OSA and self-reported depression and insomnia. Charts were excluded from the review if there were incomplete data or if the patient selected an alternative treatment for OSA, such as an oral appliance. A total of 120 charts were included in the final review. This study was approved by the Naval Medical Center San Diego Institutional Review Board.

Data Collection

Data collected included the individual’s age, sex, minimum oxygen saturation during sleep, body mass index (BMI), height, weight, ESS score at time of diagnosis, date of HST, and date of attendance at the clinic’s OSA group treatment class. Diagnosis of OSA was based on the patient’s ≥ 5 AHI. OSA severity was divided into mild (AHI 5-14), moderate (AHI 15-29), or severe (AHI ≥ 30). A patient with a CES-D score > 14 was considered to have clinically significant depression, and a patient with an ISI score of > 14 was considered to have clinically significant insomnia. ISI is a reliable and valid instrument to quantify perceived insomnia severity.¹⁸ The CES-D was used only as an indicator of symptoms relating to depression, not to clinically diagnose depression. It also has been used extensively to investigate levels of depression without a psychiatric diagnosis.¹⁹

Follow-up CPAP adherence was collected at 3- and 12-month intervals after the date of the patient’s OSA treatment group class and included AHI, median pressure setting, median days used, average time used per night, and percentage of days used for more than 4 hours for the previous 30 days. Data were obtained through Sleep Data and ResMed websites, which receive patient adherence data directly from the patient’s CPAP device. Patients were considered to be adherent with CPAP usage based on the Medicare definition: Use of the CPAP device > 4 hours per night for at least 70% of nights during a 30-day period). The 3-month time frame was used as a short interval because that is when patients are seen in the pulmonary clinic for their initial follow-up appointment. Patients are seen again at 12 months because durable medical equipment supplies must be reordered after 12 months, which requires a patient visit.

Statistical Analysis

Linear regression methods were used to characterize any potential relationships between the predictor variables and the target outcome variables associated with CPAP adherence at 3 and 12 months. Scatterplots were produced to assess whether linear structure was sufficient to characterize any detectable relationships, or whether there existed more complex, nonlinear relationships. The best-fitting linear regression line was examined in relation to the confidence bands of the corresponding LOESS line to determine whether a more complicated model structure was needed to capture the relationship.

Standard tests of assumptions required for these methods were also carried out: QQ plots of residuals to test for normality, the Durbin-Watson test for independence of residuals, and the nonconstant variance score test for heteroskedasticity (ie, Breusch-Pagan test). The results of these assumptions tests are reported only in cases in which the assumptions were revealed to be untenable. In cases in which suspicious outlying observations may have biased analyses, robust versions of the corresponding models were constructed. In no cases did the resulting conclusions change; only the results of the original analysis are reported. All analyses were carried out in R (R Foundation, r-project.org). Statistical significance was defined as P < .05.

Results

Our study population was predominately male (90%) with a median age of 41 years (range 22-65) and BMI of 29.8 (range 7.7-57.2)(Table 1). 

Predictors of CPAP Adherence

OSA severity, as measured by the AHI, was the only promising predictor of CPAP use at 3 months (b, 2.128; t₈₀, 2.854; P = .005; adjusted R², 0.081). The severity of self-reported daytime sleepiness prior to a diagnosis of OSA, as measured by the ESS, did not predict 3-month CPAP adherence (b, 0.688; t₇₇, 0.300; P = .765; adjusted R², -0.012). Self-reported depression as measured by the CES-D also did not predict CPAP use at 3 months (b, -0.078; t₈₀, -0.014; P = .941; adjusted R², -0.012). Similarly, self-reported insomnia, as measured by the ISI, did not predict 3-month CPAP adherence (b, 1.765; t₈₀, 0.939; P = .350; adjusted R², -0.001). Furthermore, a model that incorporated both depression and insomnia proved no better at accounting for variation in 3-month CPAP use (R², -0.012). Demographic variables, such as age, sex, or BMI did not predict 3-month CPAP adherence (all Ps > .20). Finally, median CPAP pressure approached statistical significance as a predictor of 3-month CPAP adherence (b, 9.493; t₆₆, 1.881; P = .064; adjusted R², 0.037) (Figure 1).

CPAP Use at 12 months

The results for CPAP use at 12 months mirrored the results for 3 months with one main exception: OSA severity, as measured by the AHI, did not predict CPAP use at 12 months (b, 1.158; t₅₂, 1.245; P = .219; adjusted R², 0.010). Neither adding a quadratic predictor nor log transforming the AHI values produced a better model (R², -0.0007 vs R², 0.0089, respectively). The severity of self-reported daytime sleepiness, as measured by the ESS, did not predict 12-month CPAP adherence (b, -2.201; t₅₀, -0.752; P = .456; adjusted R² = -0.0086). Self-reported depression as measured by the CES-D also did not predict CPAP use at 12 months (b, 0.034, t₅₂, 0.022; P = .983; adjusted R², -0.092). Self-reported insomnia, as measured by the ISI, also did not predict 12-month CPAP adherence (b, 1.765; t₈₀, 0.939; P = .350; adjusted R² = -0.001). Furthermore, a model that incorporated both depression and insomnia proved no better at accounting for variation in 12-month CPAP use, (R², -0.0298). 

Discussion

Our study did not provide evidence that self-reported depressive and insomnia symptoms, as measured by the CES-D and ISI, can serve as useful predictors of short and long-term CPAP adherence in a sample of active-duty and retired military. OSA severity, as measured by the AHI, was the only promising predictor of CPAP adherence at 3 months.

Insomnia has been shown to improve with the use of CPAP. In a pilot study, Krakow and colleagues investigated the use of CPAP, oral appliances, or bilateral turbinectomy on patients with OSA and chronic insomnia.²⁰ Objective measures of insomnia improved with 1 night of CPAP titration. Björnsdóttir and colleagues evaluated the long-term effects of positive airway pressure (PAP) treatment on 705 adults with middle insomnia.²¹ They found after 2 years of PAP treatment combined with cognitive behavioral therapy for insomnia, patients had reduced symptoms of middle insomnia. It is possible that persistent insomnia is associated with more severe OSA which was not studied in our population.²²

As reported in other studies, it is possible that patients with depressive symptoms can improve with CPAP use, suggesting that depression and CPAP use are not totally unrelated. Edwards and colleagues studied the impact of CPAP on depressive symptoms in men and woman. They found that depressive symptoms are common in OSA and markedly improve with CPAP.²³ Bopparaju and colleagues found a high prevalence of anxiety and depression in patients with OSA but did not influence CPAP adherence.²⁴

The results of this study differ from some previous findings where depression was found to predict CPAP adherence.¹⁰ This may be due in part to differences in the type of instrument used to assess depression. Wells and colleagues found that baseline depressive symptoms did not correlate with CPAP adherence and that patients with greater CPAP adherence had improvement in OSA and depressive symptoms.²⁵ Furthermore, patients with residual OSA symptoms using CPAP had more depressive symptoms, suggesting that it is the improvement in OSA symptoms that may be correlated with the improvement in depressive symptoms. Although soldiers with PTSD may have reduced CPAP adherence, use of CPAP is associated with improvement in PTSD symptoms.^11,26

Limitations

This study had several limitations, including a small sample size. Study patients were also from a single institution, and the majority of patients had mild-to-moderate OSA. A multicenter prospective study with a larger sample size that included more severe patients with OSA may have shown different results. The participants in this study were limited to members from the active-duty and retired military population. The findings in this population may not be transferrable to the general public. Another study limitation was that the ISI and the CES-D were only administered prior to the initiation of CPAP. If the CES-D and ISI were administered at the 3- and 12-month follow-up visits, we could determine whether short and long-term CPAP improved these symptoms or whether there was no association between CPAP adherence with insomnia and depressive symptoms. Another limitation is that we did not have access to information about potential PTSD symptomatology, which has been associated with reduced CPAP adherence and is more common in a military and veteran population.¹¹

Conclusion

This study found little evidence that symptoms of depression and insomnia are useful predictors of CPAP adherence, in either short- or long-term use, in an active-duty and retired military sample. Although these were not found to be predictors of CPAP adherence, further research will be necessary to determine whether CPAP adherence improves symptoms of depression and insomnia in military and veteran populations. Apnea severity did predict CPAP adherence in the short term, but not for any length of time beyond 3 months. More research is needed to explore strategies to improve CPAP adherence in military populations.

Schwannomas are benign tumors exclusively composed of Schwann cells that arise from the peripheral nerve sheath; these tumors theoretically can present anywhere in the body where nerves reside. They tend to occur in the head and neck region (classically an acoustic neuroma) but also occur in other locations, including the retroperitoneal space and the extremities, particularly flexural surfaces. Patients with cutaneous schwannomas are most likely to present to their primary care provider’s office reporting skin findings or localized pain, and providers should be aware of schwannomas on the differential for painful nodular growths.

Case Presentation

A 70-year-old man with type 2 diabetes mellitus presented to the primary care clinic for intermittent, sharp, localized left lower quadrant abdominal wall pain that was gradually progressive over the previous few months. The patient noticed the development of a small nodule 7 to 8 months prior to the visit, at which time the pain was less frequent and less severe. He reported no postprandial association of the pain, nausea, vomiting, diarrhea, constipation, or other gastrointestinal symptoms.

Ten months prior to the presentation, he was involved in a low-impact motor vehicle collision as a pedestrian in which he fell face-first onto the hood of an oncoming car. At that time, he did not note any abdominal trauma or pain. Evaluation at a local emergency department did not reveal any major injuries. In the interim, he had self-administered insulin in his abdominal region, as he had without incident for the previous 2 years. He reported that he was not injecting near the site of the nodule since it had formed. He could not recall whether the location was a previous insulin administration site.

On examination, the patient’s vital signs were normal as were the cardiac and respiratory examinations. An abdominal exam revealed normal bowel sounds and no overlying skin changes or discoloration. Palpation revealed a 1.5 x 1 cm rubbery-to-firm, well-circumscribed subcutaneous nodule along his mid-left abdomen, about 7 cm lateral to the umbilicus. The nodule was sensitive to both light touch and deep pressure. It was firmer than expected for an abdominal wall lipoma. There was no central puncta or pore to suggest an epidermal inclusion cyst. There was no surrounding erythema or induration to suggest an abscess. 

The patient was referred for surgery and underwent excisional biopsy of the mass. Pathology revealed a well-circumscribed vascular/spindle-cell lesion consistent with a schwannoma. His postoperative course was uncomplicated. At 4-week follow-up the incision had healed completely and the patient was pain free.

Discussion

Soft-tissue nodules are common—about two-thirds of soft-tissue tumors are classified into 7 diagnostic categories: lipoma and lipoma variants (16%), fibrous histiocytoma (13%), nodular fasciitis (11%), hemangioma (8%), fibromatosis (7%), neurofibroma (5%), and schwannoma (5%).¹ Peripheral nerve tumors (schwannomas, neurofibromas) can be associated with pain or paresthesias, and less commonly, neurologic deficits, such as motor weakness. Peripheral nerve tumors have several classifications, such as nonneoplastic vs neoplastic, benign vs malignant, and sheath vs nonsheath origins. Schwannomas are considered part of the neoplastic subset due to their growth; otherwise, they are benign with a sheath origin. In contrast to neurofibromas, benign schwannomas have a slower rate of progression, lower association with pain, and fewer neurologic symptoms.²

The neural sheath is made up of 3 types of cells: the fibroblast, the Schwann cell, and the perineural cell, which lacks a basement membrane. It is the Schwann cell that can give rise to the 3 main types of cutaneous nerve tumors: neuromas, neurofibromas, and schwannomas.³ A nerve that is both entering and exiting a mass is a classic presentation for a peripheral nerve sheath tumor. If the nerve is eccentric to the lesion, then it is consistent with a schwannoma (not a neurofibroma).⁴ Schwannomas are made exclusively of Schwann cells that arise from the nerve sheath, whereas neurofibromas are made up of all the different cell types that constitute a nerve. Bilateral vestibular schwannomas (acoustic neuromas) are virtually pathognomonic of neurofibromatosis 2 (NF-2), which can manifest as hearing loss, tinnitus, and equilibrium problems. In contrast, neurofibromatosis 1 (NF-1) is more common, characterized by multiple café au lait spots, freckling in the axillary and groin regions, increased risk of cancers overall, and development of pedunculated skin growths, brain, or organ-based neurofibromas.

Diagnosis

A workup generally includes a thorough history and examination as well as imaging. In cases of superficial subcutaneous lesions, an ultrasound is often the imaging modality of choice. However, magnetic resonance imaging (MRI) and computed tomography (CT) scans are frequently used for more deep-seated lesions. There can be significant differences between malignant and benign neural lesions on MRI and CT in terms of contrast-uptake and heterogeneity of tissue, but the visual features are not consistent. Best estimates for MRI suggest 61% sensitivity and 90% specificity for the diagnosis of high-grade malignant peripheral nerve sheath tumors based on imaging alone.⁵

Definitive diagnosis requires surgical excision. Fine-needle aspiration can be used to diagnose subcutaneous nodules, but there is a possibility that degenerative changes and nuclear atypia seen on a smaller sample may be confused with a more aggressive sarcoma. For example, long-standing schwannomas are often called ancient, meaning that they break down over time, and the atypia they display is a regressive phenomenon.⁶ Therefore, a small or limited tissue sampling may not be representative of the entire lesion.⁷ As such, patients will likely need referral for surgical removal to determine the exact nature of the growth.

Although schwannomas are uncommon overall, the highest incidence is in the fourth decade of life with a slight predominance in females. They are often incidentally found as a palpable mass but can be symptomatic with paresthesias, pain, or neurologic changes—particularly when identified in the retroperitoneum or along joints. Schwannomas are most commonly found in the retroperitoneum (32%), mediastinum (23%), head and neck (18%), and extremities (16%).⁸ The majority of cases (about 90%) are sporadic; whereas 2% are related to NF-2.⁹ The abdominal wall schwannoma is rare. Our review of English-language literature in PubMed and EMBASE found only 5 other case reports (Table 1).

On physical examination, superficial lesions are freely movable except for a single point of attachment, which is generally along the long axis of the nerve. 

Pathology

On gross pathology examination, schwannomas have a well-circumscribed smooth external surface. On microscopy, schwannomas are truly encapsulated, uninodular, spindle-cell proliferations arranged in a streaming pattern within a background of thick, hyalinized blood vessels. Classic schwannomas typically exhibit a biphasic pattern of alternating areas of high and low cellularity and are named for Swedish neurologist Nils Antoni. The more cellular regions are referred to as Antoni A areas and consist of streaming fascicles of compact spindle cells that often palisade around acellular eosinophilic areas of fibrillary processes known as Verocay bodies.

In contrast, the lower cellularity regions (Antoni B areas) consist of multipolar, loosely textured cells with abundant cytoplasm, haphazardly arranged processes, and an overall myxoid appearance.¹¹ Schwannomas are known to have widely variable proportions of Antoni A and Antoni B areas; in this case, the excised specimen was noted to have predominately Antoni A areas without well-defined Verocay bodies and only scattered foci showing some suggestion of the hypocellular Antoni B architecture (Figure 2).^9,12 

Immunohistochemical stains for S100 and SOX10 (used to identify cells derived from a neural crest lineage) were strongly positive, which is characteristic of schwannomas.¹³ Although there have only been rare reports of extracranial schwannomas undergoing malignant transformation, it is critical to rule out the possibility of a de novo malignant peripheral nerve sheath tumor (MPNST).¹³ In general, MPNSTs tend to be more cellular, have brisk mitotic activity, areas of necrosis, hyperchromatic nuclei, and conspicuous pleomorphism. Mitotic figures, which can be concerning for malignant potential if present in high number, were noted occasionally in our patient; however, occasional mitosis may be seen in classic schwannomas. Clinically, MPNSTs have a poor prognosis. Based on case reports, disease-specific survival at 10 years is 31.6% for localized disease and only 7.5% for metastatic disease.¹⁴ In this case, there was no evidence of any of the high-grade features of a malignant peripheral nerve sheath tumor, thus supporting the diagnosis of schwannoma (neurilemmoma).

Treatment

Schwannomas are exclusively treated by excision. Prognosis is good with low recurrence rates. It is unknown what the recurrence rates are for completely resected abdominal wall schwannomas since there are so few reports in the literature. For other well-known entities, such as vestibular schwannoma (acoustic neuromas), the recurrence rates are generally 2% to 3%.¹⁵ Transformation of schwannomas into MPNSTs are so unusual that they are only described in single case reports.

Conclusion

Soft-tissue masses are a common complaint. Most are benign and do not require excision unless it interferes with the quality of life of the patient or if the diagnosis is uncertain. It is important to be aware of schwannomas in the differential diagnosis of soft-tissue masses. Diagnosis may be achieved through the combination of imaging and biopsy, but the definitive diagnosis is made on complete excision of the mass.

Acknowledgments
Contributors: Michael Lewis, MD, Department of Pathology, VA Greater Los Angeles Healthcare System. Written permission also was obtained from the patient.

Schwannomas are benign tumors exclusively composed of Schwann cells that arise from the peripheral nerve sheath; these tumors theoretically can present anywhere in the body where nerves reside. They tend to occur in the head and neck region (classically an acoustic neuroma) but also occur in other locations, including the retroperitoneal space and the extremities, particularly flexural surfaces. Patients with cutaneous schwannomas are most likely to present to their primary care provider’s office reporting skin findings or localized pain, and providers should be aware of schwannomas on the differential for painful nodular growths.

Case Presentation

A 70-year-old man with type 2 diabetes mellitus presented to the primary care clinic for intermittent, sharp, localized left lower quadrant abdominal wall pain that was gradually progressive over the previous few months. The patient noticed the development of a small nodule 7 to 8 months prior to the visit, at which time the pain was less frequent and less severe. He reported no postprandial association of the pain, nausea, vomiting, diarrhea, constipation, or other gastrointestinal symptoms.

Ten months prior to the presentation, he was involved in a low-impact motor vehicle collision as a pedestrian in which he fell face-first onto the hood of an oncoming car. At that time, he did not note any abdominal trauma or pain. Evaluation at a local emergency department did not reveal any major injuries. In the interim, he had self-administered insulin in his abdominal region, as he had without incident for the previous 2 years. He reported that he was not injecting near the site of the nodule since it had formed. He could not recall whether the location was a previous insulin administration site.

On examination, the patient’s vital signs were normal as were the cardiac and respiratory examinations. An abdominal exam revealed normal bowel sounds and no overlying skin changes or discoloration. Palpation revealed a 1.5 x 1 cm rubbery-to-firm, well-circumscribed subcutaneous nodule along his mid-left abdomen, about 7 cm lateral to the umbilicus. The nodule was sensitive to both light touch and deep pressure. It was firmer than expected for an abdominal wall lipoma. There was no central puncta or pore to suggest an epidermal inclusion cyst. There was no surrounding erythema or induration to suggest an abscess. 

The patient was referred for surgery and underwent excisional biopsy of the mass. Pathology revealed a well-circumscribed vascular/spindle-cell lesion consistent with a schwannoma. His postoperative course was uncomplicated. At 4-week follow-up the incision had healed completely and the patient was pain free.

Discussion

Soft-tissue nodules are common—about two-thirds of soft-tissue tumors are classified into 7 diagnostic categories: lipoma and lipoma variants (16%), fibrous histiocytoma (13%), nodular fasciitis (11%), hemangioma (8%), fibromatosis (7%), neurofibroma (5%), and schwannoma (5%).¹ Peripheral nerve tumors (schwannomas, neurofibromas) can be associated with pain or paresthesias, and less commonly, neurologic deficits, such as motor weakness. Peripheral nerve tumors have several classifications, such as nonneoplastic vs neoplastic, benign vs malignant, and sheath vs nonsheath origins. Schwannomas are considered part of the neoplastic subset due to their growth; otherwise, they are benign with a sheath origin. In contrast to neurofibromas, benign schwannomas have a slower rate of progression, lower association with pain, and fewer neurologic symptoms.²

The neural sheath is made up of 3 types of cells: the fibroblast, the Schwann cell, and the perineural cell, which lacks a basement membrane. It is the Schwann cell that can give rise to the 3 main types of cutaneous nerve tumors: neuromas, neurofibromas, and schwannomas.³ A nerve that is both entering and exiting a mass is a classic presentation for a peripheral nerve sheath tumor. If the nerve is eccentric to the lesion, then it is consistent with a schwannoma (not a neurofibroma).⁴ Schwannomas are made exclusively of Schwann cells that arise from the nerve sheath, whereas neurofibromas are made up of all the different cell types that constitute a nerve. Bilateral vestibular schwannomas (acoustic neuromas) are virtually pathognomonic of neurofibromatosis 2 (NF-2), which can manifest as hearing loss, tinnitus, and equilibrium problems. In contrast, neurofibromatosis 1 (NF-1) is more common, characterized by multiple café au lait spots, freckling in the axillary and groin regions, increased risk of cancers overall, and development of pedunculated skin growths, brain, or organ-based neurofibromas.

Diagnosis

A workup generally includes a thorough history and examination as well as imaging. In cases of superficial subcutaneous lesions, an ultrasound is often the imaging modality of choice. However, magnetic resonance imaging (MRI) and computed tomography (CT) scans are frequently used for more deep-seated lesions. There can be significant differences between malignant and benign neural lesions on MRI and CT in terms of contrast-uptake and heterogeneity of tissue, but the visual features are not consistent. Best estimates for MRI suggest 61% sensitivity and 90% specificity for the diagnosis of high-grade malignant peripheral nerve sheath tumors based on imaging alone.⁵

Definitive diagnosis requires surgical excision. Fine-needle aspiration can be used to diagnose subcutaneous nodules, but there is a possibility that degenerative changes and nuclear atypia seen on a smaller sample may be confused with a more aggressive sarcoma. For example, long-standing schwannomas are often called ancient, meaning that they break down over time, and the atypia they display is a regressive phenomenon.⁶ Therefore, a small or limited tissue sampling may not be representative of the entire lesion.⁷ As such, patients will likely need referral for surgical removal to determine the exact nature of the growth.

Although schwannomas are uncommon overall, the highest incidence is in the fourth decade of life with a slight predominance in females. They are often incidentally found as a palpable mass but can be symptomatic with paresthesias, pain, or neurologic changes—particularly when identified in the retroperitoneum or along joints. Schwannomas are most commonly found in the retroperitoneum (32%), mediastinum (23%), head and neck (18%), and extremities (16%).⁸ The majority of cases (about 90%) are sporadic; whereas 2% are related to NF-2.⁹ The abdominal wall schwannoma is rare. Our review of English-language literature in PubMed and EMBASE found only 5 other case reports (Table 1).

On physical examination, superficial lesions are freely movable except for a single point of attachment, which is generally along the long axis of the nerve. 

Pathology

On gross pathology examination, schwannomas have a well-circumscribed smooth external surface. On microscopy, schwannomas are truly encapsulated, uninodular, spindle-cell proliferations arranged in a streaming pattern within a background of thick, hyalinized blood vessels. Classic schwannomas typically exhibit a biphasic pattern of alternating areas of high and low cellularity and are named for Swedish neurologist Nils Antoni. The more cellular regions are referred to as Antoni A areas and consist of streaming fascicles of compact spindle cells that often palisade around acellular eosinophilic areas of fibrillary processes known as Verocay bodies.

In contrast, the lower cellularity regions (Antoni B areas) consist of multipolar, loosely textured cells with abundant cytoplasm, haphazardly arranged processes, and an overall myxoid appearance.¹¹ Schwannomas are known to have widely variable proportions of Antoni A and Antoni B areas; in this case, the excised specimen was noted to have predominately Antoni A areas without well-defined Verocay bodies and only scattered foci showing some suggestion of the hypocellular Antoni B architecture (Figure 2).^9,12 

Immunohistochemical stains for S100 and SOX10 (used to identify cells derived from a neural crest lineage) were strongly positive, which is characteristic of schwannomas.¹³ Although there have only been rare reports of extracranial schwannomas undergoing malignant transformation, it is critical to rule out the possibility of a de novo malignant peripheral nerve sheath tumor (MPNST).¹³ In general, MPNSTs tend to be more cellular, have brisk mitotic activity, areas of necrosis, hyperchromatic nuclei, and conspicuous pleomorphism. Mitotic figures, which can be concerning for malignant potential if present in high number, were noted occasionally in our patient; however, occasional mitosis may be seen in classic schwannomas. Clinically, MPNSTs have a poor prognosis. Based on case reports, disease-specific survival at 10 years is 31.6% for localized disease and only 7.5% for metastatic disease.¹⁴ In this case, there was no evidence of any of the high-grade features of a malignant peripheral nerve sheath tumor, thus supporting the diagnosis of schwannoma (neurilemmoma).

Treatment

Schwannomas are exclusively treated by excision. Prognosis is good with low recurrence rates. It is unknown what the recurrence rates are for completely resected abdominal wall schwannomas since there are so few reports in the literature. For other well-known entities, such as vestibular schwannoma (acoustic neuromas), the recurrence rates are generally 2% to 3%.¹⁵ Transformation of schwannomas into MPNSTs are so unusual that they are only described in single case reports.

Conclusion

Soft-tissue masses are a common complaint. Most are benign and do not require excision unless it interferes with the quality of life of the patient or if the diagnosis is uncertain. It is important to be aware of schwannomas in the differential diagnosis of soft-tissue masses. Diagnosis may be achieved through the combination of imaging and biopsy, but the definitive diagnosis is made on complete excision of the mass.

Acknowledgments
Contributors: Michael Lewis, MD, Department of Pathology, VA Greater Los Angeles Healthcare System. Written permission also was obtained from the patient.

Schwannomas are benign tumors exclusively composed of Schwann cells that arise from the peripheral nerve sheath; these tumors theoretically can present anywhere in the body where nerves reside. They tend to occur in the head and neck region (classically an acoustic neuroma) but also occur in other locations, including the retroperitoneal space and the extremities, particularly flexural surfaces. Patients with cutaneous schwannomas are most likely to present to their primary care provider’s office reporting skin findings or localized pain, and providers should be aware of schwannomas on the differential for painful nodular growths.

Case Presentation

A 70-year-old man with type 2 diabetes mellitus presented to the primary care clinic for intermittent, sharp, localized left lower quadrant abdominal wall pain that was gradually progressive over the previous few months. The patient noticed the development of a small nodule 7 to 8 months prior to the visit, at which time the pain was less frequent and less severe. He reported no postprandial association of the pain, nausea, vomiting, diarrhea, constipation, or other gastrointestinal symptoms.

Ten months prior to the presentation, he was involved in a low-impact motor vehicle collision as a pedestrian in which he fell face-first onto the hood of an oncoming car. At that time, he did not note any abdominal trauma or pain. Evaluation at a local emergency department did not reveal any major injuries. In the interim, he had self-administered insulin in his abdominal region, as he had without incident for the previous 2 years. He reported that he was not injecting near the site of the nodule since it had formed. He could not recall whether the location was a previous insulin administration site.

On examination, the patient’s vital signs were normal as were the cardiac and respiratory examinations. An abdominal exam revealed normal bowel sounds and no overlying skin changes or discoloration. Palpation revealed a 1.5 x 1 cm rubbery-to-firm, well-circumscribed subcutaneous nodule along his mid-left abdomen, about 7 cm lateral to the umbilicus. The nodule was sensitive to both light touch and deep pressure. It was firmer than expected for an abdominal wall lipoma. There was no central puncta or pore to suggest an epidermal inclusion cyst. There was no surrounding erythema or induration to suggest an abscess. 

The patient was referred for surgery and underwent excisional biopsy of the mass. Pathology revealed a well-circumscribed vascular/spindle-cell lesion consistent with a schwannoma. His postoperative course was uncomplicated. At 4-week follow-up the incision had healed completely and the patient was pain free.

Discussion

Soft-tissue nodules are common—about two-thirds of soft-tissue tumors are classified into 7 diagnostic categories: lipoma and lipoma variants (16%), fibrous histiocytoma (13%), nodular fasciitis (11%), hemangioma (8%), fibromatosis (7%), neurofibroma (5%), and schwannoma (5%).¹ Peripheral nerve tumors (schwannomas, neurofibromas) can be associated with pain or paresthesias, and less commonly, neurologic deficits, such as motor weakness. Peripheral nerve tumors have several classifications, such as nonneoplastic vs neoplastic, benign vs malignant, and sheath vs nonsheath origins. Schwannomas are considered part of the neoplastic subset due to their growth; otherwise, they are benign with a sheath origin. In contrast to neurofibromas, benign schwannomas have a slower rate of progression, lower association with pain, and fewer neurologic symptoms.²

The neural sheath is made up of 3 types of cells: the fibroblast, the Schwann cell, and the perineural cell, which lacks a basement membrane. It is the Schwann cell that can give rise to the 3 main types of cutaneous nerve tumors: neuromas, neurofibromas, and schwannomas.³ A nerve that is both entering and exiting a mass is a classic presentation for a peripheral nerve sheath tumor. If the nerve is eccentric to the lesion, then it is consistent with a schwannoma (not a neurofibroma).⁴ Schwannomas are made exclusively of Schwann cells that arise from the nerve sheath, whereas neurofibromas are made up of all the different cell types that constitute a nerve. Bilateral vestibular schwannomas (acoustic neuromas) are virtually pathognomonic of neurofibromatosis 2 (NF-2), which can manifest as hearing loss, tinnitus, and equilibrium problems. In contrast, neurofibromatosis 1 (NF-1) is more common, characterized by multiple café au lait spots, freckling in the axillary and groin regions, increased risk of cancers overall, and development of pedunculated skin growths, brain, or organ-based neurofibromas.

Diagnosis

A workup generally includes a thorough history and examination as well as imaging. In cases of superficial subcutaneous lesions, an ultrasound is often the imaging modality of choice. However, magnetic resonance imaging (MRI) and computed tomography (CT) scans are frequently used for more deep-seated lesions. There can be significant differences between malignant and benign neural lesions on MRI and CT in terms of contrast-uptake and heterogeneity of tissue, but the visual features are not consistent. Best estimates for MRI suggest 61% sensitivity and 90% specificity for the diagnosis of high-grade malignant peripheral nerve sheath tumors based on imaging alone.⁵

Definitive diagnosis requires surgical excision. Fine-needle aspiration can be used to diagnose subcutaneous nodules, but there is a possibility that degenerative changes and nuclear atypia seen on a smaller sample may be confused with a more aggressive sarcoma. For example, long-standing schwannomas are often called ancient, meaning that they break down over time, and the atypia they display is a regressive phenomenon.⁶ Therefore, a small or limited tissue sampling may not be representative of the entire lesion.⁷ As such, patients will likely need referral for surgical removal to determine the exact nature of the growth.

Although schwannomas are uncommon overall, the highest incidence is in the fourth decade of life with a slight predominance in females. They are often incidentally found as a palpable mass but can be symptomatic with paresthesias, pain, or neurologic changes—particularly when identified in the retroperitoneum or along joints. Schwannomas are most commonly found in the retroperitoneum (32%), mediastinum (23%), head and neck (18%), and extremities (16%).⁸ The majority of cases (about 90%) are sporadic; whereas 2% are related to NF-2.⁹ The abdominal wall schwannoma is rare. Our review of English-language literature in PubMed and EMBASE found only 5 other case reports (Table 1).

On physical examination, superficial lesions are freely movable except for a single point of attachment, which is generally along the long axis of the nerve. 

Pathology

On gross pathology examination, schwannomas have a well-circumscribed smooth external surface. On microscopy, schwannomas are truly encapsulated, uninodular, spindle-cell proliferations arranged in a streaming pattern within a background of thick, hyalinized blood vessels. Classic schwannomas typically exhibit a biphasic pattern of alternating areas of high and low cellularity and are named for Swedish neurologist Nils Antoni. The more cellular regions are referred to as Antoni A areas and consist of streaming fascicles of compact spindle cells that often palisade around acellular eosinophilic areas of fibrillary processes known as Verocay bodies.

In contrast, the lower cellularity regions (Antoni B areas) consist of multipolar, loosely textured cells with abundant cytoplasm, haphazardly arranged processes, and an overall myxoid appearance.¹¹ Schwannomas are known to have widely variable proportions of Antoni A and Antoni B areas; in this case, the excised specimen was noted to have predominately Antoni A areas without well-defined Verocay bodies and only scattered foci showing some suggestion of the hypocellular Antoni B architecture (Figure 2).^9,12 

Immunohistochemical stains for S100 and SOX10 (used to identify cells derived from a neural crest lineage) were strongly positive, which is characteristic of schwannomas.¹³ Although there have only been rare reports of extracranial schwannomas undergoing malignant transformation, it is critical to rule out the possibility of a de novo malignant peripheral nerve sheath tumor (MPNST).¹³ In general, MPNSTs tend to be more cellular, have brisk mitotic activity, areas of necrosis, hyperchromatic nuclei, and conspicuous pleomorphism. Mitotic figures, which can be concerning for malignant potential if present in high number, were noted occasionally in our patient; however, occasional mitosis may be seen in classic schwannomas. Clinically, MPNSTs have a poor prognosis. Based on case reports, disease-specific survival at 10 years is 31.6% for localized disease and only 7.5% for metastatic disease.¹⁴ In this case, there was no evidence of any of the high-grade features of a malignant peripheral nerve sheath tumor, thus supporting the diagnosis of schwannoma (neurilemmoma).

Treatment

Schwannomas are exclusively treated by excision. Prognosis is good with low recurrence rates. It is unknown what the recurrence rates are for completely resected abdominal wall schwannomas since there are so few reports in the literature. For other well-known entities, such as vestibular schwannoma (acoustic neuromas), the recurrence rates are generally 2% to 3%.¹⁵ Transformation of schwannomas into MPNSTs are so unusual that they are only described in single case reports.

Conclusion

Soft-tissue masses are a common complaint. Most are benign and do not require excision unless it interferes with the quality of life of the patient or if the diagnosis is uncertain. It is important to be aware of schwannomas in the differential diagnosis of soft-tissue masses. Diagnosis may be achieved through the combination of imaging and biopsy, but the definitive diagnosis is made on complete excision of the mass.

Acknowledgments
Contributors: Michael Lewis, MD, Department of Pathology, VA Greater Los Angeles Healthcare System. Written permission also was obtained from the patient.

Historically, the Veterans Health Administration (VHA) has excelled at improving veterans’ access to health care and enhancing foundational services, such as prosthetics and other veteran-centric services, and this continues to be the VHA’s top priority.¹ Travel distance and time are often barriers to accessing health care for many veterans.^2-11 For veterans with disabilities who must overcome additional physical, cognitive, and emotional obstacles to access vital rehabilitation services, these geographic obstacles are magnified. Further compounding the challenge is that rehabilitation therapies frequently require multiple encounters. Telerehabilitation is a promising solution for veterans in need of rehabilitation to regain optimal functioning. This alternative mode of service delivery can help veterans overcome geographic access barriers by delivering health care directly to veterans in their homes or nearby community-based outpatient clinics.^12,13

A growing body of evidence supports telerehabilitation. In a 2017 systematic review and meta-analysis, Cottrell and colleagues reviewed and analyzed data from 13 studies that met their inclusion criteria; specifically, their meta-analytic sample comprised adults aged ≥ 18 years presenting with any diagnosed primary musculoskeletal condition; treatment interventions via a real-time telerehabilitation medium, trials that had a comparison group with the same condition; provided clinical outcomes data, and included published randomized and nonrandomized controlled trials.¹⁴ Based on their aggregated results, they concluded that real-time telerehabilitation was effective in improving physical function (standardized mean difference [SMD], 0.63; 95% CI, 0.92-2.33; I², 93%), and reducing pain (SMD, 0.66; 95% CI, −0.27- .60; I², 96%) in patients with any diagnosed primary musculoskeletal condition.¹⁴

Two other systematic reviews conducted by Pietrzak and colleagues and Agostini and colleagues also demonstrated the clinical effectiveness of telerehabilitation.^15,16 Clinical effectiveness was defined as changes in health, functional status, and satisfaction with the telerehabilitation services delivered. The studies examined in the review included those that provided online self-management and education in addition to exercise via teleconferencing in real time.

Pietrzak and colleagues found that Internet-based osteoarthritis self-management interventions significantly improved 4 of 6 health status measures reviewed (ie, pain, fatigue, activity limitation, health distress, disability, and self‐reported global health).¹⁵ User acceptance and satisfaction were high (≥ 70% satisfied) in all studies meeting the inclusion criteria.

Agostini and colleagues found that telerehabilitation was more effective than other modes of delivering rehabilitation to regain motor function in cardiac (SMD, 0.24; 95% CI, 0.04-0.43) and total knee arthroplasty (Timed Up and Go test: SMD, −5.17; 95% CI, −9.79- −0.55) patients.¹⁶ Some evidence from VHA and non-VHA studies also support the use of telerehabilitation to reduce health care costs,^17-19 improve treatment adherence,^12,20 and enhance patient physical, cognitive and mobility function, as well as patient satisfaction and health-related quality of life.^13,21-24

Since the first recorded use of telehealth in 1959, the application of technology to deliver health care, including rehabilitation services, has increased exponentially.¹⁴ In fiscal year (FY) 2017 alone, the VA provided > 2 million episodes of care for > 700,000 veterans using telehealth services.²⁵

Although the process for accessing telerehabilitation may vary throughout the VA, typically a few common factors make a veteran eligible for this mode of rehabilitation care delivery: Veterans must meet criteria for a specific program (eg, amputation, occupational therapy, and physical therapy) and receive VA care from a VA medical facility or clinic that offers telehealth services. Care providers must believe that the veteran would benefit from telerehabilitation (eg, limited mobility and long-distance travel to the facility) and that they would be able to receive an appropriate consult. The veteran must meet the following requirements: (1) willingness to consent to a visit via telehealth; (2) access to required equipment/e-mail; and (3) a caregiver to assist if they are unable to complete a visit independently.

In this article, we provide an overview of the growth of telerehabilitation in the VHA. Data are presented for specific telerehabilitation programs over time and by rurality.

Methods

The VHA Support Service Center works with VHA program offices and field users to provide field-focused business, clinical, and special topic reports. An online portal provides access to these customizable reports organized as data cubes, which represent data dimensions (ie, clinic type) and measures (ie, number of unique patients). For this study, we used the Connected Care, Telehealth, Call Centers Clinical Video Telehealth/Store and Forward Telehealth data cube clinical stop codes to identify the numbers of telerehabilitation veteran users and encounters across time. The following telerehabilitation clinic-stop codes were selected: 197 (polytrauma/traumatic brain injury [TBI]–individuals), 201 (Physical Medicine and Rehabilitation [PM&R] Service), 205 (physical therapy), 206 (occupational therapy), 211 (PM&R amputation clinic), 418 (amputation clinic), 214 (kinesiotherapy), and 240 (PM&R assistive technology clinic). Data for total unique patients served and the total number of encounters were extracted at the national level and by rurality from FY 2012 to FY 2017, providing the past 5 years of VHA telerehabilitation data.

It is important to note that in FY 2015, the VHA changed its definition of rurality to a rural-urban commuting areas (RUCA)-based system (www.ruralhealth.va.gov/rural-definition.asp). Prior to FY 2015, the VHA used the US Census Bureau (CB) urbanized area definitions. According to CB, an urbanized area contains a central city and surrounding area that totals > 50,000 in population. It also includes places outside of urbanized areas with populations > 2,500. Rural areas are defined as all other areas. VHA added a third category, highly rural, which is defined as areas that had < 7 people per square mile. In the RUCA system, each census tract defined by the CB is given a score. The VHA definitions are as follows:

• Urban (U)—census tracts with RUCA scores of 1.0 or 1.1. These tracts are determined by the CB as being in an urban core and having the majority of their workers commute within that same core (1.0). If 30% to 49% commute to an even larger urban core, then the code is 1.1;
• Rural (R)—all tracts not receiving scores in the urban or highly rural tiers; and
• Highly rural (H)—tracts with a RUCA score of 10.0. These are the most remote occupied land areas. Less than 10% of workers travel to CB-defined urbanized areas or urban clusters.

In addition, VHA recently added an “I” category to complement “U,” “R,” and “H.” The “I” value is assigned to veterans living on the US insular islands (ie, territories): Guam, American Samoa, Northern Marianas, and US Virgin Islands. For the analysis by rurality in this study, we excluded veterans living in the insular islands and those of unknown rurality (< 1.0% of patients and encounters). Further, because the numbers of highly rural veterans were relatively small (< 2% of patients and encounters), the rural and highly rural categories were combined and compared with urban-dwelling veterans.

Results

Overall, the workload for telerehabilitation nearly quadrupled over the 5-year period (Table 1 and Figure 1). 

Interesting trends were seen by clinic type. Some clinics increased substantially, whereas others showed only moderate increases, and in 1 case (PM&R Service), a decrease. For example, there is significant growth in the number of patients and encounters involving physical therapy through telerehabilitation. This telerehabilitation clinic increased its workload from 1,676 patients with 3,016 encounters in FY 2012 to 9,136 patients with 11,834 encounters in FY 2017, accounting for 62.6% of total growth in patients and 56.8% of total growth in encounters.

Other clinics showing substantial growth over time included occupational therapy and polytrauma/TBI-individual secondary evaluation. Kinesiotherapy telerehabilitation was almost nonexistent in the VHA during FY 2012, with only 23 patients having 23 encounters. By FY 2017, there were 563 patients with 624 kinesiotherapy telerehabilitation encounters, equating to staggering increases in 5 years: 2,348% for patients and 2,613% for encounters. Similarly, the Physical Medicine and Rehabilitation Assistive Technology clinics had very low numbers in FY 2012 (patients, 2; encounters, 3) and increased over time; albeit, at a slow rate.

Trends by Rurality

Trends by rural location of patients and encounters must be interpreted with caution because of the changing rural definition between FY 2014 and FY 2015 (Tables 2 and 3; Figures 3 and 4). 

The increased total number of patients seen between FY 2012 and FY 2014 (old definition) was 225% for rural veterans vs 134% for urban veterans. Between FY 2015 and FY 2017 (new definition), the increase was lower for both groups (rural, 13.4%; urban, 7.3%), but rural veterans still increased at a higher rate than did urban dwellers.

Discussion

Our primary aim was to provide data on the growth of telerehabilitation in the VHA over the past 5 years. Our secondary aim was to examine growth in the use of telerehabilitation by rurality. Specifically, we provided an overview of telerehabilitation growth in terms of unique patients and overall encounters in the VHA by rurality from FY 2012 to FY 2014 and FY 2015 to FY 2017 using the following programs: Polytrauma/TBI, PM&R Service, physical therapy, occupational therapy, PM&R amputation clinic, amputation clinic, kinesiotherapy, and PM&R assistive technology clinic. Our findings demonstrated a noteworthy increase in telerehabilitation encounters and unique patients over time for these programs. These findings were consistent with the overall trend of continued growth and expansion of telehealth within the VHA.

Our findings reveal an upward trend in the total number of rural encounters and rural unique patients despite the change in the VA’s definition of rurality in FY 2015. To our knowledge, urban and rural use of telerehabilitation has not been examined previously. Under both definitions of rurality, encounters and unique patients show an important increase over time, and by year-end 2017, more than half of all patients and encounters were attributed to rural patients (53.7% and 53.9%, respectively). Indeed, the upward trend may have been more pronounced if the rural definition had not changed in FY 2015. Our early VHA stroke patients study on the difference between rural-urban patients and taxonomies showed that the RUCA definition was more likely to reduce the number of rural patients by 8.5% than the early definition used by the VHA.²⁶

It is notable that although the use of tele-delivery of rehabilitation has continually increased, the rate of this increase was steeper from FY 2012 to FY 2014 than FY 2015 to FY 2017. For the programs under consideration in this study, the total number of rural patients/encounters increased throughout the observed periods. However, urban patients and encounters increased through FY 2016 and experienced a slight decrease in FY 2017.

The appearance of a slower rate of increase may be due to a rapid initial rate of increase through early adopters and “crossing the diffusion chasm,” a well-documented process of slower diffusion between the time of invention to penetration that often characterizes the spread of successful telehealth innovations.²⁷ Integrating technology into care delivery innovation requires the integration of technical, clinical, and administrative processes and can take time to scale successfully.²⁸

With an emphasis on increasing access to rehabilitation services, the VHA can expect to see a continuing increase in both the number and the percentage of telerehabilitation rural patients and encounters. The VHA has several telerehabilitation initiatives underway through the VHA’s Physical Medicine and Rehabilitation Telerehabilitation Enterprise Wide Initiative (TREWI) and Rural Veterans Telerehabilitation Initiative. These projects demonstrate the feasibility of this delivery approach and facilitate integration of this modality in clinical workflows. However, to sustain these efforts, facilities will need more infrastructure and personnel resources dedicated to the delivery of services.

In an ongoing evaluation of the TREWI, several factors seem to influence the uptake of the VHA Office of Rural Health TREWI programs. These factors are the presence or absence of a local site champion; the quality of hospital leadership support; the quality of past relationships between telerehabilitation sending sites and receiving sites; barriers to getting a telehealth service agreement in place; the availability of space; administrative know-how on setting up clinics appropriately; time involved to bring on staff; contracting issues; equipment availability and installation; cultural issues in embracing technologic innovation; training burden; hassle factors; and limited funds. Although early adopters may be able to negotiate and push through many of the barriers associated with the diffusion of telerehabilitation, the numerous barriers may slow its larger systemwide diffusion.

Telerehabilitation is a promising mode to deliver care to rural veterans who otherwise may not have access to this type of specialty care. Therefore, the identification of elements that foster telerehabilitation growth in future investigations can assist policy makers and key stakeholders in optimally leveraging program resources for maximal productivity. Future studies investigating the drivers of increases in telerehabilitation growth by rurality are warranted. Furthermore, more research is needed to examine telerehabilitation growth quality of care outcomes (eg, patient and provider satisfaction) to ensure that care is not only timely and accessible, but of high quality.

Conclusion

Disparities between rural and urban veterans compel a mode of expanding delivery of care. The VHA has embraced the use of telehealth modalities to extend its reach of rehabilitation services to veterans with disability and rehabilitation needs. Growth in telerehabilitation rural patient encounters increases access to rehabilitative care, reduces patient and caregiver travel burden, and helps ensure treatment adherence. Telerehabilitation utilization (unique patients and total encounters) is growing more rapidly for rural veterans than for their urban counterparts. Overall, telerehabilitation is filling a gap for rural veterans, as well as veterans in general with challenges in accessibility to health care. In order to make full use of the telerehabilitation services across its health care system, VA health care facilities may need to expand their effort in telerehabilitation dissemination and education among providers and veterans, particularly among providers who are less familiar with telerehabilitation services and among veterans who live in rural or highly rural areas and need special rehabilitation care.

Historically, the Veterans Health Administration (VHA) has excelled at improving veterans’ access to health care and enhancing foundational services, such as prosthetics and other veteran-centric services, and this continues to be the VHA’s top priority.¹ Travel distance and time are often barriers to accessing health care for many veterans.^2-11 For veterans with disabilities who must overcome additional physical, cognitive, and emotional obstacles to access vital rehabilitation services, these geographic obstacles are magnified. Further compounding the challenge is that rehabilitation therapies frequently require multiple encounters. Telerehabilitation is a promising solution for veterans in need of rehabilitation to regain optimal functioning. This alternative mode of service delivery can help veterans overcome geographic access barriers by delivering health care directly to veterans in their homes or nearby community-based outpatient clinics.^12,13

A growing body of evidence supports telerehabilitation. In a 2017 systematic review and meta-analysis, Cottrell and colleagues reviewed and analyzed data from 13 studies that met their inclusion criteria; specifically, their meta-analytic sample comprised adults aged ≥ 18 years presenting with any diagnosed primary musculoskeletal condition; treatment interventions via a real-time telerehabilitation medium, trials that had a comparison group with the same condition; provided clinical outcomes data, and included published randomized and nonrandomized controlled trials.¹⁴ Based on their aggregated results, they concluded that real-time telerehabilitation was effective in improving physical function (standardized mean difference [SMD], 0.63; 95% CI, 0.92-2.33; I², 93%), and reducing pain (SMD, 0.66; 95% CI, −0.27- .60; I², 96%) in patients with any diagnosed primary musculoskeletal condition.¹⁴

Two other systematic reviews conducted by Pietrzak and colleagues and Agostini and colleagues also demonstrated the clinical effectiveness of telerehabilitation.^15,16 Clinical effectiveness was defined as changes in health, functional status, and satisfaction with the telerehabilitation services delivered. The studies examined in the review included those that provided online self-management and education in addition to exercise via teleconferencing in real time.

Pietrzak and colleagues found that Internet-based osteoarthritis self-management interventions significantly improved 4 of 6 health status measures reviewed (ie, pain, fatigue, activity limitation, health distress, disability, and self‐reported global health).¹⁵ User acceptance and satisfaction were high (≥ 70% satisfied) in all studies meeting the inclusion criteria.

Agostini and colleagues found that telerehabilitation was more effective than other modes of delivering rehabilitation to regain motor function in cardiac (SMD, 0.24; 95% CI, 0.04-0.43) and total knee arthroplasty (Timed Up and Go test: SMD, −5.17; 95% CI, −9.79- −0.55) patients.¹⁶ Some evidence from VHA and non-VHA studies also support the use of telerehabilitation to reduce health care costs,^17-19 improve treatment adherence,^12,20 and enhance patient physical, cognitive and mobility function, as well as patient satisfaction and health-related quality of life.^13,21-24

Since the first recorded use of telehealth in 1959, the application of technology to deliver health care, including rehabilitation services, has increased exponentially.¹⁴ In fiscal year (FY) 2017 alone, the VA provided > 2 million episodes of care for > 700,000 veterans using telehealth services.²⁵

Although the process for accessing telerehabilitation may vary throughout the VA, typically a few common factors make a veteran eligible for this mode of rehabilitation care delivery: Veterans must meet criteria for a specific program (eg, amputation, occupational therapy, and physical therapy) and receive VA care from a VA medical facility or clinic that offers telehealth services. Care providers must believe that the veteran would benefit from telerehabilitation (eg, limited mobility and long-distance travel to the facility) and that they would be able to receive an appropriate consult. The veteran must meet the following requirements: (1) willingness to consent to a visit via telehealth; (2) access to required equipment/e-mail; and (3) a caregiver to assist if they are unable to complete a visit independently.

In this article, we provide an overview of the growth of telerehabilitation in the VHA. Data are presented for specific telerehabilitation programs over time and by rurality.

Methods

The VHA Support Service Center works with VHA program offices and field users to provide field-focused business, clinical, and special topic reports. An online portal provides access to these customizable reports organized as data cubes, which represent data dimensions (ie, clinic type) and measures (ie, number of unique patients). For this study, we used the Connected Care, Telehealth, Call Centers Clinical Video Telehealth/Store and Forward Telehealth data cube clinical stop codes to identify the numbers of telerehabilitation veteran users and encounters across time. The following telerehabilitation clinic-stop codes were selected: 197 (polytrauma/traumatic brain injury [TBI]–individuals), 201 (Physical Medicine and Rehabilitation [PM&R] Service), 205 (physical therapy), 206 (occupational therapy), 211 (PM&R amputation clinic), 418 (amputation clinic), 214 (kinesiotherapy), and 240 (PM&R assistive technology clinic). Data for total unique patients served and the total number of encounters were extracted at the national level and by rurality from FY 2012 to FY 2017, providing the past 5 years of VHA telerehabilitation data.

It is important to note that in FY 2015, the VHA changed its definition of rurality to a rural-urban commuting areas (RUCA)-based system (www.ruralhealth.va.gov/rural-definition.asp). Prior to FY 2015, the VHA used the US Census Bureau (CB) urbanized area definitions. According to CB, an urbanized area contains a central city and surrounding area that totals > 50,000 in population. It also includes places outside of urbanized areas with populations > 2,500. Rural areas are defined as all other areas. VHA added a third category, highly rural, which is defined as areas that had < 7 people per square mile. In the RUCA system, each census tract defined by the CB is given a score. The VHA definitions are as follows:

• Urban (U)—census tracts with RUCA scores of 1.0 or 1.1. These tracts are determined by the CB as being in an urban core and having the majority of their workers commute within that same core (1.0). If 30% to 49% commute to an even larger urban core, then the code is 1.1;
• Rural (R)—all tracts not receiving scores in the urban or highly rural tiers; and
• Highly rural (H)—tracts with a RUCA score of 10.0. These are the most remote occupied land areas. Less than 10% of workers travel to CB-defined urbanized areas or urban clusters.

In addition, VHA recently added an “I” category to complement “U,” “R,” and “H.” The “I” value is assigned to veterans living on the US insular islands (ie, territories): Guam, American Samoa, Northern Marianas, and US Virgin Islands. For the analysis by rurality in this study, we excluded veterans living in the insular islands and those of unknown rurality (< 1.0% of patients and encounters). Further, because the numbers of highly rural veterans were relatively small (< 2% of patients and encounters), the rural and highly rural categories were combined and compared with urban-dwelling veterans.

Results

Overall, the workload for telerehabilitation nearly quadrupled over the 5-year period (Table 1 and Figure 1). 

Interesting trends were seen by clinic type. Some clinics increased substantially, whereas others showed only moderate increases, and in 1 case (PM&R Service), a decrease. For example, there is significant growth in the number of patients and encounters involving physical therapy through telerehabilitation. This telerehabilitation clinic increased its workload from 1,676 patients with 3,016 encounters in FY 2012 to 9,136 patients with 11,834 encounters in FY 2017, accounting for 62.6% of total growth in patients and 56.8% of total growth in encounters.

Other clinics showing substantial growth over time included occupational therapy and polytrauma/TBI-individual secondary evaluation. Kinesiotherapy telerehabilitation was almost nonexistent in the VHA during FY 2012, with only 23 patients having 23 encounters. By FY 2017, there were 563 patients with 624 kinesiotherapy telerehabilitation encounters, equating to staggering increases in 5 years: 2,348% for patients and 2,613% for encounters. Similarly, the Physical Medicine and Rehabilitation Assistive Technology clinics had very low numbers in FY 2012 (patients, 2; encounters, 3) and increased over time; albeit, at a slow rate.

Trends by Rurality

Trends by rural location of patients and encounters must be interpreted with caution because of the changing rural definition between FY 2014 and FY 2015 (Tables 2 and 3; Figures 3 and 4). 

The increased total number of patients seen between FY 2012 and FY 2014 (old definition) was 225% for rural veterans vs 134% for urban veterans. Between FY 2015 and FY 2017 (new definition), the increase was lower for both groups (rural, 13.4%; urban, 7.3%), but rural veterans still increased at a higher rate than did urban dwellers.

Discussion

Our primary aim was to provide data on the growth of telerehabilitation in the VHA over the past 5 years. Our secondary aim was to examine growth in the use of telerehabilitation by rurality. Specifically, we provided an overview of telerehabilitation growth in terms of unique patients and overall encounters in the VHA by rurality from FY 2012 to FY 2014 and FY 2015 to FY 2017 using the following programs: Polytrauma/TBI, PM&R Service, physical therapy, occupational therapy, PM&R amputation clinic, amputation clinic, kinesiotherapy, and PM&R assistive technology clinic. Our findings demonstrated a noteworthy increase in telerehabilitation encounters and unique patients over time for these programs. These findings were consistent with the overall trend of continued growth and expansion of telehealth within the VHA.

Our findings reveal an upward trend in the total number of rural encounters and rural unique patients despite the change in the VA’s definition of rurality in FY 2015. To our knowledge, urban and rural use of telerehabilitation has not been examined previously. Under both definitions of rurality, encounters and unique patients show an important increase over time, and by year-end 2017, more than half of all patients and encounters were attributed to rural patients (53.7% and 53.9%, respectively). Indeed, the upward trend may have been more pronounced if the rural definition had not changed in FY 2015. Our early VHA stroke patients study on the difference between rural-urban patients and taxonomies showed that the RUCA definition was more likely to reduce the number of rural patients by 8.5% than the early definition used by the VHA.²⁶

It is notable that although the use of tele-delivery of rehabilitation has continually increased, the rate of this increase was steeper from FY 2012 to FY 2014 than FY 2015 to FY 2017. For the programs under consideration in this study, the total number of rural patients/encounters increased throughout the observed periods. However, urban patients and encounters increased through FY 2016 and experienced a slight decrease in FY 2017.

The appearance of a slower rate of increase may be due to a rapid initial rate of increase through early adopters and “crossing the diffusion chasm,” a well-documented process of slower diffusion between the time of invention to penetration that often characterizes the spread of successful telehealth innovations.²⁷ Integrating technology into care delivery innovation requires the integration of technical, clinical, and administrative processes and can take time to scale successfully.²⁸

With an emphasis on increasing access to rehabilitation services, the VHA can expect to see a continuing increase in both the number and the percentage of telerehabilitation rural patients and encounters. The VHA has several telerehabilitation initiatives underway through the VHA’s Physical Medicine and Rehabilitation Telerehabilitation Enterprise Wide Initiative (TREWI) and Rural Veterans Telerehabilitation Initiative. These projects demonstrate the feasibility of this delivery approach and facilitate integration of this modality in clinical workflows. However, to sustain these efforts, facilities will need more infrastructure and personnel resources dedicated to the delivery of services.

In an ongoing evaluation of the TREWI, several factors seem to influence the uptake of the VHA Office of Rural Health TREWI programs. These factors are the presence or absence of a local site champion; the quality of hospital leadership support; the quality of past relationships between telerehabilitation sending sites and receiving sites; barriers to getting a telehealth service agreement in place; the availability of space; administrative know-how on setting up clinics appropriately; time involved to bring on staff; contracting issues; equipment availability and installation; cultural issues in embracing technologic innovation; training burden; hassle factors; and limited funds. Although early adopters may be able to negotiate and push through many of the barriers associated with the diffusion of telerehabilitation, the numerous barriers may slow its larger systemwide diffusion.

Telerehabilitation is a promising mode to deliver care to rural veterans who otherwise may not have access to this type of specialty care. Therefore, the identification of elements that foster telerehabilitation growth in future investigations can assist policy makers and key stakeholders in optimally leveraging program resources for maximal productivity. Future studies investigating the drivers of increases in telerehabilitation growth by rurality are warranted. Furthermore, more research is needed to examine telerehabilitation growth quality of care outcomes (eg, patient and provider satisfaction) to ensure that care is not only timely and accessible, but of high quality.

Conclusion

Disparities between rural and urban veterans compel a mode of expanding delivery of care. The VHA has embraced the use of telehealth modalities to extend its reach of rehabilitation services to veterans with disability and rehabilitation needs. Growth in telerehabilitation rural patient encounters increases access to rehabilitative care, reduces patient and caregiver travel burden, and helps ensure treatment adherence. Telerehabilitation utilization (unique patients and total encounters) is growing more rapidly for rural veterans than for their urban counterparts. Overall, telerehabilitation is filling a gap for rural veterans, as well as veterans in general with challenges in accessibility to health care. In order to make full use of the telerehabilitation services across its health care system, VA health care facilities may need to expand their effort in telerehabilitation dissemination and education among providers and veterans, particularly among providers who are less familiar with telerehabilitation services and among veterans who live in rural or highly rural areas and need special rehabilitation care.

Historically, the Veterans Health Administration (VHA) has excelled at improving veterans’ access to health care and enhancing foundational services, such as prosthetics and other veteran-centric services, and this continues to be the VHA’s top priority.¹ Travel distance and time are often barriers to accessing health care for many veterans.^2-11 For veterans with disabilities who must overcome additional physical, cognitive, and emotional obstacles to access vital rehabilitation services, these geographic obstacles are magnified. Further compounding the challenge is that rehabilitation therapies frequently require multiple encounters. Telerehabilitation is a promising solution for veterans in need of rehabilitation to regain optimal functioning. This alternative mode of service delivery can help veterans overcome geographic access barriers by delivering health care directly to veterans in their homes or nearby community-based outpatient clinics.^12,13

A growing body of evidence supports telerehabilitation. In a 2017 systematic review and meta-analysis, Cottrell and colleagues reviewed and analyzed data from 13 studies that met their inclusion criteria; specifically, their meta-analytic sample comprised adults aged ≥ 18 years presenting with any diagnosed primary musculoskeletal condition; treatment interventions via a real-time telerehabilitation medium, trials that had a comparison group with the same condition; provided clinical outcomes data, and included published randomized and nonrandomized controlled trials.¹⁴ Based on their aggregated results, they concluded that real-time telerehabilitation was effective in improving physical function (standardized mean difference [SMD], 0.63; 95% CI, 0.92-2.33; I², 93%), and reducing pain (SMD, 0.66; 95% CI, −0.27- .60; I², 96%) in patients with any diagnosed primary musculoskeletal condition.¹⁴

Two other systematic reviews conducted by Pietrzak and colleagues and Agostini and colleagues also demonstrated the clinical effectiveness of telerehabilitation.^15,16 Clinical effectiveness was defined as changes in health, functional status, and satisfaction with the telerehabilitation services delivered. The studies examined in the review included those that provided online self-management and education in addition to exercise via teleconferencing in real time.

Pietrzak and colleagues found that Internet-based osteoarthritis self-management interventions significantly improved 4 of 6 health status measures reviewed (ie, pain, fatigue, activity limitation, health distress, disability, and self‐reported global health).¹⁵ User acceptance and satisfaction were high (≥ 70% satisfied) in all studies meeting the inclusion criteria.

Agostini and colleagues found that telerehabilitation was more effective than other modes of delivering rehabilitation to regain motor function in cardiac (SMD, 0.24; 95% CI, 0.04-0.43) and total knee arthroplasty (Timed Up and Go test: SMD, −5.17; 95% CI, −9.79- −0.55) patients.¹⁶ Some evidence from VHA and non-VHA studies also support the use of telerehabilitation to reduce health care costs,^17-19 improve treatment adherence,^12,20 and enhance patient physical, cognitive and mobility function, as well as patient satisfaction and health-related quality of life.^13,21-24

Since the first recorded use of telehealth in 1959, the application of technology to deliver health care, including rehabilitation services, has increased exponentially.¹⁴ In fiscal year (FY) 2017 alone, the VA provided > 2 million episodes of care for > 700,000 veterans using telehealth services.²⁵

Although the process for accessing telerehabilitation may vary throughout the VA, typically a few common factors make a veteran eligible for this mode of rehabilitation care delivery: Veterans must meet criteria for a specific program (eg, amputation, occupational therapy, and physical therapy) and receive VA care from a VA medical facility or clinic that offers telehealth services. Care providers must believe that the veteran would benefit from telerehabilitation (eg, limited mobility and long-distance travel to the facility) and that they would be able to receive an appropriate consult. The veteran must meet the following requirements: (1) willingness to consent to a visit via telehealth; (2) access to required equipment/e-mail; and (3) a caregiver to assist if they are unable to complete a visit independently.

In this article, we provide an overview of the growth of telerehabilitation in the VHA. Data are presented for specific telerehabilitation programs over time and by rurality.

Methods

The VHA Support Service Center works with VHA program offices and field users to provide field-focused business, clinical, and special topic reports. An online portal provides access to these customizable reports organized as data cubes, which represent data dimensions (ie, clinic type) and measures (ie, number of unique patients). For this study, we used the Connected Care, Telehealth, Call Centers Clinical Video Telehealth/Store and Forward Telehealth data cube clinical stop codes to identify the numbers of telerehabilitation veteran users and encounters across time. The following telerehabilitation clinic-stop codes were selected: 197 (polytrauma/traumatic brain injury [TBI]–individuals), 201 (Physical Medicine and Rehabilitation [PM&R] Service), 205 (physical therapy), 206 (occupational therapy), 211 (PM&R amputation clinic), 418 (amputation clinic), 214 (kinesiotherapy), and 240 (PM&R assistive technology clinic). Data for total unique patients served and the total number of encounters were extracted at the national level and by rurality from FY 2012 to FY 2017, providing the past 5 years of VHA telerehabilitation data.

It is important to note that in FY 2015, the VHA changed its definition of rurality to a rural-urban commuting areas (RUCA)-based system (www.ruralhealth.va.gov/rural-definition.asp). Prior to FY 2015, the VHA used the US Census Bureau (CB) urbanized area definitions. According to CB, an urbanized area contains a central city and surrounding area that totals > 50,000 in population. It also includes places outside of urbanized areas with populations > 2,500. Rural areas are defined as all other areas. VHA added a third category, highly rural, which is defined as areas that had < 7 people per square mile. In the RUCA system, each census tract defined by the CB is given a score. The VHA definitions are as follows:

• Urban (U)—census tracts with RUCA scores of 1.0 or 1.1. These tracts are determined by the CB as being in an urban core and having the majority of their workers commute within that same core (1.0). If 30% to 49% commute to an even larger urban core, then the code is 1.1;
• Rural (R)—all tracts not receiving scores in the urban or highly rural tiers; and
• Highly rural (H)—tracts with a RUCA score of 10.0. These are the most remote occupied land areas. Less than 10% of workers travel to CB-defined urbanized areas or urban clusters.

In addition, VHA recently added an “I” category to complement “U,” “R,” and “H.” The “I” value is assigned to veterans living on the US insular islands (ie, territories): Guam, American Samoa, Northern Marianas, and US Virgin Islands. For the analysis by rurality in this study, we excluded veterans living in the insular islands and those of unknown rurality (< 1.0% of patients and encounters). Further, because the numbers of highly rural veterans were relatively small (< 2% of patients and encounters), the rural and highly rural categories were combined and compared with urban-dwelling veterans.

Results

Overall, the workload for telerehabilitation nearly quadrupled over the 5-year period (Table 1 and Figure 1). 

Interesting trends were seen by clinic type. Some clinics increased substantially, whereas others showed only moderate increases, and in 1 case (PM&R Service), a decrease. For example, there is significant growth in the number of patients and encounters involving physical therapy through telerehabilitation. This telerehabilitation clinic increased its workload from 1,676 patients with 3,016 encounters in FY 2012 to 9,136 patients with 11,834 encounters in FY 2017, accounting for 62.6% of total growth in patients and 56.8% of total growth in encounters.

Other clinics showing substantial growth over time included occupational therapy and polytrauma/TBI-individual secondary evaluation. Kinesiotherapy telerehabilitation was almost nonexistent in the VHA during FY 2012, with only 23 patients having 23 encounters. By FY 2017, there were 563 patients with 624 kinesiotherapy telerehabilitation encounters, equating to staggering increases in 5 years: 2,348% for patients and 2,613% for encounters. Similarly, the Physical Medicine and Rehabilitation Assistive Technology clinics had very low numbers in FY 2012 (patients, 2; encounters, 3) and increased over time; albeit, at a slow rate.

Trends by Rurality

Trends by rural location of patients and encounters must be interpreted with caution because of the changing rural definition between FY 2014 and FY 2015 (Tables 2 and 3; Figures 3 and 4). 

The increased total number of patients seen between FY 2012 and FY 2014 (old definition) was 225% for rural veterans vs 134% for urban veterans. Between FY 2015 and FY 2017 (new definition), the increase was lower for both groups (rural, 13.4%; urban, 7.3%), but rural veterans still increased at a higher rate than did urban dwellers.

Discussion

Our primary aim was to provide data on the growth of telerehabilitation in the VHA over the past 5 years. Our secondary aim was to examine growth in the use of telerehabilitation by rurality. Specifically, we provided an overview of telerehabilitation growth in terms of unique patients and overall encounters in the VHA by rurality from FY 2012 to FY 2014 and FY 2015 to FY 2017 using the following programs: Polytrauma/TBI, PM&R Service, physical therapy, occupational therapy, PM&R amputation clinic, amputation clinic, kinesiotherapy, and PM&R assistive technology clinic. Our findings demonstrated a noteworthy increase in telerehabilitation encounters and unique patients over time for these programs. These findings were consistent with the overall trend of continued growth and expansion of telehealth within the VHA.

Our findings reveal an upward trend in the total number of rural encounters and rural unique patients despite the change in the VA’s definition of rurality in FY 2015. To our knowledge, urban and rural use of telerehabilitation has not been examined previously. Under both definitions of rurality, encounters and unique patients show an important increase over time, and by year-end 2017, more than half of all patients and encounters were attributed to rural patients (53.7% and 53.9%, respectively). Indeed, the upward trend may have been more pronounced if the rural definition had not changed in FY 2015. Our early VHA stroke patients study on the difference between rural-urban patients and taxonomies showed that the RUCA definition was more likely to reduce the number of rural patients by 8.5% than the early definition used by the VHA.²⁶

It is notable that although the use of tele-delivery of rehabilitation has continually increased, the rate of this increase was steeper from FY 2012 to FY 2014 than FY 2015 to FY 2017. For the programs under consideration in this study, the total number of rural patients/encounters increased throughout the observed periods. However, urban patients and encounters increased through FY 2016 and experienced a slight decrease in FY 2017.

The appearance of a slower rate of increase may be due to a rapid initial rate of increase through early adopters and “crossing the diffusion chasm,” a well-documented process of slower diffusion between the time of invention to penetration that often characterizes the spread of successful telehealth innovations.²⁷ Integrating technology into care delivery innovation requires the integration of technical, clinical, and administrative processes and can take time to scale successfully.²⁸

With an emphasis on increasing access to rehabilitation services, the VHA can expect to see a continuing increase in both the number and the percentage of telerehabilitation rural patients and encounters. The VHA has several telerehabilitation initiatives underway through the VHA’s Physical Medicine and Rehabilitation Telerehabilitation Enterprise Wide Initiative (TREWI) and Rural Veterans Telerehabilitation Initiative. These projects demonstrate the feasibility of this delivery approach and facilitate integration of this modality in clinical workflows. However, to sustain these efforts, facilities will need more infrastructure and personnel resources dedicated to the delivery of services.

In an ongoing evaluation of the TREWI, several factors seem to influence the uptake of the VHA Office of Rural Health TREWI programs. These factors are the presence or absence of a local site champion; the quality of hospital leadership support; the quality of past relationships between telerehabilitation sending sites and receiving sites; barriers to getting a telehealth service agreement in place; the availability of space; administrative know-how on setting up clinics appropriately; time involved to bring on staff; contracting issues; equipment availability and installation; cultural issues in embracing technologic innovation; training burden; hassle factors; and limited funds. Although early adopters may be able to negotiate and push through many of the barriers associated with the diffusion of telerehabilitation, the numerous barriers may slow its larger systemwide diffusion.

Telerehabilitation is a promising mode to deliver care to rural veterans who otherwise may not have access to this type of specialty care. Therefore, the identification of elements that foster telerehabilitation growth in future investigations can assist policy makers and key stakeholders in optimally leveraging program resources for maximal productivity. Future studies investigating the drivers of increases in telerehabilitation growth by rurality are warranted. Furthermore, more research is needed to examine telerehabilitation growth quality of care outcomes (eg, patient and provider satisfaction) to ensure that care is not only timely and accessible, but of high quality.

Conclusion

Disparities between rural and urban veterans compel a mode of expanding delivery of care. The VHA has embraced the use of telehealth modalities to extend its reach of rehabilitation services to veterans with disability and rehabilitation needs. Growth in telerehabilitation rural patient encounters increases access to rehabilitative care, reduces patient and caregiver travel burden, and helps ensure treatment adherence. Telerehabilitation utilization (unique patients and total encounters) is growing more rapidly for rural veterans than for their urban counterparts. Overall, telerehabilitation is filling a gap for rural veterans, as well as veterans in general with challenges in accessibility to health care. In order to make full use of the telerehabilitation services across its health care system, VA health care facilities may need to expand their effort in telerehabilitation dissemination and education among providers and veterans, particularly among providers who are less familiar with telerehabilitation services and among veterans who live in rural or highly rural areas and need special rehabilitation care.