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FDA approves avacopan for rare ANCA autoimmune disease
U.S. regulators approved avacopan (Tavneos) for a rare immune disorder after receiving additional information to address concerns raised about the drug that were previously discussed at a public meeting in May.
ChemoCentryx, the drug’s manufacturer, today announced that the U.S. Food and Drug Administration approved the drug as an adjunctive treatment for severe active antineutrophil cytoplasmic autoantibody–associated vasculitis (also known as ANCA-associated vasculitis or ANCA vasculitis).
This systemic disease results from overactivation of the complement system, leading to inflammation and eventual destruction of small blood vessels. This can lead to organ damage and failure, with the kidney as the major target, said the company in a statement.
The avacopan approval was based in large part on the results of the ADVOCATE trial, which were highlighted in a February 2021 editorial in the New England Journal of Medicine , titled “Avacopan – Time to replace glucocorticoids?” But the FDA-approved indication for avacopan is as an adjunctive treatment of adult patients with severe active ANCA-associated vasculitis (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]) in combination with standard therapy including glucocorticoids. “Tavneos does not eliminate glucocorticoid use,” the label states.
The ADVOCATE trial was a global, randomized, double-blind, active-controlled, double-dummy phase 3 trial of 330 patients with ANCA-associated vasculitis conducted in 20 countries, ChemoCentryx said. Participants were randomly assigned to receive either rituximab or cyclophosphamide (followed by azathioprine/mycophenolate) and either avacopan or study-supplied oral prednisone.
Subjects in both treatment groups could also receive nonprotocol glucocorticoids as needed. The study met its primary endpoints of disease remission at 26 weeks and sustained remission at 52 weeks, as assessed by the Birmingham Vasculitis Activity Score (BVAS), ChemoCentryx said. Common adverse reactions among study participants included nausea, headache, hypertension, diarrhea, vomiting, rash, fatigue, upper abdominal pain, dizziness, blood creatinine increase, and paresthesia.
In the ChemoCentryx statement, Peter A. Merkel, MD, MPH, a consultant to the company and the chief of rheumatology at the University of Pennsylvania, Philadelphia, called the avacopan clearance a “first-in-a-decade approval of a medicine for ANCA-associated vasculitis.”
“Patients will now have access to a new class of medication that provides beneficial effects for the treatment of ANCA-associated vasculitis,” Dr. Merkel said.
In reviewing the avacopan application, the FDA noted that the medicine is intended to treat “a rare and serious disease associated with high morbidity and increased mortality.”
“It is also a disease with high unmet need for new therapies,” the FDA staff said in a review of the ChemoCentryx application for approval of avacopan, which was posted online ahead of a meeting this past May.
Previous FDA concerns
In that review, FDA staff made public various concerns about the evidence used in seeking approval of the medicine. The FDA staff said there were “substantial uncertainties around the phase 3 study design and results, raising questions about the adequacy of this single trial to inform the benefit-risk assessment.”
Members of the FDA’s Arthritis Advisory Committee voted 10-8 on May 6 on a question of whether the risk-benefit profile of avacopan is adequate to support approval. The panel also voted 9-9 on whether the efficacy data support approval of avacopan, and 10-8 that the safety profile of avacopan is adequate to support approval.
ChemoCentryx in July said it filed an amendment to its new drug application (NDA) for avacopan. This appears to have answered regulators’ questions about the drug.
On a call with analysts Friday, ChemoCentryx officials outlined a marketing strategy for avacopan, with efforts focused on reaching influential rheumatologists and nephrologists. The company will set a U.S. wholesale acquisition cost for the drug of about $150,000-$200,000 a patient, in keeping with the range of prices often seen for orphan drugs. ChemoCentryx said it intends to offer financial support programs for the medicine.
ChemoCentryx said avacopan is also approved for the treatment of microscopic polyangiitis and granulomatosis with polyangiitis (the two main forms of ANCA-associated vasculitis) in Japan. The regulatory decision in Europe is expected by the end of this year.
A version of this article first appeared on Medscape.com.
U.S. regulators approved avacopan (Tavneos) for a rare immune disorder after receiving additional information to address concerns raised about the drug that were previously discussed at a public meeting in May.
ChemoCentryx, the drug’s manufacturer, today announced that the U.S. Food and Drug Administration approved the drug as an adjunctive treatment for severe active antineutrophil cytoplasmic autoantibody–associated vasculitis (also known as ANCA-associated vasculitis or ANCA vasculitis).
This systemic disease results from overactivation of the complement system, leading to inflammation and eventual destruction of small blood vessels. This can lead to organ damage and failure, with the kidney as the major target, said the company in a statement.
The avacopan approval was based in large part on the results of the ADVOCATE trial, which were highlighted in a February 2021 editorial in the New England Journal of Medicine , titled “Avacopan – Time to replace glucocorticoids?” But the FDA-approved indication for avacopan is as an adjunctive treatment of adult patients with severe active ANCA-associated vasculitis (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]) in combination with standard therapy including glucocorticoids. “Tavneos does not eliminate glucocorticoid use,” the label states.
The ADVOCATE trial was a global, randomized, double-blind, active-controlled, double-dummy phase 3 trial of 330 patients with ANCA-associated vasculitis conducted in 20 countries, ChemoCentryx said. Participants were randomly assigned to receive either rituximab or cyclophosphamide (followed by azathioprine/mycophenolate) and either avacopan or study-supplied oral prednisone.
Subjects in both treatment groups could also receive nonprotocol glucocorticoids as needed. The study met its primary endpoints of disease remission at 26 weeks and sustained remission at 52 weeks, as assessed by the Birmingham Vasculitis Activity Score (BVAS), ChemoCentryx said. Common adverse reactions among study participants included nausea, headache, hypertension, diarrhea, vomiting, rash, fatigue, upper abdominal pain, dizziness, blood creatinine increase, and paresthesia.
In the ChemoCentryx statement, Peter A. Merkel, MD, MPH, a consultant to the company and the chief of rheumatology at the University of Pennsylvania, Philadelphia, called the avacopan clearance a “first-in-a-decade approval of a medicine for ANCA-associated vasculitis.”
“Patients will now have access to a new class of medication that provides beneficial effects for the treatment of ANCA-associated vasculitis,” Dr. Merkel said.
In reviewing the avacopan application, the FDA noted that the medicine is intended to treat “a rare and serious disease associated with high morbidity and increased mortality.”
“It is also a disease with high unmet need for new therapies,” the FDA staff said in a review of the ChemoCentryx application for approval of avacopan, which was posted online ahead of a meeting this past May.
Previous FDA concerns
In that review, FDA staff made public various concerns about the evidence used in seeking approval of the medicine. The FDA staff said there were “substantial uncertainties around the phase 3 study design and results, raising questions about the adequacy of this single trial to inform the benefit-risk assessment.”
Members of the FDA’s Arthritis Advisory Committee voted 10-8 on May 6 on a question of whether the risk-benefit profile of avacopan is adequate to support approval. The panel also voted 9-9 on whether the efficacy data support approval of avacopan, and 10-8 that the safety profile of avacopan is adequate to support approval.
ChemoCentryx in July said it filed an amendment to its new drug application (NDA) for avacopan. This appears to have answered regulators’ questions about the drug.
On a call with analysts Friday, ChemoCentryx officials outlined a marketing strategy for avacopan, with efforts focused on reaching influential rheumatologists and nephrologists. The company will set a U.S. wholesale acquisition cost for the drug of about $150,000-$200,000 a patient, in keeping with the range of prices often seen for orphan drugs. ChemoCentryx said it intends to offer financial support programs for the medicine.
ChemoCentryx said avacopan is also approved for the treatment of microscopic polyangiitis and granulomatosis with polyangiitis (the two main forms of ANCA-associated vasculitis) in Japan. The regulatory decision in Europe is expected by the end of this year.
A version of this article first appeared on Medscape.com.
U.S. regulators approved avacopan (Tavneos) for a rare immune disorder after receiving additional information to address concerns raised about the drug that were previously discussed at a public meeting in May.
ChemoCentryx, the drug’s manufacturer, today announced that the U.S. Food and Drug Administration approved the drug as an adjunctive treatment for severe active antineutrophil cytoplasmic autoantibody–associated vasculitis (also known as ANCA-associated vasculitis or ANCA vasculitis).
This systemic disease results from overactivation of the complement system, leading to inflammation and eventual destruction of small blood vessels. This can lead to organ damage and failure, with the kidney as the major target, said the company in a statement.
The avacopan approval was based in large part on the results of the ADVOCATE trial, which were highlighted in a February 2021 editorial in the New England Journal of Medicine , titled “Avacopan – Time to replace glucocorticoids?” But the FDA-approved indication for avacopan is as an adjunctive treatment of adult patients with severe active ANCA-associated vasculitis (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]) in combination with standard therapy including glucocorticoids. “Tavneos does not eliminate glucocorticoid use,” the label states.
The ADVOCATE trial was a global, randomized, double-blind, active-controlled, double-dummy phase 3 trial of 330 patients with ANCA-associated vasculitis conducted in 20 countries, ChemoCentryx said. Participants were randomly assigned to receive either rituximab or cyclophosphamide (followed by azathioprine/mycophenolate) and either avacopan or study-supplied oral prednisone.
Subjects in both treatment groups could also receive nonprotocol glucocorticoids as needed. The study met its primary endpoints of disease remission at 26 weeks and sustained remission at 52 weeks, as assessed by the Birmingham Vasculitis Activity Score (BVAS), ChemoCentryx said. Common adverse reactions among study participants included nausea, headache, hypertension, diarrhea, vomiting, rash, fatigue, upper abdominal pain, dizziness, blood creatinine increase, and paresthesia.
In the ChemoCentryx statement, Peter A. Merkel, MD, MPH, a consultant to the company and the chief of rheumatology at the University of Pennsylvania, Philadelphia, called the avacopan clearance a “first-in-a-decade approval of a medicine for ANCA-associated vasculitis.”
“Patients will now have access to a new class of medication that provides beneficial effects for the treatment of ANCA-associated vasculitis,” Dr. Merkel said.
In reviewing the avacopan application, the FDA noted that the medicine is intended to treat “a rare and serious disease associated with high morbidity and increased mortality.”
“It is also a disease with high unmet need for new therapies,” the FDA staff said in a review of the ChemoCentryx application for approval of avacopan, which was posted online ahead of a meeting this past May.
Previous FDA concerns
In that review, FDA staff made public various concerns about the evidence used in seeking approval of the medicine. The FDA staff said there were “substantial uncertainties around the phase 3 study design and results, raising questions about the adequacy of this single trial to inform the benefit-risk assessment.”
Members of the FDA’s Arthritis Advisory Committee voted 10-8 on May 6 on a question of whether the risk-benefit profile of avacopan is adequate to support approval. The panel also voted 9-9 on whether the efficacy data support approval of avacopan, and 10-8 that the safety profile of avacopan is adequate to support approval.
ChemoCentryx in July said it filed an amendment to its new drug application (NDA) for avacopan. This appears to have answered regulators’ questions about the drug.
On a call with analysts Friday, ChemoCentryx officials outlined a marketing strategy for avacopan, with efforts focused on reaching influential rheumatologists and nephrologists. The company will set a U.S. wholesale acquisition cost for the drug of about $150,000-$200,000 a patient, in keeping with the range of prices often seen for orphan drugs. ChemoCentryx said it intends to offer financial support programs for the medicine.
ChemoCentryx said avacopan is also approved for the treatment of microscopic polyangiitis and granulomatosis with polyangiitis (the two main forms of ANCA-associated vasculitis) in Japan. The regulatory decision in Europe is expected by the end of this year.
A version of this article first appeared on Medscape.com.
FDA issues warning about use of dermal fillers with needle-free devices
.
Specifically, the warning advises consumers and health care professionals “not to use needle-free devices such as hyaluron pens for injection of hyaluronic acid (HA) or other lip and facial fillers, collectively and commonly referred to as dermal fillers or fillers.”
According to the statement, the agency “is aware of serious injuries and in some cases, permanent harm to the skin, lips, or eyes with the use of needle-free devices for injection of fillers.”
Needle-free devices and lip and facial fillers for use with these devices are being sold directly to consumers online, and are promoted on social media “to increase lip volume, improve the appearance of wrinkles, change the shape of the nose, and other similar procedures,” according to the FDA warning.
The FDA points out that FDA-approved dermal fillers are for prescription use only, and should be administered only by licensed health care professionals using a syringe with a needle or cannula, and advises consumers not to buy or use lip or facial fillers sold directly to the public.
These products may be contaminated with infectious agents or chemicals. Moreover, “needle-free injection devices for aesthetic purposes do not provide enough control over where the injected product is placed,” the statement adds. In addition to infections, other risks include bleeding and bruising, formation of lumps, allergic reactions, blockage of a blood vessel (which can result in necrosis, blindness, or stroke), and transmission of diseases from sharing devices.
The FDA’s recommendations for health care providers include not using any aesthetic fillers with a needle-free device, and not using approved dermal fillers in such devices.
The American Society for Dermatologic Surgery Association (ASDSA) commended the FDA on the safety communication in a statement issued on October 11. In February, the ASDSA issued an alert about children using hyaluron pens to self-inject hyaluronic filler into the epidermal and upper dermal skin layers.
“I am pleased that the FDA has taken notice of this disturbing new trend, especially that of children using these devices on social media,” ASDSA president Mathew Avram, MD, JD, director of the Dermatology Laser and Cosmetic Center, at Massachusetts General Hospital, Boston, said in the statement. “The complexity of facial anatomy requires in-depth knowledge and expertise, and patients should always have medical procedures done by a physician who also has knowledge of adverse events,” he added, urging consumers to see a board-certified dermatologist before undergoing any cosmetic procedure.
In response to a query, an FDA spokesperson did not have an estimate of the number of reports of these adverse events.
People who have problems or are concerned about having had a filler injected with a needle-free device should contact a licensed health care provider. Consumers and health care professionals should report adverse events related to injection of fillers with a needle-free device to the FDA’s MedWatch program. In addition to MedWatch, adverse events can also be reported to the Cutaneous Procedures Adverse Events Reporting (CAPER) Registry, established earlier this year by the ASDSA with the department of dermatology at Northwestern University, Chicago.
*This story was updated on October 12.
.
Specifically, the warning advises consumers and health care professionals “not to use needle-free devices such as hyaluron pens for injection of hyaluronic acid (HA) or other lip and facial fillers, collectively and commonly referred to as dermal fillers or fillers.”
According to the statement, the agency “is aware of serious injuries and in some cases, permanent harm to the skin, lips, or eyes with the use of needle-free devices for injection of fillers.”
Needle-free devices and lip and facial fillers for use with these devices are being sold directly to consumers online, and are promoted on social media “to increase lip volume, improve the appearance of wrinkles, change the shape of the nose, and other similar procedures,” according to the FDA warning.
The FDA points out that FDA-approved dermal fillers are for prescription use only, and should be administered only by licensed health care professionals using a syringe with a needle or cannula, and advises consumers not to buy or use lip or facial fillers sold directly to the public.
These products may be contaminated with infectious agents or chemicals. Moreover, “needle-free injection devices for aesthetic purposes do not provide enough control over where the injected product is placed,” the statement adds. In addition to infections, other risks include bleeding and bruising, formation of lumps, allergic reactions, blockage of a blood vessel (which can result in necrosis, blindness, or stroke), and transmission of diseases from sharing devices.
The FDA’s recommendations for health care providers include not using any aesthetic fillers with a needle-free device, and not using approved dermal fillers in such devices.
The American Society for Dermatologic Surgery Association (ASDSA) commended the FDA on the safety communication in a statement issued on October 11. In February, the ASDSA issued an alert about children using hyaluron pens to self-inject hyaluronic filler into the epidermal and upper dermal skin layers.
“I am pleased that the FDA has taken notice of this disturbing new trend, especially that of children using these devices on social media,” ASDSA president Mathew Avram, MD, JD, director of the Dermatology Laser and Cosmetic Center, at Massachusetts General Hospital, Boston, said in the statement. “The complexity of facial anatomy requires in-depth knowledge and expertise, and patients should always have medical procedures done by a physician who also has knowledge of adverse events,” he added, urging consumers to see a board-certified dermatologist before undergoing any cosmetic procedure.
In response to a query, an FDA spokesperson did not have an estimate of the number of reports of these adverse events.
People who have problems or are concerned about having had a filler injected with a needle-free device should contact a licensed health care provider. Consumers and health care professionals should report adverse events related to injection of fillers with a needle-free device to the FDA’s MedWatch program. In addition to MedWatch, adverse events can also be reported to the Cutaneous Procedures Adverse Events Reporting (CAPER) Registry, established earlier this year by the ASDSA with the department of dermatology at Northwestern University, Chicago.
*This story was updated on October 12.
.
Specifically, the warning advises consumers and health care professionals “not to use needle-free devices such as hyaluron pens for injection of hyaluronic acid (HA) or other lip and facial fillers, collectively and commonly referred to as dermal fillers or fillers.”
According to the statement, the agency “is aware of serious injuries and in some cases, permanent harm to the skin, lips, or eyes with the use of needle-free devices for injection of fillers.”
Needle-free devices and lip and facial fillers for use with these devices are being sold directly to consumers online, and are promoted on social media “to increase lip volume, improve the appearance of wrinkles, change the shape of the nose, and other similar procedures,” according to the FDA warning.
The FDA points out that FDA-approved dermal fillers are for prescription use only, and should be administered only by licensed health care professionals using a syringe with a needle or cannula, and advises consumers not to buy or use lip or facial fillers sold directly to the public.
These products may be contaminated with infectious agents or chemicals. Moreover, “needle-free injection devices for aesthetic purposes do not provide enough control over where the injected product is placed,” the statement adds. In addition to infections, other risks include bleeding and bruising, formation of lumps, allergic reactions, blockage of a blood vessel (which can result in necrosis, blindness, or stroke), and transmission of diseases from sharing devices.
The FDA’s recommendations for health care providers include not using any aesthetic fillers with a needle-free device, and not using approved dermal fillers in such devices.
The American Society for Dermatologic Surgery Association (ASDSA) commended the FDA on the safety communication in a statement issued on October 11. In February, the ASDSA issued an alert about children using hyaluron pens to self-inject hyaluronic filler into the epidermal and upper dermal skin layers.
“I am pleased that the FDA has taken notice of this disturbing new trend, especially that of children using these devices on social media,” ASDSA president Mathew Avram, MD, JD, director of the Dermatology Laser and Cosmetic Center, at Massachusetts General Hospital, Boston, said in the statement. “The complexity of facial anatomy requires in-depth knowledge and expertise, and patients should always have medical procedures done by a physician who also has knowledge of adverse events,” he added, urging consumers to see a board-certified dermatologist before undergoing any cosmetic procedure.
In response to a query, an FDA spokesperson did not have an estimate of the number of reports of these adverse events.
People who have problems or are concerned about having had a filler injected with a needle-free device should contact a licensed health care provider. Consumers and health care professionals should report adverse events related to injection of fillers with a needle-free device to the FDA’s MedWatch program. In addition to MedWatch, adverse events can also be reported to the Cutaneous Procedures Adverse Events Reporting (CAPER) Registry, established earlier this year by the ASDSA with the department of dermatology at Northwestern University, Chicago.
*This story was updated on October 12.
Psychiatrists shift stance on gender dysphoria, recommend therapy
A new position statement from the Royal Australian and New Zealand College of Psychiatrists (RANZCP) stresses the importance of a mental health evaluation for people with gender dysphoria – in particular for children and adolescents – before any firm decisions are made on whether to prescribe hormonal treatments to transition, or perform surgeries, often referred to as “gender-affirming care.”
“There is a paucity of quality evidence on the outcomes of those presenting with gender dysphoria. In particular, there is a need for better evidence in relation to outcomes for children and young people,” the guidance states.
Because gender dysphoria “is associated with significant distress ... each case should be assessed by a mental health professional, which will frequently be a psychiatrist, with the person at the center of care. It is important the psychological state and context in which gender dysphoria has arisen is explored to assess the most appropriate treatment,” it adds.
The move by the psychiatry body represents a big shift in the landscape regarding recommendations for the treatment of gender dysphoria in Australia and New Zealand.
Asked to explain the new RANZCP position, Philip Morris, MBBS, FRANZCP, said: “The College acknowledged the complexity of the issues and the legitimacy of different approaches.”
Exploration of a patient’s reasons for identifying as transgender is essential, he said in an interview, especially when it comes to young people.
“There may be other reasons for doing it, and we need to look for those, identify them and treat them. This needs to be done before initiating hormones and changing the whole physical nature of the child,” he said.
“A cautious psychotherapy-first approach makes sense. If we can do that with adolescents, then we will take a big step in the right direction,” stressed Dr. Morris, who is president of the National Association of Practising Psychiatrists in Australia.
Keira Bell case and Scandinavian stance lead to more open discussion
The rapid rise in gender dysphoria among adolescents in the Western world, referred to as “rapid-onset” or “late-onset” gender dysphoria, has seen a huge increase in the number of natal girls presenting and created frenzied debate that has intensified worldwide in the last 12 months about how to best treat youth with gender dysphoria.
Concerns have arisen that some transgender identification is due to social contagion, and there is a growing number of “detransitioners” – people who identified as transgender, transitioned to the opposite gender, but then regretted their decision, changed their minds, and “detransitioned” back to their birth sex. If they have had hormone therapy, and in some cases surgery, they are left with irreversible changes to their bodies.
As a result, Scandinavian countries, most notably Finland, once eager advocates of the gender-affirmative approach, have pulled back and issued new treatment guidelines in 2020 stating that psychotherapy, rather than gender reassignment, should be the first line of treatment for gender-dysphoric youth.
This, along with a landmark High Court decision in the U.K. regarding the use of puberty-blocking drugs for children with gender dysphoria, brought by detransitioner Keira Bell, which was recently overturned by the Appeal Court, but which Ms. Bell now says she will take to the Supreme Court, has led to a considerable shift in the conversation around treating transgender adolescents with hormonal therapy, says Dr. Morris.
“This [has moved from] ... a topic that could previously not be talked about freely to one that we can discuss more openly now. This is a big improvement. Previously, everyone thought it was all settled, but it’s not, certainly not from a medical angle,” he states.
At odds with prior Australian recommendations
The RANZCP had previously endorsed the standard guidelines of the Royal Children’s Hospital (RCH) Melbourne, followed by most gender-identity services in Australia and similar guidance from New Zealand, which both recommend gender-affirming care.
“Increasing evidence demonstrates that with supportive, gender-affirming care during childhood and adolescence, harms can be ameliorated and mental health and well-being outcomes can be significantly improved,” state the RCH guidelines.
But in 2019, RANZCP removed its endorsement of the RCH guidelines and started a consultation, which resulted in the new position statement.
However, Ken Pang, MD, of the Murdoch Children’s Research Institute in Melbourne and an author of the RCH guidelines, says the key recommendations of the new RANZCP position statement are consistent with their own guidelines.
The former note “the need for a skilled mental health clinician in providing comprehensive exploration of a child or adolescent’s biopsychosocial context,” Dr. Pang says.
However, it’s difficult not to see the contrast in stance when the new RANZCP statement maintains: “Research on gender dysphoria is still emerging. There are polarized views and mixed evidence regarding treatment options for people presenting with gender identity concerns, especially children and young people.”
Dr. Pang says the RCH guidelines do, however, recognize the need for further research in the field.
“I look forward to being able to incorporate such research, including from our own Trans20 study, into future revisions of our guidelines,” he told this news organization.
Watch your backs with affirmative therapy: Will there be a compromise?
Dr. Morris says there will obviously be cases where “the child might transition with a medical intervention, but that wouldn’t be the first step.”
And yet, he adds, “There are those who push the pro-trans view that everyone should be allowed to transition, and the doctors are only technicians that provide hormones with no questions asked.”
But from a doctor’s perspective, clinicians will still be held responsible in medical and legal terms for the treatments given, he stressed.
“I don’t think they will ever not be accountable for that. They will always need to determine in their own mind whether their actions have positive value that outweigh any disadvantages,” Dr. Morris continues.
The RANZCP statement does, in fact, stress just this.
All health care professionals need to “be aware of ethical and medicolegal dilemmas” pertaining to affirmative therapy, it indicates. “Psychiatrists should practice within the relevant laws and accepted professional standards in relation to assessing capacity and obtaining consent...”
Dr. Morris hopes there will ultimately be many more checks and balances in place and that courts and clinicians will need to step back and not assume every child who seeks to transition is doing it as a result of pure gender dysphoria.
He predicts that things will end in a compromise.
“In my view, this compromise will treat children with respect and approach them like any other patient that presents with a condition that requires proper assessment and treatment.”
“In the end, some cases will be transitioned, but there will be fewer than [are] transitioned at the moment,” he predicts.
Dr. Morris has reported no relevant financial relationships. Dr. Pang is a member of the Australian Professional Association for Trans Health and its research committee.
A version of this article first appeared on Medscape.com.
A new position statement from the Royal Australian and New Zealand College of Psychiatrists (RANZCP) stresses the importance of a mental health evaluation for people with gender dysphoria – in particular for children and adolescents – before any firm decisions are made on whether to prescribe hormonal treatments to transition, or perform surgeries, often referred to as “gender-affirming care.”
“There is a paucity of quality evidence on the outcomes of those presenting with gender dysphoria. In particular, there is a need for better evidence in relation to outcomes for children and young people,” the guidance states.
Because gender dysphoria “is associated with significant distress ... each case should be assessed by a mental health professional, which will frequently be a psychiatrist, with the person at the center of care. It is important the psychological state and context in which gender dysphoria has arisen is explored to assess the most appropriate treatment,” it adds.
The move by the psychiatry body represents a big shift in the landscape regarding recommendations for the treatment of gender dysphoria in Australia and New Zealand.
Asked to explain the new RANZCP position, Philip Morris, MBBS, FRANZCP, said: “The College acknowledged the complexity of the issues and the legitimacy of different approaches.”
Exploration of a patient’s reasons for identifying as transgender is essential, he said in an interview, especially when it comes to young people.
“There may be other reasons for doing it, and we need to look for those, identify them and treat them. This needs to be done before initiating hormones and changing the whole physical nature of the child,” he said.
“A cautious psychotherapy-first approach makes sense. If we can do that with adolescents, then we will take a big step in the right direction,” stressed Dr. Morris, who is president of the National Association of Practising Psychiatrists in Australia.
Keira Bell case and Scandinavian stance lead to more open discussion
The rapid rise in gender dysphoria among adolescents in the Western world, referred to as “rapid-onset” or “late-onset” gender dysphoria, has seen a huge increase in the number of natal girls presenting and created frenzied debate that has intensified worldwide in the last 12 months about how to best treat youth with gender dysphoria.
Concerns have arisen that some transgender identification is due to social contagion, and there is a growing number of “detransitioners” – people who identified as transgender, transitioned to the opposite gender, but then regretted their decision, changed their minds, and “detransitioned” back to their birth sex. If they have had hormone therapy, and in some cases surgery, they are left with irreversible changes to their bodies.
As a result, Scandinavian countries, most notably Finland, once eager advocates of the gender-affirmative approach, have pulled back and issued new treatment guidelines in 2020 stating that psychotherapy, rather than gender reassignment, should be the first line of treatment for gender-dysphoric youth.
This, along with a landmark High Court decision in the U.K. regarding the use of puberty-blocking drugs for children with gender dysphoria, brought by detransitioner Keira Bell, which was recently overturned by the Appeal Court, but which Ms. Bell now says she will take to the Supreme Court, has led to a considerable shift in the conversation around treating transgender adolescents with hormonal therapy, says Dr. Morris.
“This [has moved from] ... a topic that could previously not be talked about freely to one that we can discuss more openly now. This is a big improvement. Previously, everyone thought it was all settled, but it’s not, certainly not from a medical angle,” he states.
At odds with prior Australian recommendations
The RANZCP had previously endorsed the standard guidelines of the Royal Children’s Hospital (RCH) Melbourne, followed by most gender-identity services in Australia and similar guidance from New Zealand, which both recommend gender-affirming care.
“Increasing evidence demonstrates that with supportive, gender-affirming care during childhood and adolescence, harms can be ameliorated and mental health and well-being outcomes can be significantly improved,” state the RCH guidelines.
But in 2019, RANZCP removed its endorsement of the RCH guidelines and started a consultation, which resulted in the new position statement.
However, Ken Pang, MD, of the Murdoch Children’s Research Institute in Melbourne and an author of the RCH guidelines, says the key recommendations of the new RANZCP position statement are consistent with their own guidelines.
The former note “the need for a skilled mental health clinician in providing comprehensive exploration of a child or adolescent’s biopsychosocial context,” Dr. Pang says.
However, it’s difficult not to see the contrast in stance when the new RANZCP statement maintains: “Research on gender dysphoria is still emerging. There are polarized views and mixed evidence regarding treatment options for people presenting with gender identity concerns, especially children and young people.”
Dr. Pang says the RCH guidelines do, however, recognize the need for further research in the field.
“I look forward to being able to incorporate such research, including from our own Trans20 study, into future revisions of our guidelines,” he told this news organization.
Watch your backs with affirmative therapy: Will there be a compromise?
Dr. Morris says there will obviously be cases where “the child might transition with a medical intervention, but that wouldn’t be the first step.”
And yet, he adds, “There are those who push the pro-trans view that everyone should be allowed to transition, and the doctors are only technicians that provide hormones with no questions asked.”
But from a doctor’s perspective, clinicians will still be held responsible in medical and legal terms for the treatments given, he stressed.
“I don’t think they will ever not be accountable for that. They will always need to determine in their own mind whether their actions have positive value that outweigh any disadvantages,” Dr. Morris continues.
The RANZCP statement does, in fact, stress just this.
All health care professionals need to “be aware of ethical and medicolegal dilemmas” pertaining to affirmative therapy, it indicates. “Psychiatrists should practice within the relevant laws and accepted professional standards in relation to assessing capacity and obtaining consent...”
Dr. Morris hopes there will ultimately be many more checks and balances in place and that courts and clinicians will need to step back and not assume every child who seeks to transition is doing it as a result of pure gender dysphoria.
He predicts that things will end in a compromise.
“In my view, this compromise will treat children with respect and approach them like any other patient that presents with a condition that requires proper assessment and treatment.”
“In the end, some cases will be transitioned, but there will be fewer than [are] transitioned at the moment,” he predicts.
Dr. Morris has reported no relevant financial relationships. Dr. Pang is a member of the Australian Professional Association for Trans Health and its research committee.
A version of this article first appeared on Medscape.com.
A new position statement from the Royal Australian and New Zealand College of Psychiatrists (RANZCP) stresses the importance of a mental health evaluation for people with gender dysphoria – in particular for children and adolescents – before any firm decisions are made on whether to prescribe hormonal treatments to transition, or perform surgeries, often referred to as “gender-affirming care.”
“There is a paucity of quality evidence on the outcomes of those presenting with gender dysphoria. In particular, there is a need for better evidence in relation to outcomes for children and young people,” the guidance states.
Because gender dysphoria “is associated with significant distress ... each case should be assessed by a mental health professional, which will frequently be a psychiatrist, with the person at the center of care. It is important the psychological state and context in which gender dysphoria has arisen is explored to assess the most appropriate treatment,” it adds.
The move by the psychiatry body represents a big shift in the landscape regarding recommendations for the treatment of gender dysphoria in Australia and New Zealand.
Asked to explain the new RANZCP position, Philip Morris, MBBS, FRANZCP, said: “The College acknowledged the complexity of the issues and the legitimacy of different approaches.”
Exploration of a patient’s reasons for identifying as transgender is essential, he said in an interview, especially when it comes to young people.
“There may be other reasons for doing it, and we need to look for those, identify them and treat them. This needs to be done before initiating hormones and changing the whole physical nature of the child,” he said.
“A cautious psychotherapy-first approach makes sense. If we can do that with adolescents, then we will take a big step in the right direction,” stressed Dr. Morris, who is president of the National Association of Practising Psychiatrists in Australia.
Keira Bell case and Scandinavian stance lead to more open discussion
The rapid rise in gender dysphoria among adolescents in the Western world, referred to as “rapid-onset” or “late-onset” gender dysphoria, has seen a huge increase in the number of natal girls presenting and created frenzied debate that has intensified worldwide in the last 12 months about how to best treat youth with gender dysphoria.
Concerns have arisen that some transgender identification is due to social contagion, and there is a growing number of “detransitioners” – people who identified as transgender, transitioned to the opposite gender, but then regretted their decision, changed their minds, and “detransitioned” back to their birth sex. If they have had hormone therapy, and in some cases surgery, they are left with irreversible changes to their bodies.
As a result, Scandinavian countries, most notably Finland, once eager advocates of the gender-affirmative approach, have pulled back and issued new treatment guidelines in 2020 stating that psychotherapy, rather than gender reassignment, should be the first line of treatment for gender-dysphoric youth.
This, along with a landmark High Court decision in the U.K. regarding the use of puberty-blocking drugs for children with gender dysphoria, brought by detransitioner Keira Bell, which was recently overturned by the Appeal Court, but which Ms. Bell now says she will take to the Supreme Court, has led to a considerable shift in the conversation around treating transgender adolescents with hormonal therapy, says Dr. Morris.
“This [has moved from] ... a topic that could previously not be talked about freely to one that we can discuss more openly now. This is a big improvement. Previously, everyone thought it was all settled, but it’s not, certainly not from a medical angle,” he states.
At odds with prior Australian recommendations
The RANZCP had previously endorsed the standard guidelines of the Royal Children’s Hospital (RCH) Melbourne, followed by most gender-identity services in Australia and similar guidance from New Zealand, which both recommend gender-affirming care.
“Increasing evidence demonstrates that with supportive, gender-affirming care during childhood and adolescence, harms can be ameliorated and mental health and well-being outcomes can be significantly improved,” state the RCH guidelines.
But in 2019, RANZCP removed its endorsement of the RCH guidelines and started a consultation, which resulted in the new position statement.
However, Ken Pang, MD, of the Murdoch Children’s Research Institute in Melbourne and an author of the RCH guidelines, says the key recommendations of the new RANZCP position statement are consistent with their own guidelines.
The former note “the need for a skilled mental health clinician in providing comprehensive exploration of a child or adolescent’s biopsychosocial context,” Dr. Pang says.
However, it’s difficult not to see the contrast in stance when the new RANZCP statement maintains: “Research on gender dysphoria is still emerging. There are polarized views and mixed evidence regarding treatment options for people presenting with gender identity concerns, especially children and young people.”
Dr. Pang says the RCH guidelines do, however, recognize the need for further research in the field.
“I look forward to being able to incorporate such research, including from our own Trans20 study, into future revisions of our guidelines,” he told this news organization.
Watch your backs with affirmative therapy: Will there be a compromise?
Dr. Morris says there will obviously be cases where “the child might transition with a medical intervention, but that wouldn’t be the first step.”
And yet, he adds, “There are those who push the pro-trans view that everyone should be allowed to transition, and the doctors are only technicians that provide hormones with no questions asked.”
But from a doctor’s perspective, clinicians will still be held responsible in medical and legal terms for the treatments given, he stressed.
“I don’t think they will ever not be accountable for that. They will always need to determine in their own mind whether their actions have positive value that outweigh any disadvantages,” Dr. Morris continues.
The RANZCP statement does, in fact, stress just this.
All health care professionals need to “be aware of ethical and medicolegal dilemmas” pertaining to affirmative therapy, it indicates. “Psychiatrists should practice within the relevant laws and accepted professional standards in relation to assessing capacity and obtaining consent...”
Dr. Morris hopes there will ultimately be many more checks and balances in place and that courts and clinicians will need to step back and not assume every child who seeks to transition is doing it as a result of pure gender dysphoria.
He predicts that things will end in a compromise.
“In my view, this compromise will treat children with respect and approach them like any other patient that presents with a condition that requires proper assessment and treatment.”
“In the end, some cases will be transitioned, but there will be fewer than [are] transitioned at the moment,” he predicts.
Dr. Morris has reported no relevant financial relationships. Dr. Pang is a member of the Australian Professional Association for Trans Health and its research committee.
A version of this article first appeared on Medscape.com.
Lie down for orthostatic hypotension assessment
New research shows that supine orthostatic hypotension is more common and better predicts falls and orthostatic symptoms than seated OH, supporting a supine OH protocol in clinical practice, the researchers say.
“Older adults at risk for falls undergoing assessment for OH should lie supine rather than sitting prior to standing to get the most informative OH assessment,” study author Stephen Juraschek, MD, PhD, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, said in an interview.
“The findings call for a change in current practice,” Dr. Juraschek said.
He presented the study Sept. 29 at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.
The seated position for detecting OH is “commonly used for convenience. Since many clinics already perform a seated blood pressure, it saves time for people to stand shortly afterward,” he explained.
“It has also been thought that the two are interchangeable [i.e., the change in blood pressure from seated to standing was just a lower magnitude than the change from supine to standing]. However, we showed that the physiology is on average quite different, questioning prior perspectives on the interchangeability of the two protocols,” he added.
The researchers studied 522 adults (mean age, 76 years; 42% women) at high risk for falls and with vitamin D levels in the insufficient/deficient range participating in the Study to Understand Fall Reduction and Vitamin D (STURDY).
The study showed that vitamin D supplementation was not associated with OH or the main study outcome of falls.
The study used two different OH assessment protocols – seated to standing and supine to standing – and Dr. Juraschek’s team used the data to gauge the impact of supine and seated positions on OH prevalence and its relation with fall risk and orthostatic symptoms.
OH was defined as a drop in systolic BP of at least 20 mm Hg or diastolic BP of at least 10 mm Hg.
At baseline, mean BP was 129/68 mm Hg. Mean BP increased 3.4/2.6 mm Hg after sitting, but decreased 3.7/0.7 mm Hg after lying supine.
Of the 953 OH assessments (supine and seated), OH was detected in 14.8% of the supine measurements but in only 2.2% of the seated measures.
Supine OH better predicted falls (hazard ratio, 1.60; 95% CI, 0.98-2.61; P = .06) than seated OH (HR, 0.70; 95% CI, 0.30-1.60; P = .39).
Although both were nonsignificant, “potentially due to power,” the association with falls was stronger for supine OH than for seated OH, Dr. Juraschek said.
In addition, seated OH was not associated with orthostatic symptoms, whereas supine OH was significantly associated with a greater risk of fainting, blacking out, seeing spots, room spinning, and headache in the previous month (P = .048-.002).
Useful study confirms anecdotal evidence
This is a “useful study” from a “reputable” group, “and the results reveal what I would have expected,” Robert Carey, MD, University of Virginia, Charlottesville, who wasn’t involved in the study, said in an interview.
The findings, Dr. Carey said, show that measuring supine, compared with standing, “actually correlates much better with the untoward effects of orthostatic hypotension which are falls and symptoms such as dizziness and spots before your eyes.”
“Seated BP is mostly used for convenience and a little bit shorter protocol. Most clinical trials do seated orthostatic hypotension measurements. I’ve always taught my medical students and others to use the supine to standing because I’ve just anecdotally felt that this was a much better way of detecting true orthostatic hypotension and that’s how we do it at the University of Virginia Hospital,” Dr. Carey said.
The study had no funding. Dr. Juraschek and Dr. Carey have no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
New research shows that supine orthostatic hypotension is more common and better predicts falls and orthostatic symptoms than seated OH, supporting a supine OH protocol in clinical practice, the researchers say.
“Older adults at risk for falls undergoing assessment for OH should lie supine rather than sitting prior to standing to get the most informative OH assessment,” study author Stephen Juraschek, MD, PhD, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, said in an interview.
“The findings call for a change in current practice,” Dr. Juraschek said.
He presented the study Sept. 29 at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.
The seated position for detecting OH is “commonly used for convenience. Since many clinics already perform a seated blood pressure, it saves time for people to stand shortly afterward,” he explained.
“It has also been thought that the two are interchangeable [i.e., the change in blood pressure from seated to standing was just a lower magnitude than the change from supine to standing]. However, we showed that the physiology is on average quite different, questioning prior perspectives on the interchangeability of the two protocols,” he added.
The researchers studied 522 adults (mean age, 76 years; 42% women) at high risk for falls and with vitamin D levels in the insufficient/deficient range participating in the Study to Understand Fall Reduction and Vitamin D (STURDY).
The study showed that vitamin D supplementation was not associated with OH or the main study outcome of falls.
The study used two different OH assessment protocols – seated to standing and supine to standing – and Dr. Juraschek’s team used the data to gauge the impact of supine and seated positions on OH prevalence and its relation with fall risk and orthostatic symptoms.
OH was defined as a drop in systolic BP of at least 20 mm Hg or diastolic BP of at least 10 mm Hg.
At baseline, mean BP was 129/68 mm Hg. Mean BP increased 3.4/2.6 mm Hg after sitting, but decreased 3.7/0.7 mm Hg after lying supine.
Of the 953 OH assessments (supine and seated), OH was detected in 14.8% of the supine measurements but in only 2.2% of the seated measures.
Supine OH better predicted falls (hazard ratio, 1.60; 95% CI, 0.98-2.61; P = .06) than seated OH (HR, 0.70; 95% CI, 0.30-1.60; P = .39).
Although both were nonsignificant, “potentially due to power,” the association with falls was stronger for supine OH than for seated OH, Dr. Juraschek said.
In addition, seated OH was not associated with orthostatic symptoms, whereas supine OH was significantly associated with a greater risk of fainting, blacking out, seeing spots, room spinning, and headache in the previous month (P = .048-.002).
Useful study confirms anecdotal evidence
This is a “useful study” from a “reputable” group, “and the results reveal what I would have expected,” Robert Carey, MD, University of Virginia, Charlottesville, who wasn’t involved in the study, said in an interview.
The findings, Dr. Carey said, show that measuring supine, compared with standing, “actually correlates much better with the untoward effects of orthostatic hypotension which are falls and symptoms such as dizziness and spots before your eyes.”
“Seated BP is mostly used for convenience and a little bit shorter protocol. Most clinical trials do seated orthostatic hypotension measurements. I’ve always taught my medical students and others to use the supine to standing because I’ve just anecdotally felt that this was a much better way of detecting true orthostatic hypotension and that’s how we do it at the University of Virginia Hospital,” Dr. Carey said.
The study had no funding. Dr. Juraschek and Dr. Carey have no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
New research shows that supine orthostatic hypotension is more common and better predicts falls and orthostatic symptoms than seated OH, supporting a supine OH protocol in clinical practice, the researchers say.
“Older adults at risk for falls undergoing assessment for OH should lie supine rather than sitting prior to standing to get the most informative OH assessment,” study author Stephen Juraschek, MD, PhD, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, said in an interview.
“The findings call for a change in current practice,” Dr. Juraschek said.
He presented the study Sept. 29 at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.
The seated position for detecting OH is “commonly used for convenience. Since many clinics already perform a seated blood pressure, it saves time for people to stand shortly afterward,” he explained.
“It has also been thought that the two are interchangeable [i.e., the change in blood pressure from seated to standing was just a lower magnitude than the change from supine to standing]. However, we showed that the physiology is on average quite different, questioning prior perspectives on the interchangeability of the two protocols,” he added.
The researchers studied 522 adults (mean age, 76 years; 42% women) at high risk for falls and with vitamin D levels in the insufficient/deficient range participating in the Study to Understand Fall Reduction and Vitamin D (STURDY).
The study showed that vitamin D supplementation was not associated with OH or the main study outcome of falls.
The study used two different OH assessment protocols – seated to standing and supine to standing – and Dr. Juraschek’s team used the data to gauge the impact of supine and seated positions on OH prevalence and its relation with fall risk and orthostatic symptoms.
OH was defined as a drop in systolic BP of at least 20 mm Hg or diastolic BP of at least 10 mm Hg.
At baseline, mean BP was 129/68 mm Hg. Mean BP increased 3.4/2.6 mm Hg after sitting, but decreased 3.7/0.7 mm Hg after lying supine.
Of the 953 OH assessments (supine and seated), OH was detected in 14.8% of the supine measurements but in only 2.2% of the seated measures.
Supine OH better predicted falls (hazard ratio, 1.60; 95% CI, 0.98-2.61; P = .06) than seated OH (HR, 0.70; 95% CI, 0.30-1.60; P = .39).
Although both were nonsignificant, “potentially due to power,” the association with falls was stronger for supine OH than for seated OH, Dr. Juraschek said.
In addition, seated OH was not associated with orthostatic symptoms, whereas supine OH was significantly associated with a greater risk of fainting, blacking out, seeing spots, room spinning, and headache in the previous month (P = .048-.002).
Useful study confirms anecdotal evidence
This is a “useful study” from a “reputable” group, “and the results reveal what I would have expected,” Robert Carey, MD, University of Virginia, Charlottesville, who wasn’t involved in the study, said in an interview.
The findings, Dr. Carey said, show that measuring supine, compared with standing, “actually correlates much better with the untoward effects of orthostatic hypotension which are falls and symptoms such as dizziness and spots before your eyes.”
“Seated BP is mostly used for convenience and a little bit shorter protocol. Most clinical trials do seated orthostatic hypotension measurements. I’ve always taught my medical students and others to use the supine to standing because I’ve just anecdotally felt that this was a much better way of detecting true orthostatic hypotension and that’s how we do it at the University of Virginia Hospital,” Dr. Carey said.
The study had no funding. Dr. Juraschek and Dr. Carey have no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Adolescents who exercised after a concussion recovered faster in RCT
After a concussion, resuming aerobic exercise relatively early on – at an intensity that does not worsen symptoms – may help young athletes recover sooner, compared with stretching, a randomized controlled trial (RCT) shows.
The study adds to emerging evidence that clinicians should prescribe exercise, rather than strict rest, to facilitate concussion recovery, researchers said.
Tamara McLeod, PhD, ATC, professor and director of athletic training programs at A.T. Still University in Mesa, Ariz., hopes the findings help clinicians see that “this is an approach that should be taken.”
“Too often with concussion, patients are given a laundry list of things they are NOT allowed to do,” including sports, school, and social activities, said Dr. McLeod, who was not involved in the study.
The research, published in The Lancet Child & Adolescent Health, largely replicates the findings of a prior trial while addressing limitations of the previous study’s design, researchers said.
For the trial, John J. Leddy, MD, with the State University of New York at Buffalo and colleagues recruited 118 male and female adolescent athletes aged 13-18 years who had had a sport-related concussion in the past 10 days. Investigators at three community and hospital-affiliated sports medicine concussion centers in the United States randomly assigned the athletes to individualized subsymptom-threshold aerobic exercise (61 participants) or stretching exercise (57 participants) at least 20 minutes per day for up to 4 weeks. Aerobic exercise included walking, jogging, or stationary cycling at home.
“It is important that the general clinician community appreciates that prolonged rest and avoidance of physical activity until spontaneous symptom resolution is no longer an acceptable approach to caring for adolescents with concussion,” Dr. Leddy and coauthors said.
The investigators improved on the “the scientific rigor of their previous RCT by including intention-to-treat and per-protocol analyses, daily symptom reporting, objective exercise adherence measurements, and greater heterogeneity of concussion severity,” said Carolyn A. Emery, PhD, and Jonathan Smirl, PhD, both with the University of Calgary (Alta.), in a related commentary. The new study is the first to show that early targeted heart rate subsymptom-threshold aerobic exercise, relative to stretching, shortened recovery time within 4 weeks after sport-related concussion (hazard ratio, 0.52) when controlling for sex, study site, and average daily exercise time, Dr. Emery and Dr. Smirl said.
A larger proportion of athletes assigned to stretching did not recover by 4 weeks, compared with those assigned to aerobic exercise (32% vs. 21%). The median time to full recovery was longer for the stretching group than for the aerobic exercise group (19 days vs. 14 days).
Among athletes who adhered to their assigned regimens, the differences were more pronounced: The median recovery time was 21 days for the stretching group, compared with 12 days for the aerobic exercise group. The rate of postconcussion symptoms beyond 28 days was 9% in the aerobic exercise group versus 31% in the stretching group, among adherent participants.
More research is needed to establish the efficacy of postconcussion aerobic exercise in adults and for nonsport injury, the researchers noted. Possible mechanisms underlying aerobic exercise’s benefits could include increased parasympathetic autonomic tone, improved cerebral blood flow regulation, or enhanced neuron repair, they suggested.
The right amount and timing of exercise, and doing so at an intensity that does not exacerbate symptoms, may be key. Other research has suggested that too much exercise, too soon may delay recovery, Dr. Emery said in an interview. “But there is now a lot of evidence to support low and moderate levels of physical activity to expedite recovery,” she said.
The study was funded by the American Medical Society for Sports Medicine. The study and commentary authors and Dr. McLeod had no disclosures.
After a concussion, resuming aerobic exercise relatively early on – at an intensity that does not worsen symptoms – may help young athletes recover sooner, compared with stretching, a randomized controlled trial (RCT) shows.
The study adds to emerging evidence that clinicians should prescribe exercise, rather than strict rest, to facilitate concussion recovery, researchers said.
Tamara McLeod, PhD, ATC, professor and director of athletic training programs at A.T. Still University in Mesa, Ariz., hopes the findings help clinicians see that “this is an approach that should be taken.”
“Too often with concussion, patients are given a laundry list of things they are NOT allowed to do,” including sports, school, and social activities, said Dr. McLeod, who was not involved in the study.
The research, published in The Lancet Child & Adolescent Health, largely replicates the findings of a prior trial while addressing limitations of the previous study’s design, researchers said.
For the trial, John J. Leddy, MD, with the State University of New York at Buffalo and colleagues recruited 118 male and female adolescent athletes aged 13-18 years who had had a sport-related concussion in the past 10 days. Investigators at three community and hospital-affiliated sports medicine concussion centers in the United States randomly assigned the athletes to individualized subsymptom-threshold aerobic exercise (61 participants) or stretching exercise (57 participants) at least 20 minutes per day for up to 4 weeks. Aerobic exercise included walking, jogging, or stationary cycling at home.
“It is important that the general clinician community appreciates that prolonged rest and avoidance of physical activity until spontaneous symptom resolution is no longer an acceptable approach to caring for adolescents with concussion,” Dr. Leddy and coauthors said.
The investigators improved on the “the scientific rigor of their previous RCT by including intention-to-treat and per-protocol analyses, daily symptom reporting, objective exercise adherence measurements, and greater heterogeneity of concussion severity,” said Carolyn A. Emery, PhD, and Jonathan Smirl, PhD, both with the University of Calgary (Alta.), in a related commentary. The new study is the first to show that early targeted heart rate subsymptom-threshold aerobic exercise, relative to stretching, shortened recovery time within 4 weeks after sport-related concussion (hazard ratio, 0.52) when controlling for sex, study site, and average daily exercise time, Dr. Emery and Dr. Smirl said.
A larger proportion of athletes assigned to stretching did not recover by 4 weeks, compared with those assigned to aerobic exercise (32% vs. 21%). The median time to full recovery was longer for the stretching group than for the aerobic exercise group (19 days vs. 14 days).
Among athletes who adhered to their assigned regimens, the differences were more pronounced: The median recovery time was 21 days for the stretching group, compared with 12 days for the aerobic exercise group. The rate of postconcussion symptoms beyond 28 days was 9% in the aerobic exercise group versus 31% in the stretching group, among adherent participants.
More research is needed to establish the efficacy of postconcussion aerobic exercise in adults and for nonsport injury, the researchers noted. Possible mechanisms underlying aerobic exercise’s benefits could include increased parasympathetic autonomic tone, improved cerebral blood flow regulation, or enhanced neuron repair, they suggested.
The right amount and timing of exercise, and doing so at an intensity that does not exacerbate symptoms, may be key. Other research has suggested that too much exercise, too soon may delay recovery, Dr. Emery said in an interview. “But there is now a lot of evidence to support low and moderate levels of physical activity to expedite recovery,” she said.
The study was funded by the American Medical Society for Sports Medicine. The study and commentary authors and Dr. McLeod had no disclosures.
After a concussion, resuming aerobic exercise relatively early on – at an intensity that does not worsen symptoms – may help young athletes recover sooner, compared with stretching, a randomized controlled trial (RCT) shows.
The study adds to emerging evidence that clinicians should prescribe exercise, rather than strict rest, to facilitate concussion recovery, researchers said.
Tamara McLeod, PhD, ATC, professor and director of athletic training programs at A.T. Still University in Mesa, Ariz., hopes the findings help clinicians see that “this is an approach that should be taken.”
“Too often with concussion, patients are given a laundry list of things they are NOT allowed to do,” including sports, school, and social activities, said Dr. McLeod, who was not involved in the study.
The research, published in The Lancet Child & Adolescent Health, largely replicates the findings of a prior trial while addressing limitations of the previous study’s design, researchers said.
For the trial, John J. Leddy, MD, with the State University of New York at Buffalo and colleagues recruited 118 male and female adolescent athletes aged 13-18 years who had had a sport-related concussion in the past 10 days. Investigators at three community and hospital-affiliated sports medicine concussion centers in the United States randomly assigned the athletes to individualized subsymptom-threshold aerobic exercise (61 participants) or stretching exercise (57 participants) at least 20 minutes per day for up to 4 weeks. Aerobic exercise included walking, jogging, or stationary cycling at home.
“It is important that the general clinician community appreciates that prolonged rest and avoidance of physical activity until spontaneous symptom resolution is no longer an acceptable approach to caring for adolescents with concussion,” Dr. Leddy and coauthors said.
The investigators improved on the “the scientific rigor of their previous RCT by including intention-to-treat and per-protocol analyses, daily symptom reporting, objective exercise adherence measurements, and greater heterogeneity of concussion severity,” said Carolyn A. Emery, PhD, and Jonathan Smirl, PhD, both with the University of Calgary (Alta.), in a related commentary. The new study is the first to show that early targeted heart rate subsymptom-threshold aerobic exercise, relative to stretching, shortened recovery time within 4 weeks after sport-related concussion (hazard ratio, 0.52) when controlling for sex, study site, and average daily exercise time, Dr. Emery and Dr. Smirl said.
A larger proportion of athletes assigned to stretching did not recover by 4 weeks, compared with those assigned to aerobic exercise (32% vs. 21%). The median time to full recovery was longer for the stretching group than for the aerobic exercise group (19 days vs. 14 days).
Among athletes who adhered to their assigned regimens, the differences were more pronounced: The median recovery time was 21 days for the stretching group, compared with 12 days for the aerobic exercise group. The rate of postconcussion symptoms beyond 28 days was 9% in the aerobic exercise group versus 31% in the stretching group, among adherent participants.
More research is needed to establish the efficacy of postconcussion aerobic exercise in adults and for nonsport injury, the researchers noted. Possible mechanisms underlying aerobic exercise’s benefits could include increased parasympathetic autonomic tone, improved cerebral blood flow regulation, or enhanced neuron repair, they suggested.
The right amount and timing of exercise, and doing so at an intensity that does not exacerbate symptoms, may be key. Other research has suggested that too much exercise, too soon may delay recovery, Dr. Emery said in an interview. “But there is now a lot of evidence to support low and moderate levels of physical activity to expedite recovery,” she said.
The study was funded by the American Medical Society for Sports Medicine. The study and commentary authors and Dr. McLeod had no disclosures.
FROM THE LANCET CHILD & ADOLESCENT HEALTH
Retraining the brain may eliminate chronic back pain
Psychological therapy that changes an individual’s beliefs about pain not only provides lasting chronic pain relief but also alters brain regions related to pain generation, new research shows.
In the first randomized controlled test of pain-reprocessing therapy (PRT), two-thirds of patients with chronic back pain (CBP) who received 4 weeks of PRT were pain free or nearly pain free afterward – and for most patients, relief was maintained for 1 year, the researchers found.
“Primary chronic back pain can be dramatically reduced or even eliminated by psychological treatment focused on changing how threatening we perceive the pain to be,” first author Yoni Ashar, PhD, department of psychiatry, Weill Cornell Medicine, New York, said in an interview.
“ given that large reductions in pain have rarely been observed in studies that tested psychological therapies for chronic back pain.
The study was published online Sept. 29, 2021, in JAMA Psychiatry.
Rethinking pain
CBP is a leading cause of disability, and treatment is often ineffective. In about 85% of cases of primary CBP, a definitive cause of the pain can’t be identified. In these cases, fear, avoidance, and beliefs that pain indicates injury may contribute to ongoing CBP.
PRT educates patients about the role of the brain in generating chronic pain; helps them reappraise their pain as they engage in movements that they had been afraid to undertake; and helps them address emotions that may exacerbate pain.
The study included 151 adults (54% women; mean age, 41 years) who had primary CBP of low to moderate severity (mean pain intensity, 4 of 10) for an average of 10 years.
A total of 50 participants were randomly allocated to undergo PRT (one telehealth session with a physician and eight PRT sessions over 4 weeks), 51 to receive placebo (subcutaneous saline injection in the back), and 50 to continue their routine, usual ongoing care.
Large group differences in pain were observed after treatment. The mean pain score was 1.18 in the PRT group, 2.84 in the placebo group, and 3.13 in the usual-care group. Hedges’ g was –1.14 for PRT versus placebo and –1.74 for PRT versus usual care (P < .001).
Two-thirds (66%) of adults in the PRT group were pain free or nearly pain free following treatment (pain-intensity score of 0 or 1 out of 10), compared with 20% of those in the placebo group and 10% of those who received usual care.
Treatment effects were maintained at 1-year follow-up. The mean pain score was 1.51 in the PRT group, 2.79 in the placebo group, and 3.00 in the usual-care group. Neither age nor sex moderated the effect of PRT on pain intensity.
Retraining the brain
The researchers said the effects of PRT on pain were mediated by lessening the belief that pain indicates tissue damage. Of note, PRT also reduced experimentally evoked back pain and spontaneous pain during functional MRI, with large effect sizes.
“The idea is that by thinking about the pain as safe rather than threatening, patients can alter the brain networks reinforcing the pain, and neutralize it,” Dr. Ashar said in a news release.
The authors noted that study participants were relatively well educated and active. The participants reported having longstanding low to moderate pain and disability at baseline.
The physician and therapists were experts in delivering PRT. Future studies should test generalizability to other patient populations, therapists, and treatment contexts.
“Our clinical experience shows that PRT is effective for other primary chronic pain conditions as well,” said Dr. Ashar, including primary knee pain and tension headache.
Restoring function
Commenting on the findings, Shaheen E. Lakhan, MD, PhD, neurologist and pain specialist in Newton, Mass., said he has long experience using psychological approaches to address pain, with good results.
“Imagine telling a person suffering from decades of chronic pain that your pain is all in your head. I’ve done that for years as a board-certified pain physician managing only the most severe and debilitating forms of pain. When used to ground brain retraining, I could ultimately restore function to people living with chronic pain,” Dr. Lakhan said.
“The statement is true – the brain ultimately processes signals from throughout the body, forms the perception of pain, and links it to emotional brain centers, among others. Pain is an important survival mechanism so that when your body is at threat of injury, you protect yourself from further damage and withdraw. The problem lies when pain outlasts its welcome and chronifies,” said Dr. Lakhan, senior vice president of research and development of Click Therapeutics in Boston.
The investigators in this study “eloquently prove” that with 4 weeks of PRT, patients can learn that chronic pain is largely a “brain-generated false alarm and that constantly affirming this truth can actually reduce or eliminate it,” Dr. Lakhan said.
“Further, the brain areas implicated with pain are calmed after going through the therapy to both resting pain and pain induced by extending the back,” he noted.
“Pain-reprocessing therapy can improve the lives of chronic [pain patients] who have low to moderate levels of pain and disability; however, much work needs to be done to make this scalable and universally available and covered by insurers as a treatment modality,” Dr. Lakhan added.
He cautioned that he has not seen therapies such as this work when there is significant depression, withdrawal, or lack of control over one’s situation such that one behaves in a helpless manner – “a terrible state of mind called learned helplessness.”
The study was funded by the National Institutes of Health, the National Center for Advancing Translational Sciences, the Radiological Society of North America, the German Research Foundation, the Psychophysiologic Disorders Association, the Foundation for the Study of the Therapeutic Encounter, and community donations. Dr. Ashar received grants from the National Institutes of Health during the conduct of the study and personal fees from UnitedHealth Group, Lin Health, Pain Reprocessing Therapy Center, and Mental Health Partners of Boulder County outside the submitted work. Dr. Lakhan disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Psychological therapy that changes an individual’s beliefs about pain not only provides lasting chronic pain relief but also alters brain regions related to pain generation, new research shows.
In the first randomized controlled test of pain-reprocessing therapy (PRT), two-thirds of patients with chronic back pain (CBP) who received 4 weeks of PRT were pain free or nearly pain free afterward – and for most patients, relief was maintained for 1 year, the researchers found.
“Primary chronic back pain can be dramatically reduced or even eliminated by psychological treatment focused on changing how threatening we perceive the pain to be,” first author Yoni Ashar, PhD, department of psychiatry, Weill Cornell Medicine, New York, said in an interview.
“ given that large reductions in pain have rarely been observed in studies that tested psychological therapies for chronic back pain.
The study was published online Sept. 29, 2021, in JAMA Psychiatry.
Rethinking pain
CBP is a leading cause of disability, and treatment is often ineffective. In about 85% of cases of primary CBP, a definitive cause of the pain can’t be identified. In these cases, fear, avoidance, and beliefs that pain indicates injury may contribute to ongoing CBP.
PRT educates patients about the role of the brain in generating chronic pain; helps them reappraise their pain as they engage in movements that they had been afraid to undertake; and helps them address emotions that may exacerbate pain.
The study included 151 adults (54% women; mean age, 41 years) who had primary CBP of low to moderate severity (mean pain intensity, 4 of 10) for an average of 10 years.
A total of 50 participants were randomly allocated to undergo PRT (one telehealth session with a physician and eight PRT sessions over 4 weeks), 51 to receive placebo (subcutaneous saline injection in the back), and 50 to continue their routine, usual ongoing care.
Large group differences in pain were observed after treatment. The mean pain score was 1.18 in the PRT group, 2.84 in the placebo group, and 3.13 in the usual-care group. Hedges’ g was –1.14 for PRT versus placebo and –1.74 for PRT versus usual care (P < .001).
Two-thirds (66%) of adults in the PRT group were pain free or nearly pain free following treatment (pain-intensity score of 0 or 1 out of 10), compared with 20% of those in the placebo group and 10% of those who received usual care.
Treatment effects were maintained at 1-year follow-up. The mean pain score was 1.51 in the PRT group, 2.79 in the placebo group, and 3.00 in the usual-care group. Neither age nor sex moderated the effect of PRT on pain intensity.
Retraining the brain
The researchers said the effects of PRT on pain were mediated by lessening the belief that pain indicates tissue damage. Of note, PRT also reduced experimentally evoked back pain and spontaneous pain during functional MRI, with large effect sizes.
“The idea is that by thinking about the pain as safe rather than threatening, patients can alter the brain networks reinforcing the pain, and neutralize it,” Dr. Ashar said in a news release.
The authors noted that study participants were relatively well educated and active. The participants reported having longstanding low to moderate pain and disability at baseline.
The physician and therapists were experts in delivering PRT. Future studies should test generalizability to other patient populations, therapists, and treatment contexts.
“Our clinical experience shows that PRT is effective for other primary chronic pain conditions as well,” said Dr. Ashar, including primary knee pain and tension headache.
Restoring function
Commenting on the findings, Shaheen E. Lakhan, MD, PhD, neurologist and pain specialist in Newton, Mass., said he has long experience using psychological approaches to address pain, with good results.
“Imagine telling a person suffering from decades of chronic pain that your pain is all in your head. I’ve done that for years as a board-certified pain physician managing only the most severe and debilitating forms of pain. When used to ground brain retraining, I could ultimately restore function to people living with chronic pain,” Dr. Lakhan said.
“The statement is true – the brain ultimately processes signals from throughout the body, forms the perception of pain, and links it to emotional brain centers, among others. Pain is an important survival mechanism so that when your body is at threat of injury, you protect yourself from further damage and withdraw. The problem lies when pain outlasts its welcome and chronifies,” said Dr. Lakhan, senior vice president of research and development of Click Therapeutics in Boston.
The investigators in this study “eloquently prove” that with 4 weeks of PRT, patients can learn that chronic pain is largely a “brain-generated false alarm and that constantly affirming this truth can actually reduce or eliminate it,” Dr. Lakhan said.
“Further, the brain areas implicated with pain are calmed after going through the therapy to both resting pain and pain induced by extending the back,” he noted.
“Pain-reprocessing therapy can improve the lives of chronic [pain patients] who have low to moderate levels of pain and disability; however, much work needs to be done to make this scalable and universally available and covered by insurers as a treatment modality,” Dr. Lakhan added.
He cautioned that he has not seen therapies such as this work when there is significant depression, withdrawal, or lack of control over one’s situation such that one behaves in a helpless manner – “a terrible state of mind called learned helplessness.”
The study was funded by the National Institutes of Health, the National Center for Advancing Translational Sciences, the Radiological Society of North America, the German Research Foundation, the Psychophysiologic Disorders Association, the Foundation for the Study of the Therapeutic Encounter, and community donations. Dr. Ashar received grants from the National Institutes of Health during the conduct of the study and personal fees from UnitedHealth Group, Lin Health, Pain Reprocessing Therapy Center, and Mental Health Partners of Boulder County outside the submitted work. Dr. Lakhan disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Psychological therapy that changes an individual’s beliefs about pain not only provides lasting chronic pain relief but also alters brain regions related to pain generation, new research shows.
In the first randomized controlled test of pain-reprocessing therapy (PRT), two-thirds of patients with chronic back pain (CBP) who received 4 weeks of PRT were pain free or nearly pain free afterward – and for most patients, relief was maintained for 1 year, the researchers found.
“Primary chronic back pain can be dramatically reduced or even eliminated by psychological treatment focused on changing how threatening we perceive the pain to be,” first author Yoni Ashar, PhD, department of psychiatry, Weill Cornell Medicine, New York, said in an interview.
“ given that large reductions in pain have rarely been observed in studies that tested psychological therapies for chronic back pain.
The study was published online Sept. 29, 2021, in JAMA Psychiatry.
Rethinking pain
CBP is a leading cause of disability, and treatment is often ineffective. In about 85% of cases of primary CBP, a definitive cause of the pain can’t be identified. In these cases, fear, avoidance, and beliefs that pain indicates injury may contribute to ongoing CBP.
PRT educates patients about the role of the brain in generating chronic pain; helps them reappraise their pain as they engage in movements that they had been afraid to undertake; and helps them address emotions that may exacerbate pain.
The study included 151 adults (54% women; mean age, 41 years) who had primary CBP of low to moderate severity (mean pain intensity, 4 of 10) for an average of 10 years.
A total of 50 participants were randomly allocated to undergo PRT (one telehealth session with a physician and eight PRT sessions over 4 weeks), 51 to receive placebo (subcutaneous saline injection in the back), and 50 to continue their routine, usual ongoing care.
Large group differences in pain were observed after treatment. The mean pain score was 1.18 in the PRT group, 2.84 in the placebo group, and 3.13 in the usual-care group. Hedges’ g was –1.14 for PRT versus placebo and –1.74 for PRT versus usual care (P < .001).
Two-thirds (66%) of adults in the PRT group were pain free or nearly pain free following treatment (pain-intensity score of 0 or 1 out of 10), compared with 20% of those in the placebo group and 10% of those who received usual care.
Treatment effects were maintained at 1-year follow-up. The mean pain score was 1.51 in the PRT group, 2.79 in the placebo group, and 3.00 in the usual-care group. Neither age nor sex moderated the effect of PRT on pain intensity.
Retraining the brain
The researchers said the effects of PRT on pain were mediated by lessening the belief that pain indicates tissue damage. Of note, PRT also reduced experimentally evoked back pain and spontaneous pain during functional MRI, with large effect sizes.
“The idea is that by thinking about the pain as safe rather than threatening, patients can alter the brain networks reinforcing the pain, and neutralize it,” Dr. Ashar said in a news release.
The authors noted that study participants were relatively well educated and active. The participants reported having longstanding low to moderate pain and disability at baseline.
The physician and therapists were experts in delivering PRT. Future studies should test generalizability to other patient populations, therapists, and treatment contexts.
“Our clinical experience shows that PRT is effective for other primary chronic pain conditions as well,” said Dr. Ashar, including primary knee pain and tension headache.
Restoring function
Commenting on the findings, Shaheen E. Lakhan, MD, PhD, neurologist and pain specialist in Newton, Mass., said he has long experience using psychological approaches to address pain, with good results.
“Imagine telling a person suffering from decades of chronic pain that your pain is all in your head. I’ve done that for years as a board-certified pain physician managing only the most severe and debilitating forms of pain. When used to ground brain retraining, I could ultimately restore function to people living with chronic pain,” Dr. Lakhan said.
“The statement is true – the brain ultimately processes signals from throughout the body, forms the perception of pain, and links it to emotional brain centers, among others. Pain is an important survival mechanism so that when your body is at threat of injury, you protect yourself from further damage and withdraw. The problem lies when pain outlasts its welcome and chronifies,” said Dr. Lakhan, senior vice president of research and development of Click Therapeutics in Boston.
The investigators in this study “eloquently prove” that with 4 weeks of PRT, patients can learn that chronic pain is largely a “brain-generated false alarm and that constantly affirming this truth can actually reduce or eliminate it,” Dr. Lakhan said.
“Further, the brain areas implicated with pain are calmed after going through the therapy to both resting pain and pain induced by extending the back,” he noted.
“Pain-reprocessing therapy can improve the lives of chronic [pain patients] who have low to moderate levels of pain and disability; however, much work needs to be done to make this scalable and universally available and covered by insurers as a treatment modality,” Dr. Lakhan added.
He cautioned that he has not seen therapies such as this work when there is significant depression, withdrawal, or lack of control over one’s situation such that one behaves in a helpless manner – “a terrible state of mind called learned helplessness.”
The study was funded by the National Institutes of Health, the National Center for Advancing Translational Sciences, the Radiological Society of North America, the German Research Foundation, the Psychophysiologic Disorders Association, the Foundation for the Study of the Therapeutic Encounter, and community donations. Dr. Ashar received grants from the National Institutes of Health during the conduct of the study and personal fees from UnitedHealth Group, Lin Health, Pain Reprocessing Therapy Center, and Mental Health Partners of Boulder County outside the submitted work. Dr. Lakhan disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Do you use intrapartum warm compresses to the perineum or perineal massage in your practice?
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[polldaddy:10937454]
[polldaddy:10937454]
Comparison of Adverse Events With Vancomycin Diluted in Normal Saline vs Dextrose 5%
Vancomycin is a widely used IV antibiotic due to its broad-spectrum of activity, bactericidal nature, and low rates of resistance; however, adverse effects (AEs), including nephrotoxicity, are commonly associated with its use.1 The vancomycin therapeutic monitoring guidelines recognize the incidence of nephrotoxicity and suggest strategies for reducing the risk, including area under the curve/mean inhibitory concentration (AUC/MIC) monitoring rather than trough-only monitoring. Vancomycin-associated acute kidney injury (AKI) has been defined as an increase in serum creatinine (SCr) over a 48-hour period of ≥ 0.3 mg/dL or a percentage increase of ≥ 50%, which is consistent with the Acute Kidney Injury Network (AKIN) guidelines.2,3 Vancomycin-associated AKI is a common AE, with its incidence reported in previous studies ranging from 10 to 20%.4,5
The most common crystalloid fluid administered to patients in the United States is 0.9% sodium chloride (NaCl), also known as normal saline (NS), and recent trials have explored its potential to cause AEs.6-8 Balanced crystalloid solutions, such as Plasma-Lyte and lactated Ringer’s solution (LR), contain buffering agents and lower concentrations of sodium and chloride compared with that of NS. Trials in the intensive care unit (ICU) and emergency department, such as the SMART-MED, SMART-SURG, and SALT-ED have reported a significantly lower rate of AKI when using balanced crystalloids compared with NS due to the concentration of sodium and chloride in NS being supraphysiologic to normal serum concentrations.6,7 Alternatively, the SPLIT trial evaluated the use of NS compared with Plasma-Lyte for ICU fluid therapy and did not find a statistically significant difference in AKI.8 Furthermore, some studies have reported increased risk for hyperchloremia when using NS compared with dextrose 5% in water (D5W) or balanced crystalloids, which can result in metabolic acidosis.6,7,9,10 These studies have shown how the choice of fluid can have a large effect on the incidence of AEs; bringing into question whether these effects could be additive when combined with the nephrotoxicity associated with vancomycin.6-9
Vancomycin is physically and chemically stable if diluted in D5W, NS, 5% dextrose in NS, LR, or 5% dextrose in LR.1 It is not known whether the selection of diluent has an effect on nephrotoxicity or other AEs of vancomycin therapy. Furthermore, clinicians may be unaware or unable to specify which diluent to use. There are currently no practice guidelines that favor one diluent over another for vancomycin; however, trials showing higher rates of AKI and hyperchloremia using NS for fluid resuscitation may indicate an increased potential for vancomycin-associated AKI when using NS as a diluent.6,7,9 This study was performed to evaluate whether the type of crystalloid used (D5W vs NS) can influence adverse outcomes for patients. While many factors may contribute to these AEs, the potential to reduce the risk of negative adverse outcomes for hospitalized patients is a significant area of exploration.
The primary outcome of this study was the incidence of AKI, defined using AKIN guidelines where the increase in SCr occurred at least 24 hours after starting vancomycin and within 36 hours of receiving the last vancomycin dose.3 AKI was staged using the AKIN guidelines (stage 1: increase in SCr of ≥ 0.3 mg/dL or by 50 to 99%; stage 2: increase in SCr by 100 to 199%; stage 3: increase in SCr by > 200%) based on changes in SCr from baseline during vancomycin therapy or within 36 hours of stopping vancomycin therapy.3 Secondary outcomes included the incidence of hyperglycemia, hyperchloremia, metabolic acidosis, hypernatremia, mortality in hospital, and mortality within 30 days from hospital discharge.
Methods
This single-center, retrospective study of veterans who received IV vancomycin within the North Florida/South Georgia Veterans Health System (NF/SGVHS) in Gainesville, Florida, from July 1, 2015 to June 30, 2020, compared veterans who received vancomycin diluted in NS with those who received vancomycin diluted in D5W to assess for differences in AEs, including AKI, metabolic acidosis (serum bicarbonate level < 23 mmol/L), hyperchloremia (serum chloride levels > 108 mmol/L), hypernatremia (serum sodium > 145 mmol/L), and hyperglycemia (blood glucose > 180 mg/dL). The endpoint values were defined using the reference ranges determined by the local laboratory. At NF/SGVHS, vancomycin is diluted in D5W or NS based primarily on factors such as product availability and cost.
Study Criteria
Veterans were included if they received IV vancomycin between July 1, 2015 and June 30, 2020. The cohorts were grouped into those receiving vancomycin doses diluted in NS and those receiving vancomycin doses diluted in D5W. Veterans were excluded if they received < 80% of vancomycin doses diluted in their respective fluid, if they were on vancomycin for < 48 hours, or if they did not have laboratory results collected both before and after vancomycin therapy to assess a change. There were more patients receiving vancomycin in D5W, so a random sample was selected to have an equal size comparison group with those receiving NS. A sample size calculation was performed with an anticipated AKI incidence of 14%.5 To detect a 10% difference in the primary outcome with an α of 0.05 and 75% power, 226 patients (113 in each cohort) were needed for inclusion.
Data were collected using the Data Access Request Tracker tool through the US Department of Veterans Affairs (VA) Informatics and Computing Infrastructure. Data collected included demographics, laboratory data at baseline and during vancomycin therapy, characteristics of antibiotic therapy, and mortality data. Of note, all laboratory values assessed in this study were obtained while the veteran was receiving vancomycin or within 36 hours of receiving the last vancomycin dose to appropriately assess any changes.
Statistical analysis of categorical data were analyzed using a χ2 test on the GraphPad online program. This study received institutional review board approval from the University of Florida and was conducted in accordance with protections for human subjects.
Results
A total of 792 veterans received IV vancomycin NF/SGVHS in the defined study period. Of these, 381 veterans were excluded, including having < 80% of doses in a single solution (213 veterans), receiving IV vancomycin for < 48 hours (149 veterans), and not having necessary laboratory data available to assess a change in kidney function (19 veterans). An additional 165 veterans were randomly excluded from the D5W cohort in order to have an equal comparison group to the NS cohort; therefore, a total of 246 veterans were included in the final assessment (123 veterans in each cohort). The median patient age was 73 years (IQR, 68.0, 80.5) in the D5W group and 66 years (IQR, 60.0, 74.0) in the NS group; 83.7% of veterans in the D5W group and 74% veterans in the NS group were white; 94.3% of the D5W group and 100% of the NS group were male (Table 1).
The percentage of AKI in the D5W group was 22.8% compared with 14.6% in the NS group (P = .14), and all cases were classified as stage 1 AKI. Baseline cases of hyperglycemia, hypernatremia, hyperchloremia, or metabolic acidosis were not included in the reported rates of each in order to determine a change during vancomycin therapy (Table 2).
The percentage of patients with hyperglycemia in the D5W group was 32.5% compared with 39.8% in the NS group (P = .29). The percentage of patients with hypernatremia in the D5W group was 15.4% compared with 10.6% in the NS group (P = .34). The percentage of patients with hyperchloremia in the D5W group was 22.8% compared with 17.9% in the NS group (P = .43). The percentage of patients with metabolic acidosis in the D5W group was 48.0% compared with 49.6% in the NS group (P = .90).
There were no significant differences in either in-hospital or posthospital mortality between the D5W and NS groups (in-hospital: 4.9% vs 5.7%, respectively; P = .78; 30-day posthospitalization: 8.5% vs 4.5%, respectively; P = .30).
Discussion
This retrospective cohort study comparing the AEs of vancomycin diluted in NS and vancomycin diluted with D5W showed no statistically significant differences in the incidence of AKI or any metabolic AEs. Although these results did not show an association between the incidence of AEs and the dilution fluid for vancomycin, other factors may contribute to the overall incidence of AEs. Factors such as cumulative vancomycin dose, duration of therapy, and presence of concomitant nephrotoxins have been known to increase the incidence of AKI and may have a greater impact on this incidence than the fluid used in administering the vancomycin.
These results specifically the incidence of AKI were not consistent with previous trials evaluating the AEs of NS. Based on previous trials, we expected the vancomycin in the NS cohort to have a significantly higher incidence of hypernatremia, hyperchloremia, and AKI. Our results may indicate that the volume of crystalloid received played a greater role on the incidence of AEs. Our study assessed the effect of a diluent for one IV medication that may have been only a few hundred milliliters of fluid per day. The total volume of IV fluid received from vancomycin was not assessed; thus, it is not known how the volume of fluid may have impacted the results.
One consideration with this study is the method used for monitoring vancomycin levels. Most of the patients included in this study were admitted prior to the release of the updated vancomycin guidelines, which advocated for the transition from traditional trough-only monitoring to AUC/MIC. In September 2019, NF/SGVHS ICUs made the transition to this new method of monitoring with a hospital-wide transition following the study end date. The D5W group had a slightly higher percentage of patients admitted to the ICU, thus were more likely to be monitored using AUC/MIC during this period. Literature has shown the AUC/MIC method of monitoring can result in a decreased daily dose, decreased trough levels, and decreased incidence of nephrotoxicity.11-14 Although the method for monitoring vancomycin has the potential to affect the incidence of AKI, the majority of patients were monitored using the traditional trough-only method with similar trough levels reported in both groups.
Limitations
This study is limited by its retrospective nature, the potential introduction of biases, and the inability to control for confounders that may have influenced the incidence of AEs. Potential confounders present in this study included the use of concomitant nephrotoxic medications, vancomycin dose, and underlying conditions, as these could have impacted the overall incidence of AEs.
The combination of piperacillin/tazobactam plus vancomycin has commonly been associated with an increased risk of nephrotoxicity. Previous studies have identified this nephrotoxic combination to have a significantly increased risk of AKI compared with vancomycin alone or when used in combination with alternative antibiotics such as cefepime or meropenem.15,16 In our study, there was a higher percentage of patients in the NS group with concomitant piperacillin/tazobactam, so this difference between the groups may have influenced the incidence of AKI. Nephrotoxic medications other than antibiotics were not assessed in this study; however, these also could have impacted our results significantly. While the vancomycin duration of therapy and highest trough levels were similar between groups, the NS group had a larger average daily dose and overall cumulative dose. Studies have identified the risk of nephrotoxicity increases with a vancomycin daily dose of 4 g, troughs > 15 mg/mL, and a duration of therapy > 7 days.15,16 In our study, the daily doses in both groups were < 4 g, so it is likely the average daily vancomycin dose had little impact on the incidence of AKI.
Another potential confounder identified was assessment of underlying conditions in the patients. Due to the limitations associated with the data extraction method, we could not assess for underlying conditions that may have impacted the results. Notably, the potential nephrotoxicity of NS has mostly been shown in critically ill patients. Therefore, the mixed acutely ill patient sample in this study may have been less likely to develop AKI from NS compared with an exclusively critically ill patient sample.
Selection bias and information bias are common with observational studies. In our study, selection bias may have been present since prospective randomization of patient samples was not possible. Since all data were extracted from the medical health record, information bias may have been present with the potential to impact the results. Due to the single-center nature of this study with a predominantly older, white male veteran patient sample, generalizability to other patient populations may be limited. We would expect the results of this study to be similar among other patient populations of a similar age and demographic; however, the external validity of this study may be weak among other populations. Although this study included enough patients based on sample size estimate, a larger sample size could have allowed for detection of smaller differences between groups and decreased the chance for type II error.
Conclusions
Overall, the results of this study do not suggest that the crystalloid used to dilute IV vancomycin is associated with differences in nephrotoxicity or other relevant AEs. Future studies evaluating the potential for AEs from medication diluent are warranted and would benefit from a prospective, randomized design. Further studies are both necessary and crucial for enhancing the quality of care to minimize the rates of AEs of commonly used medications.
Acknowledgment
This material is the result of work supported with resources and the use of facilities at the North Florida/South Georgia Veterans Health System in Gainesville, Florida.
1. Vancomycin hydrochloride intravenous injection, pharmacy bulk package. Package insert. Schaumburg, IL: APP Pharmaceuticals, LLC; 2011.
2. Rybak MJ, Le J, Lodise TP, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J Health-System Pharm. 2020;77(11):835-864. doi:10.1093/ajhp/zxaa036
3. Mehta RL, Kellum JA, Shah SV, et al; Acute Kidney Injury Network. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31. doi:10.1186/cc5713
4. Elaysi S, Khalili H, Dashti-Khavidaki S, Mohammadpour A. Vancomycin-induced nephrotoxicity: mechanism, incidence, risk factors and special populations–a literature review. Eur J Clin Pharmacol. 2012;68(9):1243-1255. doi:10.1007/s00228-012-1259-9
5. Gyamlani G, Potukuchi PK, Thomas F, et al. Vancomycin-associated acute kidney injury in a large veteran population. Am J Nephrol. 2019;49(2):133-142. doi:10.1159/000496484
6. Semler MW, Self WH, Wanderer JB, et al; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced crystalloids versus saline in critically ill adults. N Engl Med. 2018;378(9):829-839. doi:10.1056/NEJMoa1711584
7. Self WH, Semler MW, Wanderer JP, et al; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018;378(20):819-828. doi:10.1056/NEJMc1804294
8. Young P, Bailey M, Beasley R, et al; SPLIT Investigators; ANZICS CTG. Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT Randomized Clinical Trial. JAMA. 2015;314(16):1701-1710. doi:10.1001/jama.2015.12334
9. Magee CA, Bastin ML, Bastin T, et al. Insidious harm of medication diluents as a contributor to cumulative volume and hyperchloremia: a prospective, open-label, sequential period pilot study. Crit Care Med. 2018;46(8):1217-1223. doi:10.1097/CCM.0000000000003191
10. Adeva-Andany MM, Fernández-Fernández C, Mouriño-Bayolo D, Castro-Quintela E, Domínguez-Montero A. Sodium bicarbonate therapy in patients with metabolic acidosis. ScientificWorldJournal. 2014;2014:627673. doi:10.1155/2014/627673
11. Mcgrady KA, Benton M, Tart S, Bowers R. Evaluation of traditional vancomycin dosing versus utilizing an electronic AUC/MIC dosing program. Pharm Pract (Granada). 2020;18(3):2024. doi:10.18549/PharmPract.2020.3.2024
12. Clark L, Skrupky LP, Servais R, Brummitt CF, Dilworth TJ. Examining the relationship between vancomycin area under the concentration time curve and serum trough levels in adults with presumed or documented staphylococcal infections. Ther Drug Monit. 2019;41(4):483-488. doi:10.1097/FTD.0000000000000622
13. Neely MN, Kato L, Youn G, et al. Prospective trial on the use of trough concentration versus area under the curve to determine therapeutic vancomycin dosing. Antimicrob Agents Chemother. 2018;62(2):e02042-17. doi:10.1128/AAC.02042-17
14. Aljefri DM, Avedissian SN, Youn G, et al. Vancomycin area under the curve and acute kidney injury: a meta-analysis. Clin Infect Dis. 2019;69(11):1881-1887. doi:10.1128/AAC.02042-17
15. Molina KC, Barletta JF, Hall ST, Yazdani C, Huang V. The risk of acute kidney injury in critically ill patients receiving concomitant vancomycin with piperacillin-tazobactam or cefepime. J Intensive Care Med. 2019;35(12):1434-1438. doi:10.1177/0885066619828290
16. Burgess LD, Drew RH. Comparison of the incidence of vancomycin-induced nephrotoxicity in hospitalized patients with and without concomitant piperacillin-tazobactam. Pharmacotherapy. 2014; 34(7):670-676. doi:10.1002/phar.1442
Vancomycin is a widely used IV antibiotic due to its broad-spectrum of activity, bactericidal nature, and low rates of resistance; however, adverse effects (AEs), including nephrotoxicity, are commonly associated with its use.1 The vancomycin therapeutic monitoring guidelines recognize the incidence of nephrotoxicity and suggest strategies for reducing the risk, including area under the curve/mean inhibitory concentration (AUC/MIC) monitoring rather than trough-only monitoring. Vancomycin-associated acute kidney injury (AKI) has been defined as an increase in serum creatinine (SCr) over a 48-hour period of ≥ 0.3 mg/dL or a percentage increase of ≥ 50%, which is consistent with the Acute Kidney Injury Network (AKIN) guidelines.2,3 Vancomycin-associated AKI is a common AE, with its incidence reported in previous studies ranging from 10 to 20%.4,5
The most common crystalloid fluid administered to patients in the United States is 0.9% sodium chloride (NaCl), also known as normal saline (NS), and recent trials have explored its potential to cause AEs.6-8 Balanced crystalloid solutions, such as Plasma-Lyte and lactated Ringer’s solution (LR), contain buffering agents and lower concentrations of sodium and chloride compared with that of NS. Trials in the intensive care unit (ICU) and emergency department, such as the SMART-MED, SMART-SURG, and SALT-ED have reported a significantly lower rate of AKI when using balanced crystalloids compared with NS due to the concentration of sodium and chloride in NS being supraphysiologic to normal serum concentrations.6,7 Alternatively, the SPLIT trial evaluated the use of NS compared with Plasma-Lyte for ICU fluid therapy and did not find a statistically significant difference in AKI.8 Furthermore, some studies have reported increased risk for hyperchloremia when using NS compared with dextrose 5% in water (D5W) or balanced crystalloids, which can result in metabolic acidosis.6,7,9,10 These studies have shown how the choice of fluid can have a large effect on the incidence of AEs; bringing into question whether these effects could be additive when combined with the nephrotoxicity associated with vancomycin.6-9
Vancomycin is physically and chemically stable if diluted in D5W, NS, 5% dextrose in NS, LR, or 5% dextrose in LR.1 It is not known whether the selection of diluent has an effect on nephrotoxicity or other AEs of vancomycin therapy. Furthermore, clinicians may be unaware or unable to specify which diluent to use. There are currently no practice guidelines that favor one diluent over another for vancomycin; however, trials showing higher rates of AKI and hyperchloremia using NS for fluid resuscitation may indicate an increased potential for vancomycin-associated AKI when using NS as a diluent.6,7,9 This study was performed to evaluate whether the type of crystalloid used (D5W vs NS) can influence adverse outcomes for patients. While many factors may contribute to these AEs, the potential to reduce the risk of negative adverse outcomes for hospitalized patients is a significant area of exploration.
The primary outcome of this study was the incidence of AKI, defined using AKIN guidelines where the increase in SCr occurred at least 24 hours after starting vancomycin and within 36 hours of receiving the last vancomycin dose.3 AKI was staged using the AKIN guidelines (stage 1: increase in SCr of ≥ 0.3 mg/dL or by 50 to 99%; stage 2: increase in SCr by 100 to 199%; stage 3: increase in SCr by > 200%) based on changes in SCr from baseline during vancomycin therapy or within 36 hours of stopping vancomycin therapy.3 Secondary outcomes included the incidence of hyperglycemia, hyperchloremia, metabolic acidosis, hypernatremia, mortality in hospital, and mortality within 30 days from hospital discharge.
Methods
This single-center, retrospective study of veterans who received IV vancomycin within the North Florida/South Georgia Veterans Health System (NF/SGVHS) in Gainesville, Florida, from July 1, 2015 to June 30, 2020, compared veterans who received vancomycin diluted in NS with those who received vancomycin diluted in D5W to assess for differences in AEs, including AKI, metabolic acidosis (serum bicarbonate level < 23 mmol/L), hyperchloremia (serum chloride levels > 108 mmol/L), hypernatremia (serum sodium > 145 mmol/L), and hyperglycemia (blood glucose > 180 mg/dL). The endpoint values were defined using the reference ranges determined by the local laboratory. At NF/SGVHS, vancomycin is diluted in D5W or NS based primarily on factors such as product availability and cost.
Study Criteria
Veterans were included if they received IV vancomycin between July 1, 2015 and June 30, 2020. The cohorts were grouped into those receiving vancomycin doses diluted in NS and those receiving vancomycin doses diluted in D5W. Veterans were excluded if they received < 80% of vancomycin doses diluted in their respective fluid, if they were on vancomycin for < 48 hours, or if they did not have laboratory results collected both before and after vancomycin therapy to assess a change. There were more patients receiving vancomycin in D5W, so a random sample was selected to have an equal size comparison group with those receiving NS. A sample size calculation was performed with an anticipated AKI incidence of 14%.5 To detect a 10% difference in the primary outcome with an α of 0.05 and 75% power, 226 patients (113 in each cohort) were needed for inclusion.
Data were collected using the Data Access Request Tracker tool through the US Department of Veterans Affairs (VA) Informatics and Computing Infrastructure. Data collected included demographics, laboratory data at baseline and during vancomycin therapy, characteristics of antibiotic therapy, and mortality data. Of note, all laboratory values assessed in this study were obtained while the veteran was receiving vancomycin or within 36 hours of receiving the last vancomycin dose to appropriately assess any changes.
Statistical analysis of categorical data were analyzed using a χ2 test on the GraphPad online program. This study received institutional review board approval from the University of Florida and was conducted in accordance with protections for human subjects.
Results
A total of 792 veterans received IV vancomycin NF/SGVHS in the defined study period. Of these, 381 veterans were excluded, including having < 80% of doses in a single solution (213 veterans), receiving IV vancomycin for < 48 hours (149 veterans), and not having necessary laboratory data available to assess a change in kidney function (19 veterans). An additional 165 veterans were randomly excluded from the D5W cohort in order to have an equal comparison group to the NS cohort; therefore, a total of 246 veterans were included in the final assessment (123 veterans in each cohort). The median patient age was 73 years (IQR, 68.0, 80.5) in the D5W group and 66 years (IQR, 60.0, 74.0) in the NS group; 83.7% of veterans in the D5W group and 74% veterans in the NS group were white; 94.3% of the D5W group and 100% of the NS group were male (Table 1).
The percentage of AKI in the D5W group was 22.8% compared with 14.6% in the NS group (P = .14), and all cases were classified as stage 1 AKI. Baseline cases of hyperglycemia, hypernatremia, hyperchloremia, or metabolic acidosis were not included in the reported rates of each in order to determine a change during vancomycin therapy (Table 2).
The percentage of patients with hyperglycemia in the D5W group was 32.5% compared with 39.8% in the NS group (P = .29). The percentage of patients with hypernatremia in the D5W group was 15.4% compared with 10.6% in the NS group (P = .34). The percentage of patients with hyperchloremia in the D5W group was 22.8% compared with 17.9% in the NS group (P = .43). The percentage of patients with metabolic acidosis in the D5W group was 48.0% compared with 49.6% in the NS group (P = .90).
There were no significant differences in either in-hospital or posthospital mortality between the D5W and NS groups (in-hospital: 4.9% vs 5.7%, respectively; P = .78; 30-day posthospitalization: 8.5% vs 4.5%, respectively; P = .30).
Discussion
This retrospective cohort study comparing the AEs of vancomycin diluted in NS and vancomycin diluted with D5W showed no statistically significant differences in the incidence of AKI or any metabolic AEs. Although these results did not show an association between the incidence of AEs and the dilution fluid for vancomycin, other factors may contribute to the overall incidence of AEs. Factors such as cumulative vancomycin dose, duration of therapy, and presence of concomitant nephrotoxins have been known to increase the incidence of AKI and may have a greater impact on this incidence than the fluid used in administering the vancomycin.
These results specifically the incidence of AKI were not consistent with previous trials evaluating the AEs of NS. Based on previous trials, we expected the vancomycin in the NS cohort to have a significantly higher incidence of hypernatremia, hyperchloremia, and AKI. Our results may indicate that the volume of crystalloid received played a greater role on the incidence of AEs. Our study assessed the effect of a diluent for one IV medication that may have been only a few hundred milliliters of fluid per day. The total volume of IV fluid received from vancomycin was not assessed; thus, it is not known how the volume of fluid may have impacted the results.
One consideration with this study is the method used for monitoring vancomycin levels. Most of the patients included in this study were admitted prior to the release of the updated vancomycin guidelines, which advocated for the transition from traditional trough-only monitoring to AUC/MIC. In September 2019, NF/SGVHS ICUs made the transition to this new method of monitoring with a hospital-wide transition following the study end date. The D5W group had a slightly higher percentage of patients admitted to the ICU, thus were more likely to be monitored using AUC/MIC during this period. Literature has shown the AUC/MIC method of monitoring can result in a decreased daily dose, decreased trough levels, and decreased incidence of nephrotoxicity.11-14 Although the method for monitoring vancomycin has the potential to affect the incidence of AKI, the majority of patients were monitored using the traditional trough-only method with similar trough levels reported in both groups.
Limitations
This study is limited by its retrospective nature, the potential introduction of biases, and the inability to control for confounders that may have influenced the incidence of AEs. Potential confounders present in this study included the use of concomitant nephrotoxic medications, vancomycin dose, and underlying conditions, as these could have impacted the overall incidence of AEs.
The combination of piperacillin/tazobactam plus vancomycin has commonly been associated with an increased risk of nephrotoxicity. Previous studies have identified this nephrotoxic combination to have a significantly increased risk of AKI compared with vancomycin alone or when used in combination with alternative antibiotics such as cefepime or meropenem.15,16 In our study, there was a higher percentage of patients in the NS group with concomitant piperacillin/tazobactam, so this difference between the groups may have influenced the incidence of AKI. Nephrotoxic medications other than antibiotics were not assessed in this study; however, these also could have impacted our results significantly. While the vancomycin duration of therapy and highest trough levels were similar between groups, the NS group had a larger average daily dose and overall cumulative dose. Studies have identified the risk of nephrotoxicity increases with a vancomycin daily dose of 4 g, troughs > 15 mg/mL, and a duration of therapy > 7 days.15,16 In our study, the daily doses in both groups were < 4 g, so it is likely the average daily vancomycin dose had little impact on the incidence of AKI.
Another potential confounder identified was assessment of underlying conditions in the patients. Due to the limitations associated with the data extraction method, we could not assess for underlying conditions that may have impacted the results. Notably, the potential nephrotoxicity of NS has mostly been shown in critically ill patients. Therefore, the mixed acutely ill patient sample in this study may have been less likely to develop AKI from NS compared with an exclusively critically ill patient sample.
Selection bias and information bias are common with observational studies. In our study, selection bias may have been present since prospective randomization of patient samples was not possible. Since all data were extracted from the medical health record, information bias may have been present with the potential to impact the results. Due to the single-center nature of this study with a predominantly older, white male veteran patient sample, generalizability to other patient populations may be limited. We would expect the results of this study to be similar among other patient populations of a similar age and demographic; however, the external validity of this study may be weak among other populations. Although this study included enough patients based on sample size estimate, a larger sample size could have allowed for detection of smaller differences between groups and decreased the chance for type II error.
Conclusions
Overall, the results of this study do not suggest that the crystalloid used to dilute IV vancomycin is associated with differences in nephrotoxicity or other relevant AEs. Future studies evaluating the potential for AEs from medication diluent are warranted and would benefit from a prospective, randomized design. Further studies are both necessary and crucial for enhancing the quality of care to minimize the rates of AEs of commonly used medications.
Acknowledgment
This material is the result of work supported with resources and the use of facilities at the North Florida/South Georgia Veterans Health System in Gainesville, Florida.
Vancomycin is a widely used IV antibiotic due to its broad-spectrum of activity, bactericidal nature, and low rates of resistance; however, adverse effects (AEs), including nephrotoxicity, are commonly associated with its use.1 The vancomycin therapeutic monitoring guidelines recognize the incidence of nephrotoxicity and suggest strategies for reducing the risk, including area under the curve/mean inhibitory concentration (AUC/MIC) monitoring rather than trough-only monitoring. Vancomycin-associated acute kidney injury (AKI) has been defined as an increase in serum creatinine (SCr) over a 48-hour period of ≥ 0.3 mg/dL or a percentage increase of ≥ 50%, which is consistent with the Acute Kidney Injury Network (AKIN) guidelines.2,3 Vancomycin-associated AKI is a common AE, with its incidence reported in previous studies ranging from 10 to 20%.4,5
The most common crystalloid fluid administered to patients in the United States is 0.9% sodium chloride (NaCl), also known as normal saline (NS), and recent trials have explored its potential to cause AEs.6-8 Balanced crystalloid solutions, such as Plasma-Lyte and lactated Ringer’s solution (LR), contain buffering agents and lower concentrations of sodium and chloride compared with that of NS. Trials in the intensive care unit (ICU) and emergency department, such as the SMART-MED, SMART-SURG, and SALT-ED have reported a significantly lower rate of AKI when using balanced crystalloids compared with NS due to the concentration of sodium and chloride in NS being supraphysiologic to normal serum concentrations.6,7 Alternatively, the SPLIT trial evaluated the use of NS compared with Plasma-Lyte for ICU fluid therapy and did not find a statistically significant difference in AKI.8 Furthermore, some studies have reported increased risk for hyperchloremia when using NS compared with dextrose 5% in water (D5W) or balanced crystalloids, which can result in metabolic acidosis.6,7,9,10 These studies have shown how the choice of fluid can have a large effect on the incidence of AEs; bringing into question whether these effects could be additive when combined with the nephrotoxicity associated with vancomycin.6-9
Vancomycin is physically and chemically stable if diluted in D5W, NS, 5% dextrose in NS, LR, or 5% dextrose in LR.1 It is not known whether the selection of diluent has an effect on nephrotoxicity or other AEs of vancomycin therapy. Furthermore, clinicians may be unaware or unable to specify which diluent to use. There are currently no practice guidelines that favor one diluent over another for vancomycin; however, trials showing higher rates of AKI and hyperchloremia using NS for fluid resuscitation may indicate an increased potential for vancomycin-associated AKI when using NS as a diluent.6,7,9 This study was performed to evaluate whether the type of crystalloid used (D5W vs NS) can influence adverse outcomes for patients. While many factors may contribute to these AEs, the potential to reduce the risk of negative adverse outcomes for hospitalized patients is a significant area of exploration.
The primary outcome of this study was the incidence of AKI, defined using AKIN guidelines where the increase in SCr occurred at least 24 hours after starting vancomycin and within 36 hours of receiving the last vancomycin dose.3 AKI was staged using the AKIN guidelines (stage 1: increase in SCr of ≥ 0.3 mg/dL or by 50 to 99%; stage 2: increase in SCr by 100 to 199%; stage 3: increase in SCr by > 200%) based on changes in SCr from baseline during vancomycin therapy or within 36 hours of stopping vancomycin therapy.3 Secondary outcomes included the incidence of hyperglycemia, hyperchloremia, metabolic acidosis, hypernatremia, mortality in hospital, and mortality within 30 days from hospital discharge.
Methods
This single-center, retrospective study of veterans who received IV vancomycin within the North Florida/South Georgia Veterans Health System (NF/SGVHS) in Gainesville, Florida, from July 1, 2015 to June 30, 2020, compared veterans who received vancomycin diluted in NS with those who received vancomycin diluted in D5W to assess for differences in AEs, including AKI, metabolic acidosis (serum bicarbonate level < 23 mmol/L), hyperchloremia (serum chloride levels > 108 mmol/L), hypernatremia (serum sodium > 145 mmol/L), and hyperglycemia (blood glucose > 180 mg/dL). The endpoint values were defined using the reference ranges determined by the local laboratory. At NF/SGVHS, vancomycin is diluted in D5W or NS based primarily on factors such as product availability and cost.
Study Criteria
Veterans were included if they received IV vancomycin between July 1, 2015 and June 30, 2020. The cohorts were grouped into those receiving vancomycin doses diluted in NS and those receiving vancomycin doses diluted in D5W. Veterans were excluded if they received < 80% of vancomycin doses diluted in their respective fluid, if they were on vancomycin for < 48 hours, or if they did not have laboratory results collected both before and after vancomycin therapy to assess a change. There were more patients receiving vancomycin in D5W, so a random sample was selected to have an equal size comparison group with those receiving NS. A sample size calculation was performed with an anticipated AKI incidence of 14%.5 To detect a 10% difference in the primary outcome with an α of 0.05 and 75% power, 226 patients (113 in each cohort) were needed for inclusion.
Data were collected using the Data Access Request Tracker tool through the US Department of Veterans Affairs (VA) Informatics and Computing Infrastructure. Data collected included demographics, laboratory data at baseline and during vancomycin therapy, characteristics of antibiotic therapy, and mortality data. Of note, all laboratory values assessed in this study were obtained while the veteran was receiving vancomycin or within 36 hours of receiving the last vancomycin dose to appropriately assess any changes.
Statistical analysis of categorical data were analyzed using a χ2 test on the GraphPad online program. This study received institutional review board approval from the University of Florida and was conducted in accordance with protections for human subjects.
Results
A total of 792 veterans received IV vancomycin NF/SGVHS in the defined study period. Of these, 381 veterans were excluded, including having < 80% of doses in a single solution (213 veterans), receiving IV vancomycin for < 48 hours (149 veterans), and not having necessary laboratory data available to assess a change in kidney function (19 veterans). An additional 165 veterans were randomly excluded from the D5W cohort in order to have an equal comparison group to the NS cohort; therefore, a total of 246 veterans were included in the final assessment (123 veterans in each cohort). The median patient age was 73 years (IQR, 68.0, 80.5) in the D5W group and 66 years (IQR, 60.0, 74.0) in the NS group; 83.7% of veterans in the D5W group and 74% veterans in the NS group were white; 94.3% of the D5W group and 100% of the NS group were male (Table 1).
The percentage of AKI in the D5W group was 22.8% compared with 14.6% in the NS group (P = .14), and all cases were classified as stage 1 AKI. Baseline cases of hyperglycemia, hypernatremia, hyperchloremia, or metabolic acidosis were not included in the reported rates of each in order to determine a change during vancomycin therapy (Table 2).
The percentage of patients with hyperglycemia in the D5W group was 32.5% compared with 39.8% in the NS group (P = .29). The percentage of patients with hypernatremia in the D5W group was 15.4% compared with 10.6% in the NS group (P = .34). The percentage of patients with hyperchloremia in the D5W group was 22.8% compared with 17.9% in the NS group (P = .43). The percentage of patients with metabolic acidosis in the D5W group was 48.0% compared with 49.6% in the NS group (P = .90).
There were no significant differences in either in-hospital or posthospital mortality between the D5W and NS groups (in-hospital: 4.9% vs 5.7%, respectively; P = .78; 30-day posthospitalization: 8.5% vs 4.5%, respectively; P = .30).
Discussion
This retrospective cohort study comparing the AEs of vancomycin diluted in NS and vancomycin diluted with D5W showed no statistically significant differences in the incidence of AKI or any metabolic AEs. Although these results did not show an association between the incidence of AEs and the dilution fluid for vancomycin, other factors may contribute to the overall incidence of AEs. Factors such as cumulative vancomycin dose, duration of therapy, and presence of concomitant nephrotoxins have been known to increase the incidence of AKI and may have a greater impact on this incidence than the fluid used in administering the vancomycin.
These results specifically the incidence of AKI were not consistent with previous trials evaluating the AEs of NS. Based on previous trials, we expected the vancomycin in the NS cohort to have a significantly higher incidence of hypernatremia, hyperchloremia, and AKI. Our results may indicate that the volume of crystalloid received played a greater role on the incidence of AEs. Our study assessed the effect of a diluent for one IV medication that may have been only a few hundred milliliters of fluid per day. The total volume of IV fluid received from vancomycin was not assessed; thus, it is not known how the volume of fluid may have impacted the results.
One consideration with this study is the method used for monitoring vancomycin levels. Most of the patients included in this study were admitted prior to the release of the updated vancomycin guidelines, which advocated for the transition from traditional trough-only monitoring to AUC/MIC. In September 2019, NF/SGVHS ICUs made the transition to this new method of monitoring with a hospital-wide transition following the study end date. The D5W group had a slightly higher percentage of patients admitted to the ICU, thus were more likely to be monitored using AUC/MIC during this period. Literature has shown the AUC/MIC method of monitoring can result in a decreased daily dose, decreased trough levels, and decreased incidence of nephrotoxicity.11-14 Although the method for monitoring vancomycin has the potential to affect the incidence of AKI, the majority of patients were monitored using the traditional trough-only method with similar trough levels reported in both groups.
Limitations
This study is limited by its retrospective nature, the potential introduction of biases, and the inability to control for confounders that may have influenced the incidence of AEs. Potential confounders present in this study included the use of concomitant nephrotoxic medications, vancomycin dose, and underlying conditions, as these could have impacted the overall incidence of AEs.
The combination of piperacillin/tazobactam plus vancomycin has commonly been associated with an increased risk of nephrotoxicity. Previous studies have identified this nephrotoxic combination to have a significantly increased risk of AKI compared with vancomycin alone or when used in combination with alternative antibiotics such as cefepime or meropenem.15,16 In our study, there was a higher percentage of patients in the NS group with concomitant piperacillin/tazobactam, so this difference between the groups may have influenced the incidence of AKI. Nephrotoxic medications other than antibiotics were not assessed in this study; however, these also could have impacted our results significantly. While the vancomycin duration of therapy and highest trough levels were similar between groups, the NS group had a larger average daily dose and overall cumulative dose. Studies have identified the risk of nephrotoxicity increases with a vancomycin daily dose of 4 g, troughs > 15 mg/mL, and a duration of therapy > 7 days.15,16 In our study, the daily doses in both groups were < 4 g, so it is likely the average daily vancomycin dose had little impact on the incidence of AKI.
Another potential confounder identified was assessment of underlying conditions in the patients. Due to the limitations associated with the data extraction method, we could not assess for underlying conditions that may have impacted the results. Notably, the potential nephrotoxicity of NS has mostly been shown in critically ill patients. Therefore, the mixed acutely ill patient sample in this study may have been less likely to develop AKI from NS compared with an exclusively critically ill patient sample.
Selection bias and information bias are common with observational studies. In our study, selection bias may have been present since prospective randomization of patient samples was not possible. Since all data were extracted from the medical health record, information bias may have been present with the potential to impact the results. Due to the single-center nature of this study with a predominantly older, white male veteran patient sample, generalizability to other patient populations may be limited. We would expect the results of this study to be similar among other patient populations of a similar age and demographic; however, the external validity of this study may be weak among other populations. Although this study included enough patients based on sample size estimate, a larger sample size could have allowed for detection of smaller differences between groups and decreased the chance for type II error.
Conclusions
Overall, the results of this study do not suggest that the crystalloid used to dilute IV vancomycin is associated with differences in nephrotoxicity or other relevant AEs. Future studies evaluating the potential for AEs from medication diluent are warranted and would benefit from a prospective, randomized design. Further studies are both necessary and crucial for enhancing the quality of care to minimize the rates of AEs of commonly used medications.
Acknowledgment
This material is the result of work supported with resources and the use of facilities at the North Florida/South Georgia Veterans Health System in Gainesville, Florida.
1. Vancomycin hydrochloride intravenous injection, pharmacy bulk package. Package insert. Schaumburg, IL: APP Pharmaceuticals, LLC; 2011.
2. Rybak MJ, Le J, Lodise TP, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J Health-System Pharm. 2020;77(11):835-864. doi:10.1093/ajhp/zxaa036
3. Mehta RL, Kellum JA, Shah SV, et al; Acute Kidney Injury Network. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31. doi:10.1186/cc5713
4. Elaysi S, Khalili H, Dashti-Khavidaki S, Mohammadpour A. Vancomycin-induced nephrotoxicity: mechanism, incidence, risk factors and special populations–a literature review. Eur J Clin Pharmacol. 2012;68(9):1243-1255. doi:10.1007/s00228-012-1259-9
5. Gyamlani G, Potukuchi PK, Thomas F, et al. Vancomycin-associated acute kidney injury in a large veteran population. Am J Nephrol. 2019;49(2):133-142. doi:10.1159/000496484
6. Semler MW, Self WH, Wanderer JB, et al; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced crystalloids versus saline in critically ill adults. N Engl Med. 2018;378(9):829-839. doi:10.1056/NEJMoa1711584
7. Self WH, Semler MW, Wanderer JP, et al; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018;378(20):819-828. doi:10.1056/NEJMc1804294
8. Young P, Bailey M, Beasley R, et al; SPLIT Investigators; ANZICS CTG. Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT Randomized Clinical Trial. JAMA. 2015;314(16):1701-1710. doi:10.1001/jama.2015.12334
9. Magee CA, Bastin ML, Bastin T, et al. Insidious harm of medication diluents as a contributor to cumulative volume and hyperchloremia: a prospective, open-label, sequential period pilot study. Crit Care Med. 2018;46(8):1217-1223. doi:10.1097/CCM.0000000000003191
10. Adeva-Andany MM, Fernández-Fernández C, Mouriño-Bayolo D, Castro-Quintela E, Domínguez-Montero A. Sodium bicarbonate therapy in patients with metabolic acidosis. ScientificWorldJournal. 2014;2014:627673. doi:10.1155/2014/627673
11. Mcgrady KA, Benton M, Tart S, Bowers R. Evaluation of traditional vancomycin dosing versus utilizing an electronic AUC/MIC dosing program. Pharm Pract (Granada). 2020;18(3):2024. doi:10.18549/PharmPract.2020.3.2024
12. Clark L, Skrupky LP, Servais R, Brummitt CF, Dilworth TJ. Examining the relationship between vancomycin area under the concentration time curve and serum trough levels in adults with presumed or documented staphylococcal infections. Ther Drug Monit. 2019;41(4):483-488. doi:10.1097/FTD.0000000000000622
13. Neely MN, Kato L, Youn G, et al. Prospective trial on the use of trough concentration versus area under the curve to determine therapeutic vancomycin dosing. Antimicrob Agents Chemother. 2018;62(2):e02042-17. doi:10.1128/AAC.02042-17
14. Aljefri DM, Avedissian SN, Youn G, et al. Vancomycin area under the curve and acute kidney injury: a meta-analysis. Clin Infect Dis. 2019;69(11):1881-1887. doi:10.1128/AAC.02042-17
15. Molina KC, Barletta JF, Hall ST, Yazdani C, Huang V. The risk of acute kidney injury in critically ill patients receiving concomitant vancomycin with piperacillin-tazobactam or cefepime. J Intensive Care Med. 2019;35(12):1434-1438. doi:10.1177/0885066619828290
16. Burgess LD, Drew RH. Comparison of the incidence of vancomycin-induced nephrotoxicity in hospitalized patients with and without concomitant piperacillin-tazobactam. Pharmacotherapy. 2014; 34(7):670-676. doi:10.1002/phar.1442
1. Vancomycin hydrochloride intravenous injection, pharmacy bulk package. Package insert. Schaumburg, IL: APP Pharmaceuticals, LLC; 2011.
2. Rybak MJ, Le J, Lodise TP, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J Health-System Pharm. 2020;77(11):835-864. doi:10.1093/ajhp/zxaa036
3. Mehta RL, Kellum JA, Shah SV, et al; Acute Kidney Injury Network. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31. doi:10.1186/cc5713
4. Elaysi S, Khalili H, Dashti-Khavidaki S, Mohammadpour A. Vancomycin-induced nephrotoxicity: mechanism, incidence, risk factors and special populations–a literature review. Eur J Clin Pharmacol. 2012;68(9):1243-1255. doi:10.1007/s00228-012-1259-9
5. Gyamlani G, Potukuchi PK, Thomas F, et al. Vancomycin-associated acute kidney injury in a large veteran population. Am J Nephrol. 2019;49(2):133-142. doi:10.1159/000496484
6. Semler MW, Self WH, Wanderer JB, et al; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced crystalloids versus saline in critically ill adults. N Engl Med. 2018;378(9):829-839. doi:10.1056/NEJMoa1711584
7. Self WH, Semler MW, Wanderer JP, et al; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018;378(20):819-828. doi:10.1056/NEJMc1804294
8. Young P, Bailey M, Beasley R, et al; SPLIT Investigators; ANZICS CTG. Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT Randomized Clinical Trial. JAMA. 2015;314(16):1701-1710. doi:10.1001/jama.2015.12334
9. Magee CA, Bastin ML, Bastin T, et al. Insidious harm of medication diluents as a contributor to cumulative volume and hyperchloremia: a prospective, open-label, sequential period pilot study. Crit Care Med. 2018;46(8):1217-1223. doi:10.1097/CCM.0000000000003191
10. Adeva-Andany MM, Fernández-Fernández C, Mouriño-Bayolo D, Castro-Quintela E, Domínguez-Montero A. Sodium bicarbonate therapy in patients with metabolic acidosis. ScientificWorldJournal. 2014;2014:627673. doi:10.1155/2014/627673
11. Mcgrady KA, Benton M, Tart S, Bowers R. Evaluation of traditional vancomycin dosing versus utilizing an electronic AUC/MIC dosing program. Pharm Pract (Granada). 2020;18(3):2024. doi:10.18549/PharmPract.2020.3.2024
12. Clark L, Skrupky LP, Servais R, Brummitt CF, Dilworth TJ. Examining the relationship between vancomycin area under the concentration time curve and serum trough levels in adults with presumed or documented staphylococcal infections. Ther Drug Monit. 2019;41(4):483-488. doi:10.1097/FTD.0000000000000622
13. Neely MN, Kato L, Youn G, et al. Prospective trial on the use of trough concentration versus area under the curve to determine therapeutic vancomycin dosing. Antimicrob Agents Chemother. 2018;62(2):e02042-17. doi:10.1128/AAC.02042-17
14. Aljefri DM, Avedissian SN, Youn G, et al. Vancomycin area under the curve and acute kidney injury: a meta-analysis. Clin Infect Dis. 2019;69(11):1881-1887. doi:10.1128/AAC.02042-17
15. Molina KC, Barletta JF, Hall ST, Yazdani C, Huang V. The risk of acute kidney injury in critically ill patients receiving concomitant vancomycin with piperacillin-tazobactam or cefepime. J Intensive Care Med. 2019;35(12):1434-1438. doi:10.1177/0885066619828290
16. Burgess LD, Drew RH. Comparison of the incidence of vancomycin-induced nephrotoxicity in hospitalized patients with and without concomitant piperacillin-tazobactam. Pharmacotherapy. 2014; 34(7):670-676. doi:10.1002/phar.1442
Enhancing Access to Yoga for Older Male Veterans After Cancer: Examining Beliefs About Yoga
Yoga is an effective clinical intervention for cancer survivors. Studies indicate a wide range of benefits, including improvements in physical functioning, emotional well-being and overall quality of life.1-7 Two-thirds of National Cancer Institute designated comprehensive cancer centers offer yoga on-site.8 Yoga is endorsed by the National Comprehensive Cancer Network and American Society of Clinical Oncology for managing symptoms, such as cancer-related anxiety and depression and for improving overall quality of life.9,10
Although the positive effects of yoga on cancer patients are well studied, most published research in this area reports on predominantly middle-aged women with breast cancer.11,12 Less is known about the use of yoga in other groups of cancer patients, such as older adults, veterans, and those from diverse racial or ethnic backgrounds. This gap in the literature is concerning considering that the majority of cancer survivors are aged 60 years or older, and veterans face unique risk factors for cancer associated with herbicide exposure (eg, Agent Orange) and other military-related noxious exposures.13,14 Older cancer survivors may have more difficulty recovering from treatment-related adverse effects, making it especially important to target recovery efforts to older adults.15 Yoga can be adapted for older cancer survivors with age-related comorbidities, similar to adaptations made for older adults who are not cancer survivors but require accommodations for physical limitations.16-20 Similarly, yoga programs targeted to racially diverse cancer survivors are associated with improved mood and well-being in racially diverse cancer survivors, but studies suggest community engagement and cultural adaptation may be important to address the needs of culturally diverse cancer survivors.21-23
Yoga has been increasingly studied within the Veterans Health Administration (VHA) for treatment of posttraumatic stress disorder (PTSD) and has been found effective in reducing symptoms through the use of trauma-informed and military-relevant instruction as well as a military veteran yoga teacher.24-26 This work has not targeted older veterans or cancer survivors who may be more difficult to recruit into such programs, but who would nevertheless benefit.
Clinically, the VHA whole health model is providing increased opportunities for veterans to engage in holistic care including yoga.27 Resources include in-person yoga classes (varies by facility), videos, and handouts with practices uniquely designed for veterans or wounded warriors. As clinicians increasingly refer veterans to these programs, it will be important to develop strategies to engage older veterans in these services.
One important strategy to enhancing access to yoga for older veterans is to consider beliefs about yoga. Beliefs about yoga or general expectations about the outcomes of yoga may be critical to consider in expanding access to yoga in underrepresented groups. Beliefs about yoga may include beliefs about yoga improving health, yoga being difficult or producing discomfort, and yoga involving specific social norms.28 For example, confidence in one’s ability to perform yoga despite discomfort predicted class attendance and practice in a sample of 32 breast cancer survivors.29 Relatedly, positive beliefs about the impact of yoga on health were associated with improvements in mood and quality of life in a sample of 66 cancer survivors.30
The aim of this study was to examine avenues to enhance access to yoga for older veterans, including those from diverse backgrounds, with a focus on the role of beliefs. In the first study we investigate the association between beliefs about and barriers to yoga in a group of older cancer survivors, and we consider the role of demographic and clinical variables in such beliefs and how education may alter beliefs. In alignment with the whole health model of holistic health, we posit that yoga educational materials and resources may contribute to yoga beliefs and work to decrease these barriers. We apply these findings in a second study that enrolled older veterans in yoga and examining the impact of program participation on beliefs and the role of beliefs in program outcomes. In the discussion we return to consider how to increase access to yoga to older veterans based on these findings.
Methods
Study 1 participants were identified from VHA tumor registries. Eligible patients had head and neck, esophageal, gastric, or colorectal cancers and were excluded if they were in hospice care, had dementia, or had a psychotic spectrum disorder. Participants completed a face-to-face semistructured interview at 6, 12, and 18 months after their cancer diagnosis with a trained interviewer. Complete protocol methods, including nonresponder information, are described elsewhere.31
Questions about yoga were asked at the 12 month postdiagnosis interview. Participants were read the following: “Here is a list of services some patients use to recover from cancer. Please tell me if you have used any of these.” The list included yoga, physical therapy, occupational therapy, exercise, meditation, or massage therapy. Next participants were provided education about yoga via the following description: “Yoga is a practice of stress reduction and exercise with stretching, holding positions and deep breathing. For some, it may improve your sleep, energy, flexibility, anxiety, and pain. The postures are done standing, sitting, or lying down. If needed, it can be done all from a chair.” We then asked whether they would attend if yoga was offered at the VHA hospital (yes, no, maybe). Participants provided brief responses to 2 open-ended questions: (“If I came to a yoga class, I …”; and “Is there anything that might make you more likely to come to a yoga class?”) Responses were transcribed verbatim and entered into a database for qualitative analysis. Subsequently, participants completed standardized measures of health-related quality of life and beliefs about yoga as described below.
Study 2 participants were identified from VHA tumor registries and a cancer support group. Eligible patients had a diagnosis of cancer (any type except basil cell carcinoma) within the previous 3 years and were excluded if they were in hospice care, had dementia, or had a psychotic spectrum disorder. Participants completed face-to-face semistructured interviews with a trained interviewer before and after participation in an 8-week yoga group that met twice per week. Complete protocol methods are described elsewhere.16 This paper focuses on 28 of the 37 enrolled patients for whom we have complete pre- and postclass interview data. We previously reported on adaptations made to yoga in our pilot group of 14 individuals, who in this small sample did not show statistically significant changes in their quality of life from before to after the class.16 This analysis includes those 14 individuals and 14 who participated in additional classes, focusing on beliefs, which were not previously reported.
Measures
Participants reported their age, gender, ethnicity (Hispanic/Latino or not), race, and level of education. Information about the cancer diagnosis, American Joint Committee on Cancer (AJCC) cancer stage, and treatments was obtained from the medical record. The Physical Function and Anxiety Subscales from the Patient-Reported Outcomes Measurement Information System were used to measure health-related quality of life (HRQoL).32-34 Items are rated on a Likert scale from 1 (not at all) to 5 (very much).
The Beliefs About Yoga Scale (BAYS) was used to measure beliefs about the outcomes of engaging in yoga.28 The 11-item scale has 3 factors: expected health benefits (5 items), expected discomfort (3 items), and expected social norms (3 items). Items from the expected discomfort and expected social norms are reverse scored so that a higher score indicates more positive beliefs. To reduce participant burden, in study 1 we selected 1 item from each factor with high factor loadings in the original cross-validation sample.28 It would improve my overall health (Benefit, factor loading = .89); I would have to be more flexible to take a class (Discomfort, factor loading = .67); I would be embarrassed in a class (Social norms, factor loading = .75). Participants in study 2 completed the entire 11-item scale. Items were summed to create subscales and total scales.
Analysis
Descriptive statistics were used in study 1 to characterize participants’ yoga experience and interest. Changes in interest pre- and posteducation were evaluated with χ2 comparison of distribution. The association of beliefs about yoga with 3 levels of interest (yes, no, maybe) was evaluated through analysis of variance (ANOVA) comparing the mean score on the summed BAYS items among the 3 groups. The association of demographic (age, education, race) and clinical factors (AJCC stage, physical function) with BAYS was determined through multivariate linear regression.
For analytic purposes, due to small subgroup sample sizes we compared those who identified as non-Hispanic White adults to those who identified as African American/Hispanic/other persons. To further evaluate the relationship of age to yoga beliefs, we examined beliefs about yoga in 3 age groups (40-59 years [n = 24]; 60-69 years [n = 58]; 70-89 years [n = 28]) using ANOVA comparing the mean score on the summed BAYS items among the 3 groups. In study 2, changes in interest before and after the yoga program were evaluated with paired t tests and repeated ANOVA, with beliefs about yoga prior to class as a covariate. The association of demographic and clinical factors with BAYS was determined as in the first sample through multivariate linear regression, except the variable of race was not included due to small sample size (ie, only 3 individuals identified as persons of color).
Thematic analysis in which content-related codes were developed and subsequently grouped together was applied to the data of 110 participants who responded to the open-ended survey questions in study 1 to further illuminate responses to closed-ended questions.35 Transcribed responses to the open-ended questions were transferred to a spreadsheet. An initial code book with code names, definitions, and examples was developed based on an inductive method by one team member (EA).35 Initially, coding and tabulation were conducted separately for each question but it was noted that content extended across response prompts (eg, responses to question 2 “What might make you more likely to come?” were spontaneously provided when answering question 1), thus coding was collapsed across questions. Next, 2 team members (EA, KD) coded the same responses, meeting weekly to discuss discrepancies. The code book was revised following each meeting to reflect refinements in code names and definitions, adding newly generated codes as needed. The process continued until consensus and data saturation was obtained, with 90% intercoder agreement. Next, these codes were subjected to thematic analysis by 2 team members (EA, KD) combining codes into 6 overarching themes. The entire team reviewed the codes and identified 2 supra themes: positive beliefs or facilitators and negative beliefs or barriers.
Consistent with the concept of reflexivity in qualitative research, we acknowledge the influence of the research team members on the qualitative process.36 The primary coding team (EA, KD) are both researchers and employees of Veterans Affairs Boston Healthcare System who have participated in other research projects involving veterans and qualitative analyses but are not yoga instructors or yoga researchers.
Results
Study 1
The sample of 110 military veterans was mostly male (99.1%) with a mean (SD) age of 64.9 (9.4) years (range, 41-88)(Table 1). The majority (70.9%) described their race/ethnicity as White, non-Hispanic followed by Black/African American (18.2%) and Hispanic (8.2%) persons; 50.0% had no more than a high school education. The most common cancer diagnoses were colorectal (50.9%), head and neck (39.1%), and esophageal and gastric (10.0%) and ranged from AJCC stages I to IV.
When first asked, the majority of participants (78.2%) reported that they were not interested in yoga, 16.4% reported they might be interested, and 5.5% reported they had tried a yoga class since their cancer diagnosis. In contrast, 40.9% used exercise, 32.7% used meditation, 14.5% used physical or occupational therapy, and 11.8% used massage therapy since their cancer diagnosis.
After participants were provided the brief scripted education about yoga, the level of interest shifted: 46.4% not interested, 21.8% interested, and 31.8% definitely interested, demonstrating a statistically significant shift in interest following education (χ2 = 22.25, P < .001) (Figure 1). Those with the most positive beliefs about yoga were most likely to indicate interest. Using the BAYS 3-item survey, the mean (SD) for the definitely interested, might be interested, and not interested groups was 15.1 (3.2), 14.1 (3.2), and 12.3 (2.5), respectively (F = 10.63, P < .001).
A multivariable regression was run to examine possible associations between participants’ demographic characteristics, clinical characteristics, and beliefs about yoga as measured by the 3 BAYS items (Table 2). Higher expected health benefits of yoga was associated with identifying as
Six themes were identified in qualitative analysis of semistructured interviews reflecting older veterans’ beliefs about yoga, which were grouped into the following suprathemes of positive vs negative beliefs (Figure 2). Exemplar responses appear in Table 3.
Study 2 Intervention Sample
This sample of 28 veterans was mostly male (96.4%) with a mean (SD) age of 69.2 (10.9) years (range, 57-87). The majority (89.3%) described their race as White, followed by Black/African American (10.7%); no participants self-identified in other categories for race/ethnicity. Twelve veterans (42.9%) had no more than a high school education. The most common cancer diagnosis was genitourinary (35.7%) and the AJCC stage ranged from I to IV.
We employed information learned in study 1 to enhance access in study 2. We mailed letters to 278 veterans diagnosed with cancer in the previous 3 years that provided education about yoga based on study 1 findings. Of 207 veterans reached by phone, 133 (64%) stated they were not interested in coming to a yoga class; 74 (36%) were interested, but 30 felt they were unable to attend due to obstacles such as illness or travel. Ultimately 37 (18%) veterans agreed and consented to the class, and 28 (14%) completed postclass surveys.
In multivariate regression, higher expected health benefits of yoga were associated with higher physical function, lower concern about expected discomfort was also associated with higher physical function as well as higher education; similarly, lower concern about expected social norms was associated with higher physical function. Age was not associated with any of the BAYS factors.
Beliefs about yoga improved from before to after class for all 3 domains with greater expected benefit and lower concerns about discomfort or social norms:
Discussion
Yoga is an effective clinical intervention for addressing some long-term adverse effects in cancer survivors, although the body of research focuses predominantly on middle aged, female, White, college-educated breast cancer survivors. There is no evidence to suggest yoga would be less effective in other groups, but it has not been extensively studied in survivors from diverse subgroups. Beliefs about yoga are a factor that may enhance interest in yoga interventions and research, and measures aimed at addressing potential beliefs and fears may capture information that can be used to support older cancer survivors in holistic health. The aims of this study were to examine beliefs about yoga in 2 samples of older cancer survivors who received VHA care. The main findings are (1) interest in yoga was initially low and lower than that of other complementary or exercise-based interventions, but increased when participants were provided brief education about yoga; (2) interest in yoga was associated with beliefs about yoga with qualitative comments illuminating these beliefs; (3) demographic characteristics (education, race) and physical function were associated with beliefs about yoga; and (4) positive beliefs about yoga increased following a brief yoga intervention and was associated with improvements in physical function.
Willingness to consider a class appeared to shift for some older veterans when they were presented brief information about yoga that explained what is involved, how it might help, and that it could be done from a chair if needed. These findings clearly indicated that when trying to enhance participation in yoga in clinical or research programs, it will be important that recruitment materials provide such information. This finding is consistent with the qualitative findings that reflected a lack of knowledge or skepticism about benefits of yoga among some participants. Given the finding that physical function was associated with beliefs about yoga and was also a prominent theme in qualitative analyses,
Age was not associated with beliefs about yoga in either study. Importantly, in a more detailed study 1 follow-up analysis, beliefs about yoga were equivalent for aged > 70 years compared with those aged 40 to 69 years. It is not entirely clear why older adults have been underrepresented in studies of yoga in cancer survivors. However, older adults are vastly underrepresented in clinical trials for many health conditions, even though they are more likely to experience many diseases, including cancer.37 A new National Institutes of Health policy requires that individuals of all ages, including older adults, must be included in all human subjects research unless there are scientific reasons not to include them.38 It is therefore imperative to consider strategies to address underrepresentation of older adults.
Qualitative findings here suggest it will be important to consider logistical barriers including transportation and affordability as well as adaptations requested by older adults (eg, preferences for older teachers).18
Although our sample was small, we also found that adults from diverse racial and ethnic backgrounds had more positive beliefs about yoga, such that this finding should be interpreted with caution. Similar to older adults, individuals from diverse racial and ethnic groups are also underrepresented in clinical trials and may have lower access to complementary treatments. Cultural and linguistic adaptations and building community partnerships should be considered in both recruitment and intervention delivery strategies.40We learned that education about yoga may increase interest and that it is possible to recruit older veterans to yoga class. Nevertheless, in study 2, our rate of full participation was low, with only about 1 in 10 participating. Additional efforts to enhance beliefs about yoga and to addresslogistical barriers (offering telehealth yoga) are needed to best reach older veterans.
Limitations
These findings have several limitations. First, participants were homogeneous in age, gender, race/ethnicity and veteran status, which provides a window into this understudied population but limits generalizability and our ability to control across populations. Second, the sample size limited the ability to conduct subgroup and interaction analyses, such as examining potential differential effects of cancer type, treatment, and PTSD on yoga beliefs or to consider the relationship of yoga beliefs with changes in quality of life before and after the yoga intervention in study 2. Additionally, age was not associated with beliefs about yoga in these samples that of mostly older adults. We were able to compare middle-aged and older adults but could not compare beliefs about yoga to adults aged in their 20s and 30s. Last, our study excluded people with dementia and psychotic disorders. Further research is needed to examine yoga for older cancer survivors who have these conditions.
Conclusions
Education that specifically informs potential participants about yoga practice, potential modifications, and potential benefits, as well as adaptations to programs that address physical and logistical barriers may be useful in increasing access to and participation in yoga for older Veterans who are cancer survivors.
Acknowledgments/Funding
The authors have no financial or personal relationships to disclose. This work was supported by the US Department of Veterans Affairs (VA) Rehabilitation Research and Development Service. This material is the result of work supported with resources and the use of facilities at the VA Boston Healthcare System, Bedford VA Medical Center, and Michael E. DeBakey VA Medical Center in Houston, Texas. We thank the members of the Veterans Cancer Rehabilitation Study (Vetcares) Research teams in Boston and in Houston and the veterans who have participated in our research studies and allow us to contribute to their health care.
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5. Loudon A, Barnett T, Piller N, Immink MA, Williams AD. Yoga management of breast cancer-related lymphoedema: a randomised controlled pilot-trial. BMC Complement Altern Med. 2014;14:214. Published 2014 Jul 1. doi:10.1186/1472-6882-14-214
6. Browning KK, Kue J, Lyons F, Overcash J. Feasibility of mind-body movement programs for cancer survivors. Oncol Nurs Forum. 2017;44(4):446-456. doi:10.1188/17.ONF.446-456
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8. Yun H, Sun L, Mao JJ. Growth of integrative medicine at leading cancer centers between 2009 and 2016: a systematic analysis of NCI-designated comprehensive cancer center websites. J Natl Cancer Inst Monogr. 2017;2017(52):lgx004. doi:10.1093/jncimonographs/lgx004
9. Sanft T, Denlinger CS, Armenian S, et al. NCCN guidelines insights: survivorship, version 2.2019. J Natl Compr Canc Netw. 2019;17(7):784-794. doi:10.6004/jnccn.2019.0034
10. Lyman GH, Greenlee H, Bohlke K, et al. Integrative therapies during and after breast cancer treatment: ASCO endorsement of the SIO clinical practice guideline. J Clin Oncol. 2018;36(25):2647-2655. doi:10.1200/JCO.2018.79.2721
11. Culos-Reed SN, Mackenzie MJ, Sohl SJ, Jesse MT, Zahavich AN, Danhauer SC. Yoga & cancer interventions: a review of the clinical significance of patient reported outcomes for cancer survivors. Evid Based Complement Alternat Med. 2012;2012:642576. doi:10.1155/2012/642576
12. Danhauer SC, Addington EL, Cohen L, et al. Yoga for symptom management in oncology: a review of the evidence base and future directions for research. Cancer. 2019;125(12):1979-1989. doi:10.1002/cncr.31979
13. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34. doi:10.3322/caac.21551
14. US Department of Veterans Affairs. Veterans’ diseases associated with Agent Orange. Updated June 16, 2021. Accessed September 22, 2021. https://www.publichealth.va.gov/exposures/agentorange/conditions
15. Deimling GT, Arendt JA, Kypriotakis G, Bowman KF. Functioning of older, long-term cancer survivors: the role of cancer and comorbidities. J Am Geriatr Soc. 2009;57(suppl 2):S289-S292. doi:10.1111/j.1532-5415.2009.02515.x
16. King K, Gosian J, Doherty K, et al. Implementing yoga therapy adapted for older veterans who are cancer survivors. Int J Yoga Therap. 2014;24:87-96.
17. Wertman A, Wister AV, Mitchell BA. On and off the mat: yoga experiences of middle-aged and older adults. Can J Aging. 2016;35(2):190-205. doi:10.1017/S0714980816000155
18. Chen KM, Wang HH, Li CH, Chen MH. Community vs. institutional elders’ evaluations of and preferences for yoga exercises. J Clin Nurs. 2011;20(7-8):1000-1007. doi:10.1111/j.1365-2702.2010.03337.x
19. Saravanakumar P, Higgins IJ, Van Der Riet PJ, Sibbritt D. Tai chi and yoga in residential aged care: perspectives of participants: A qualitative study. J Clin Nurs. 2018;27(23-24):4390-4399. doi:10.1111/jocn.14590
20. Fan JT, Chen KM. Using silver yoga exercises to promote physical and mental health of elders with dementia in long-term care facilities. Int Psychogeriatr. 2011;23(8):1222-1230. doi:10.1017/S1041610211000287
21. Taylor TR, Barrow J, Makambi K, et al. A restorative yoga intervention for African-American breast cancer survivors: a pilot study. J Racial Ethn Health Disparities. 2018;5(1):62-72. doi:10.1007/s40615-017-0342-4
22. Moadel AB, Shah C, Wylie-Rosett J, et al. Randomized controlled trial of yoga among a multiethnic sample of breast cancer patients: effects on quality of life. J Clin Oncol. 2007;25(28):4387-4395. doi:10.1200/JCO.2006.06.6027
23. Smith SA, Whitehead MS, Sheats JQ, Chubb B, Alema-Mensah E, Ansa BE. Community engagement to address socio-ecological barriers to physical activity among African American breast cancer survivors. J Ga Public Health Assoc. 2017;6(3):393-397. doi:10.21633/jgpha.6.312
24. Cushing RE, Braun KL, Alden C-Iayt SW, Katz AR. Military-Tailored Yoga for Veterans with Post-traumatic Stress Disorder. Mil Med. 2018;183(5-6):e223-e231. doi:10.1093/milmed/usx071
25. Davis LW, Schmid AA, Daggy JK, et al. Symptoms improve after a yoga program designed for PTSD in a randomized controlled trial with veterans and civilians. Psychol Trauma. 2020;12(8):904-912. doi:10.1037/tra0000564
26. Chopin SM, Sheerin CM, Meyer BL. Yoga for warriors: An intervention for veterans with comorbid chronic pain and PTSD. Psychol Trauma. 2020;12(8):888-896. doi:10.1037/tra0000649
27. US Department of Veterans Affairs. Whole health. Updated September 13, 2021. Accessed September 22, 2021. https://www.va.gov/wholehealth
28. Sohl SJ, Schnur JB, Daly L, Suslov K, Montgomery GH. Development of the beliefs about yoga scale. Int J Yoga Therap. 2011;(21):85-91.
29. Cadmus-Bertram L, Littman AJ, Ulrich CM, et al. Predictors of adherence to a 26-week viniyoga intervention among post-treatment breast cancer survivors. J Altern Complement Med. 2013;19(9):751-758. doi:10.1089/acm.2012.0118
30. Mackenzie MJ, Carlson LE, Ekkekakis P, Paskevich DM, Culos-Reed SN. Affect and mindfulness as predictors of change in mood disturbance, stress symptoms, and quality of life in a community-based yoga program for cancer survivors. Evid Based Complement Alternat Med. 2013;2013:419496. doi:10.1155/2013/419496
31. Naik AD, Martin LA, Karel M, et al. Cancer survivor rehabilitation and recovery: protocol for the Veterans Cancer Rehabilitation Study (Vet-CaRes). BMC Health Serv Res. 2013;13:93. Published 2013 Mar 11. doi:10.1186/1472-6963-13-93
32. Northwestern University. PROMIS Health Organization and the PROMIS Cooperative Group. PROMIS Short Form v2.0 - Physical Function 6b. Accessed September 24, 2021. https://www.healthmeasures.net/index.php?option=com_instruments&view=measure&id=793&Itemid=992
33. Northwestern University. PROMIS Health Organization and the PROMIS Cooperative Group. PROMIS Short Form v1.0 - Anxiety 6a. Accessed September 24, 2021. https://www.healthmeasures.net/index.php?option=com_instruments&view=measure&id=145&Itemid=992
34. Northwestern University. PROMIS Health Organization and the PROMIS Cooperative Group. PROMIS-43 Profile v2.1. Accessed September 24, 2021. https://www.healthmeasures.net/index.php?option=com_instruments&view=measure&id=858&Itemid=992
35. Todd NJ, Jones SH, Lobban FA. “Recovery” in bipolar disorder: how can service users be supported through a self-management intervention? A qualitative focus group study. J Ment Health. 2012;21(2):114-126. doi:10.3109/09638237.2011.621471
36. Finlay L. “Outing” the researcher: the provenance, process, and practice of reflexivity. Qual Health Res. 2002;12(4):531-545. doi:10.1177/104973202129120052
37. Herrera AP, Snipes SA, King DW, Torres-Vigil I, Goldberg DS, Weinberg AD. Disparate inclusion of older adults in clinical trials: priorities and opportunities for policy and practice change. Am J Public Health. 2010;10(suppl 1):S105-S112. doi:10.2105/AJPH.2009.162982
38. National Institutes of Health. Revision: NIH policy and guidelines on the inclusion of individuals across the lifespan as participants in research involving human subjects. Published December 19, 2017. Accessed September 22, 2021. https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-116.html
39. Townsley CA, Selby R, Siu LL. Systematic review of barriers to the recruitment of older patients with cancer onto clinical trials. J Clin Oncol. 2005;23(13):3112-3124. doi:10.1200/JCO.2005.00.141
40. Vuong I, Wright J, Nolan MB, et al. Overcoming barriers: evidence-based strategies to increase enrollment of underrepresented populations in cancer therapeutic clinical trials-a narrative review. J Cancer Educ. 2020;35(5):841-849. doi:10.1007/s13187-019-01650-y
Yoga is an effective clinical intervention for cancer survivors. Studies indicate a wide range of benefits, including improvements in physical functioning, emotional well-being and overall quality of life.1-7 Two-thirds of National Cancer Institute designated comprehensive cancer centers offer yoga on-site.8 Yoga is endorsed by the National Comprehensive Cancer Network and American Society of Clinical Oncology for managing symptoms, such as cancer-related anxiety and depression and for improving overall quality of life.9,10
Although the positive effects of yoga on cancer patients are well studied, most published research in this area reports on predominantly middle-aged women with breast cancer.11,12 Less is known about the use of yoga in other groups of cancer patients, such as older adults, veterans, and those from diverse racial or ethnic backgrounds. This gap in the literature is concerning considering that the majority of cancer survivors are aged 60 years or older, and veterans face unique risk factors for cancer associated with herbicide exposure (eg, Agent Orange) and other military-related noxious exposures.13,14 Older cancer survivors may have more difficulty recovering from treatment-related adverse effects, making it especially important to target recovery efforts to older adults.15 Yoga can be adapted for older cancer survivors with age-related comorbidities, similar to adaptations made for older adults who are not cancer survivors but require accommodations for physical limitations.16-20 Similarly, yoga programs targeted to racially diverse cancer survivors are associated with improved mood and well-being in racially diverse cancer survivors, but studies suggest community engagement and cultural adaptation may be important to address the needs of culturally diverse cancer survivors.21-23
Yoga has been increasingly studied within the Veterans Health Administration (VHA) for treatment of posttraumatic stress disorder (PTSD) and has been found effective in reducing symptoms through the use of trauma-informed and military-relevant instruction as well as a military veteran yoga teacher.24-26 This work has not targeted older veterans or cancer survivors who may be more difficult to recruit into such programs, but who would nevertheless benefit.
Clinically, the VHA whole health model is providing increased opportunities for veterans to engage in holistic care including yoga.27 Resources include in-person yoga classes (varies by facility), videos, and handouts with practices uniquely designed for veterans or wounded warriors. As clinicians increasingly refer veterans to these programs, it will be important to develop strategies to engage older veterans in these services.
One important strategy to enhancing access to yoga for older veterans is to consider beliefs about yoga. Beliefs about yoga or general expectations about the outcomes of yoga may be critical to consider in expanding access to yoga in underrepresented groups. Beliefs about yoga may include beliefs about yoga improving health, yoga being difficult or producing discomfort, and yoga involving specific social norms.28 For example, confidence in one’s ability to perform yoga despite discomfort predicted class attendance and practice in a sample of 32 breast cancer survivors.29 Relatedly, positive beliefs about the impact of yoga on health were associated with improvements in mood and quality of life in a sample of 66 cancer survivors.30
The aim of this study was to examine avenues to enhance access to yoga for older veterans, including those from diverse backgrounds, with a focus on the role of beliefs. In the first study we investigate the association between beliefs about and barriers to yoga in a group of older cancer survivors, and we consider the role of demographic and clinical variables in such beliefs and how education may alter beliefs. In alignment with the whole health model of holistic health, we posit that yoga educational materials and resources may contribute to yoga beliefs and work to decrease these barriers. We apply these findings in a second study that enrolled older veterans in yoga and examining the impact of program participation on beliefs and the role of beliefs in program outcomes. In the discussion we return to consider how to increase access to yoga to older veterans based on these findings.
Methods
Study 1 participants were identified from VHA tumor registries. Eligible patients had head and neck, esophageal, gastric, or colorectal cancers and were excluded if they were in hospice care, had dementia, or had a psychotic spectrum disorder. Participants completed a face-to-face semistructured interview at 6, 12, and 18 months after their cancer diagnosis with a trained interviewer. Complete protocol methods, including nonresponder information, are described elsewhere.31
Questions about yoga were asked at the 12 month postdiagnosis interview. Participants were read the following: “Here is a list of services some patients use to recover from cancer. Please tell me if you have used any of these.” The list included yoga, physical therapy, occupational therapy, exercise, meditation, or massage therapy. Next participants were provided education about yoga via the following description: “Yoga is a practice of stress reduction and exercise with stretching, holding positions and deep breathing. For some, it may improve your sleep, energy, flexibility, anxiety, and pain. The postures are done standing, sitting, or lying down. If needed, it can be done all from a chair.” We then asked whether they would attend if yoga was offered at the VHA hospital (yes, no, maybe). Participants provided brief responses to 2 open-ended questions: (“If I came to a yoga class, I …”; and “Is there anything that might make you more likely to come to a yoga class?”) Responses were transcribed verbatim and entered into a database for qualitative analysis. Subsequently, participants completed standardized measures of health-related quality of life and beliefs about yoga as described below.
Study 2 participants were identified from VHA tumor registries and a cancer support group. Eligible patients had a diagnosis of cancer (any type except basil cell carcinoma) within the previous 3 years and were excluded if they were in hospice care, had dementia, or had a psychotic spectrum disorder. Participants completed face-to-face semistructured interviews with a trained interviewer before and after participation in an 8-week yoga group that met twice per week. Complete protocol methods are described elsewhere.16 This paper focuses on 28 of the 37 enrolled patients for whom we have complete pre- and postclass interview data. We previously reported on adaptations made to yoga in our pilot group of 14 individuals, who in this small sample did not show statistically significant changes in their quality of life from before to after the class.16 This analysis includes those 14 individuals and 14 who participated in additional classes, focusing on beliefs, which were not previously reported.
Measures
Participants reported their age, gender, ethnicity (Hispanic/Latino or not), race, and level of education. Information about the cancer diagnosis, American Joint Committee on Cancer (AJCC) cancer stage, and treatments was obtained from the medical record. The Physical Function and Anxiety Subscales from the Patient-Reported Outcomes Measurement Information System were used to measure health-related quality of life (HRQoL).32-34 Items are rated on a Likert scale from 1 (not at all) to 5 (very much).
The Beliefs About Yoga Scale (BAYS) was used to measure beliefs about the outcomes of engaging in yoga.28 The 11-item scale has 3 factors: expected health benefits (5 items), expected discomfort (3 items), and expected social norms (3 items). Items from the expected discomfort and expected social norms are reverse scored so that a higher score indicates more positive beliefs. To reduce participant burden, in study 1 we selected 1 item from each factor with high factor loadings in the original cross-validation sample.28 It would improve my overall health (Benefit, factor loading = .89); I would have to be more flexible to take a class (Discomfort, factor loading = .67); I would be embarrassed in a class (Social norms, factor loading = .75). Participants in study 2 completed the entire 11-item scale. Items were summed to create subscales and total scales.
Analysis
Descriptive statistics were used in study 1 to characterize participants’ yoga experience and interest. Changes in interest pre- and posteducation were evaluated with χ2 comparison of distribution. The association of beliefs about yoga with 3 levels of interest (yes, no, maybe) was evaluated through analysis of variance (ANOVA) comparing the mean score on the summed BAYS items among the 3 groups. The association of demographic (age, education, race) and clinical factors (AJCC stage, physical function) with BAYS was determined through multivariate linear regression.
For analytic purposes, due to small subgroup sample sizes we compared those who identified as non-Hispanic White adults to those who identified as African American/Hispanic/other persons. To further evaluate the relationship of age to yoga beliefs, we examined beliefs about yoga in 3 age groups (40-59 years [n = 24]; 60-69 years [n = 58]; 70-89 years [n = 28]) using ANOVA comparing the mean score on the summed BAYS items among the 3 groups. In study 2, changes in interest before and after the yoga program were evaluated with paired t tests and repeated ANOVA, with beliefs about yoga prior to class as a covariate. The association of demographic and clinical factors with BAYS was determined as in the first sample through multivariate linear regression, except the variable of race was not included due to small sample size (ie, only 3 individuals identified as persons of color).
Thematic analysis in which content-related codes were developed and subsequently grouped together was applied to the data of 110 participants who responded to the open-ended survey questions in study 1 to further illuminate responses to closed-ended questions.35 Transcribed responses to the open-ended questions were transferred to a spreadsheet. An initial code book with code names, definitions, and examples was developed based on an inductive method by one team member (EA).35 Initially, coding and tabulation were conducted separately for each question but it was noted that content extended across response prompts (eg, responses to question 2 “What might make you more likely to come?” were spontaneously provided when answering question 1), thus coding was collapsed across questions. Next, 2 team members (EA, KD) coded the same responses, meeting weekly to discuss discrepancies. The code book was revised following each meeting to reflect refinements in code names and definitions, adding newly generated codes as needed. The process continued until consensus and data saturation was obtained, with 90% intercoder agreement. Next, these codes were subjected to thematic analysis by 2 team members (EA, KD) combining codes into 6 overarching themes. The entire team reviewed the codes and identified 2 supra themes: positive beliefs or facilitators and negative beliefs or barriers.
Consistent with the concept of reflexivity in qualitative research, we acknowledge the influence of the research team members on the qualitative process.36 The primary coding team (EA, KD) are both researchers and employees of Veterans Affairs Boston Healthcare System who have participated in other research projects involving veterans and qualitative analyses but are not yoga instructors or yoga researchers.
Results
Study 1
The sample of 110 military veterans was mostly male (99.1%) with a mean (SD) age of 64.9 (9.4) years (range, 41-88)(Table 1). The majority (70.9%) described their race/ethnicity as White, non-Hispanic followed by Black/African American (18.2%) and Hispanic (8.2%) persons; 50.0% had no more than a high school education. The most common cancer diagnoses were colorectal (50.9%), head and neck (39.1%), and esophageal and gastric (10.0%) and ranged from AJCC stages I to IV.
When first asked, the majority of participants (78.2%) reported that they were not interested in yoga, 16.4% reported they might be interested, and 5.5% reported they had tried a yoga class since their cancer diagnosis. In contrast, 40.9% used exercise, 32.7% used meditation, 14.5% used physical or occupational therapy, and 11.8% used massage therapy since their cancer diagnosis.
After participants were provided the brief scripted education about yoga, the level of interest shifted: 46.4% not interested, 21.8% interested, and 31.8% definitely interested, demonstrating a statistically significant shift in interest following education (χ2 = 22.25, P < .001) (Figure 1). Those with the most positive beliefs about yoga were most likely to indicate interest. Using the BAYS 3-item survey, the mean (SD) for the definitely interested, might be interested, and not interested groups was 15.1 (3.2), 14.1 (3.2), and 12.3 (2.5), respectively (F = 10.63, P < .001).
A multivariable regression was run to examine possible associations between participants’ demographic characteristics, clinical characteristics, and beliefs about yoga as measured by the 3 BAYS items (Table 2). Higher expected health benefits of yoga was associated with identifying as
Six themes were identified in qualitative analysis of semistructured interviews reflecting older veterans’ beliefs about yoga, which were grouped into the following suprathemes of positive vs negative beliefs (Figure 2). Exemplar responses appear in Table 3.
Study 2 Intervention Sample
This sample of 28 veterans was mostly male (96.4%) with a mean (SD) age of 69.2 (10.9) years (range, 57-87). The majority (89.3%) described their race as White, followed by Black/African American (10.7%); no participants self-identified in other categories for race/ethnicity. Twelve veterans (42.9%) had no more than a high school education. The most common cancer diagnosis was genitourinary (35.7%) and the AJCC stage ranged from I to IV.
We employed information learned in study 1 to enhance access in study 2. We mailed letters to 278 veterans diagnosed with cancer in the previous 3 years that provided education about yoga based on study 1 findings. Of 207 veterans reached by phone, 133 (64%) stated they were not interested in coming to a yoga class; 74 (36%) were interested, but 30 felt they were unable to attend due to obstacles such as illness or travel. Ultimately 37 (18%) veterans agreed and consented to the class, and 28 (14%) completed postclass surveys.
In multivariate regression, higher expected health benefits of yoga were associated with higher physical function, lower concern about expected discomfort was also associated with higher physical function as well as higher education; similarly, lower concern about expected social norms was associated with higher physical function. Age was not associated with any of the BAYS factors.
Beliefs about yoga improved from before to after class for all 3 domains with greater expected benefit and lower concerns about discomfort or social norms:
Discussion
Yoga is an effective clinical intervention for addressing some long-term adverse effects in cancer survivors, although the body of research focuses predominantly on middle aged, female, White, college-educated breast cancer survivors. There is no evidence to suggest yoga would be less effective in other groups, but it has not been extensively studied in survivors from diverse subgroups. Beliefs about yoga are a factor that may enhance interest in yoga interventions and research, and measures aimed at addressing potential beliefs and fears may capture information that can be used to support older cancer survivors in holistic health. The aims of this study were to examine beliefs about yoga in 2 samples of older cancer survivors who received VHA care. The main findings are (1) interest in yoga was initially low and lower than that of other complementary or exercise-based interventions, but increased when participants were provided brief education about yoga; (2) interest in yoga was associated with beliefs about yoga with qualitative comments illuminating these beliefs; (3) demographic characteristics (education, race) and physical function were associated with beliefs about yoga; and (4) positive beliefs about yoga increased following a brief yoga intervention and was associated with improvements in physical function.
Willingness to consider a class appeared to shift for some older veterans when they were presented brief information about yoga that explained what is involved, how it might help, and that it could be done from a chair if needed. These findings clearly indicated that when trying to enhance participation in yoga in clinical or research programs, it will be important that recruitment materials provide such information. This finding is consistent with the qualitative findings that reflected a lack of knowledge or skepticism about benefits of yoga among some participants. Given the finding that physical function was associated with beliefs about yoga and was also a prominent theme in qualitative analyses,
Age was not associated with beliefs about yoga in either study. Importantly, in a more detailed study 1 follow-up analysis, beliefs about yoga were equivalent for aged > 70 years compared with those aged 40 to 69 years. It is not entirely clear why older adults have been underrepresented in studies of yoga in cancer survivors. However, older adults are vastly underrepresented in clinical trials for many health conditions, even though they are more likely to experience many diseases, including cancer.37 A new National Institutes of Health policy requires that individuals of all ages, including older adults, must be included in all human subjects research unless there are scientific reasons not to include them.38 It is therefore imperative to consider strategies to address underrepresentation of older adults.
Qualitative findings here suggest it will be important to consider logistical barriers including transportation and affordability as well as adaptations requested by older adults (eg, preferences for older teachers).18
Although our sample was small, we also found that adults from diverse racial and ethnic backgrounds had more positive beliefs about yoga, such that this finding should be interpreted with caution. Similar to older adults, individuals from diverse racial and ethnic groups are also underrepresented in clinical trials and may have lower access to complementary treatments. Cultural and linguistic adaptations and building community partnerships should be considered in both recruitment and intervention delivery strategies.40We learned that education about yoga may increase interest and that it is possible to recruit older veterans to yoga class. Nevertheless, in study 2, our rate of full participation was low, with only about 1 in 10 participating. Additional efforts to enhance beliefs about yoga and to addresslogistical barriers (offering telehealth yoga) are needed to best reach older veterans.
Limitations
These findings have several limitations. First, participants were homogeneous in age, gender, race/ethnicity and veteran status, which provides a window into this understudied population but limits generalizability and our ability to control across populations. Second, the sample size limited the ability to conduct subgroup and interaction analyses, such as examining potential differential effects of cancer type, treatment, and PTSD on yoga beliefs or to consider the relationship of yoga beliefs with changes in quality of life before and after the yoga intervention in study 2. Additionally, age was not associated with beliefs about yoga in these samples that of mostly older adults. We were able to compare middle-aged and older adults but could not compare beliefs about yoga to adults aged in their 20s and 30s. Last, our study excluded people with dementia and psychotic disorders. Further research is needed to examine yoga for older cancer survivors who have these conditions.
Conclusions
Education that specifically informs potential participants about yoga practice, potential modifications, and potential benefits, as well as adaptations to programs that address physical and logistical barriers may be useful in increasing access to and participation in yoga for older Veterans who are cancer survivors.
Acknowledgments/Funding
The authors have no financial or personal relationships to disclose. This work was supported by the US Department of Veterans Affairs (VA) Rehabilitation Research and Development Service. This material is the result of work supported with resources and the use of facilities at the VA Boston Healthcare System, Bedford VA Medical Center, and Michael E. DeBakey VA Medical Center in Houston, Texas. We thank the members of the Veterans Cancer Rehabilitation Study (Vetcares) Research teams in Boston and in Houston and the veterans who have participated in our research studies and allow us to contribute to their health care.
Yoga is an effective clinical intervention for cancer survivors. Studies indicate a wide range of benefits, including improvements in physical functioning, emotional well-being and overall quality of life.1-7 Two-thirds of National Cancer Institute designated comprehensive cancer centers offer yoga on-site.8 Yoga is endorsed by the National Comprehensive Cancer Network and American Society of Clinical Oncology for managing symptoms, such as cancer-related anxiety and depression and for improving overall quality of life.9,10
Although the positive effects of yoga on cancer patients are well studied, most published research in this area reports on predominantly middle-aged women with breast cancer.11,12 Less is known about the use of yoga in other groups of cancer patients, such as older adults, veterans, and those from diverse racial or ethnic backgrounds. This gap in the literature is concerning considering that the majority of cancer survivors are aged 60 years or older, and veterans face unique risk factors for cancer associated with herbicide exposure (eg, Agent Orange) and other military-related noxious exposures.13,14 Older cancer survivors may have more difficulty recovering from treatment-related adverse effects, making it especially important to target recovery efforts to older adults.15 Yoga can be adapted for older cancer survivors with age-related comorbidities, similar to adaptations made for older adults who are not cancer survivors but require accommodations for physical limitations.16-20 Similarly, yoga programs targeted to racially diverse cancer survivors are associated with improved mood and well-being in racially diverse cancer survivors, but studies suggest community engagement and cultural adaptation may be important to address the needs of culturally diverse cancer survivors.21-23
Yoga has been increasingly studied within the Veterans Health Administration (VHA) for treatment of posttraumatic stress disorder (PTSD) and has been found effective in reducing symptoms through the use of trauma-informed and military-relevant instruction as well as a military veteran yoga teacher.24-26 This work has not targeted older veterans or cancer survivors who may be more difficult to recruit into such programs, but who would nevertheless benefit.
Clinically, the VHA whole health model is providing increased opportunities for veterans to engage in holistic care including yoga.27 Resources include in-person yoga classes (varies by facility), videos, and handouts with practices uniquely designed for veterans or wounded warriors. As clinicians increasingly refer veterans to these programs, it will be important to develop strategies to engage older veterans in these services.
One important strategy to enhancing access to yoga for older veterans is to consider beliefs about yoga. Beliefs about yoga or general expectations about the outcomes of yoga may be critical to consider in expanding access to yoga in underrepresented groups. Beliefs about yoga may include beliefs about yoga improving health, yoga being difficult or producing discomfort, and yoga involving specific social norms.28 For example, confidence in one’s ability to perform yoga despite discomfort predicted class attendance and practice in a sample of 32 breast cancer survivors.29 Relatedly, positive beliefs about the impact of yoga on health were associated with improvements in mood and quality of life in a sample of 66 cancer survivors.30
The aim of this study was to examine avenues to enhance access to yoga for older veterans, including those from diverse backgrounds, with a focus on the role of beliefs. In the first study we investigate the association between beliefs about and barriers to yoga in a group of older cancer survivors, and we consider the role of demographic and clinical variables in such beliefs and how education may alter beliefs. In alignment with the whole health model of holistic health, we posit that yoga educational materials and resources may contribute to yoga beliefs and work to decrease these barriers. We apply these findings in a second study that enrolled older veterans in yoga and examining the impact of program participation on beliefs and the role of beliefs in program outcomes. In the discussion we return to consider how to increase access to yoga to older veterans based on these findings.
Methods
Study 1 participants were identified from VHA tumor registries. Eligible patients had head and neck, esophageal, gastric, or colorectal cancers and were excluded if they were in hospice care, had dementia, or had a psychotic spectrum disorder. Participants completed a face-to-face semistructured interview at 6, 12, and 18 months after their cancer diagnosis with a trained interviewer. Complete protocol methods, including nonresponder information, are described elsewhere.31
Questions about yoga were asked at the 12 month postdiagnosis interview. Participants were read the following: “Here is a list of services some patients use to recover from cancer. Please tell me if you have used any of these.” The list included yoga, physical therapy, occupational therapy, exercise, meditation, or massage therapy. Next participants were provided education about yoga via the following description: “Yoga is a practice of stress reduction and exercise with stretching, holding positions and deep breathing. For some, it may improve your sleep, energy, flexibility, anxiety, and pain. The postures are done standing, sitting, or lying down. If needed, it can be done all from a chair.” We then asked whether they would attend if yoga was offered at the VHA hospital (yes, no, maybe). Participants provided brief responses to 2 open-ended questions: (“If I came to a yoga class, I …”; and “Is there anything that might make you more likely to come to a yoga class?”) Responses were transcribed verbatim and entered into a database for qualitative analysis. Subsequently, participants completed standardized measures of health-related quality of life and beliefs about yoga as described below.
Study 2 participants were identified from VHA tumor registries and a cancer support group. Eligible patients had a diagnosis of cancer (any type except basil cell carcinoma) within the previous 3 years and were excluded if they were in hospice care, had dementia, or had a psychotic spectrum disorder. Participants completed face-to-face semistructured interviews with a trained interviewer before and after participation in an 8-week yoga group that met twice per week. Complete protocol methods are described elsewhere.16 This paper focuses on 28 of the 37 enrolled patients for whom we have complete pre- and postclass interview data. We previously reported on adaptations made to yoga in our pilot group of 14 individuals, who in this small sample did not show statistically significant changes in their quality of life from before to after the class.16 This analysis includes those 14 individuals and 14 who participated in additional classes, focusing on beliefs, which were not previously reported.
Measures
Participants reported their age, gender, ethnicity (Hispanic/Latino or not), race, and level of education. Information about the cancer diagnosis, American Joint Committee on Cancer (AJCC) cancer stage, and treatments was obtained from the medical record. The Physical Function and Anxiety Subscales from the Patient-Reported Outcomes Measurement Information System were used to measure health-related quality of life (HRQoL).32-34 Items are rated on a Likert scale from 1 (not at all) to 5 (very much).
The Beliefs About Yoga Scale (BAYS) was used to measure beliefs about the outcomes of engaging in yoga.28 The 11-item scale has 3 factors: expected health benefits (5 items), expected discomfort (3 items), and expected social norms (3 items). Items from the expected discomfort and expected social norms are reverse scored so that a higher score indicates more positive beliefs. To reduce participant burden, in study 1 we selected 1 item from each factor with high factor loadings in the original cross-validation sample.28 It would improve my overall health (Benefit, factor loading = .89); I would have to be more flexible to take a class (Discomfort, factor loading = .67); I would be embarrassed in a class (Social norms, factor loading = .75). Participants in study 2 completed the entire 11-item scale. Items were summed to create subscales and total scales.
Analysis
Descriptive statistics were used in study 1 to characterize participants’ yoga experience and interest. Changes in interest pre- and posteducation were evaluated with χ2 comparison of distribution. The association of beliefs about yoga with 3 levels of interest (yes, no, maybe) was evaluated through analysis of variance (ANOVA) comparing the mean score on the summed BAYS items among the 3 groups. The association of demographic (age, education, race) and clinical factors (AJCC stage, physical function) with BAYS was determined through multivariate linear regression.
For analytic purposes, due to small subgroup sample sizes we compared those who identified as non-Hispanic White adults to those who identified as African American/Hispanic/other persons. To further evaluate the relationship of age to yoga beliefs, we examined beliefs about yoga in 3 age groups (40-59 years [n = 24]; 60-69 years [n = 58]; 70-89 years [n = 28]) using ANOVA comparing the mean score on the summed BAYS items among the 3 groups. In study 2, changes in interest before and after the yoga program were evaluated with paired t tests and repeated ANOVA, with beliefs about yoga prior to class as a covariate. The association of demographic and clinical factors with BAYS was determined as in the first sample through multivariate linear regression, except the variable of race was not included due to small sample size (ie, only 3 individuals identified as persons of color).
Thematic analysis in which content-related codes were developed and subsequently grouped together was applied to the data of 110 participants who responded to the open-ended survey questions in study 1 to further illuminate responses to closed-ended questions.35 Transcribed responses to the open-ended questions were transferred to a spreadsheet. An initial code book with code names, definitions, and examples was developed based on an inductive method by one team member (EA).35 Initially, coding and tabulation were conducted separately for each question but it was noted that content extended across response prompts (eg, responses to question 2 “What might make you more likely to come?” were spontaneously provided when answering question 1), thus coding was collapsed across questions. Next, 2 team members (EA, KD) coded the same responses, meeting weekly to discuss discrepancies. The code book was revised following each meeting to reflect refinements in code names and definitions, adding newly generated codes as needed. The process continued until consensus and data saturation was obtained, with 90% intercoder agreement. Next, these codes were subjected to thematic analysis by 2 team members (EA, KD) combining codes into 6 overarching themes. The entire team reviewed the codes and identified 2 supra themes: positive beliefs or facilitators and negative beliefs or barriers.
Consistent with the concept of reflexivity in qualitative research, we acknowledge the influence of the research team members on the qualitative process.36 The primary coding team (EA, KD) are both researchers and employees of Veterans Affairs Boston Healthcare System who have participated in other research projects involving veterans and qualitative analyses but are not yoga instructors or yoga researchers.
Results
Study 1
The sample of 110 military veterans was mostly male (99.1%) with a mean (SD) age of 64.9 (9.4) years (range, 41-88)(Table 1). The majority (70.9%) described their race/ethnicity as White, non-Hispanic followed by Black/African American (18.2%) and Hispanic (8.2%) persons; 50.0% had no more than a high school education. The most common cancer diagnoses were colorectal (50.9%), head and neck (39.1%), and esophageal and gastric (10.0%) and ranged from AJCC stages I to IV.
When first asked, the majority of participants (78.2%) reported that they were not interested in yoga, 16.4% reported they might be interested, and 5.5% reported they had tried a yoga class since their cancer diagnosis. In contrast, 40.9% used exercise, 32.7% used meditation, 14.5% used physical or occupational therapy, and 11.8% used massage therapy since their cancer diagnosis.
After participants were provided the brief scripted education about yoga, the level of interest shifted: 46.4% not interested, 21.8% interested, and 31.8% definitely interested, demonstrating a statistically significant shift in interest following education (χ2 = 22.25, P < .001) (Figure 1). Those with the most positive beliefs about yoga were most likely to indicate interest. Using the BAYS 3-item survey, the mean (SD) for the definitely interested, might be interested, and not interested groups was 15.1 (3.2), 14.1 (3.2), and 12.3 (2.5), respectively (F = 10.63, P < .001).
A multivariable regression was run to examine possible associations between participants’ demographic characteristics, clinical characteristics, and beliefs about yoga as measured by the 3 BAYS items (Table 2). Higher expected health benefits of yoga was associated with identifying as
Six themes were identified in qualitative analysis of semistructured interviews reflecting older veterans’ beliefs about yoga, which were grouped into the following suprathemes of positive vs negative beliefs (Figure 2). Exemplar responses appear in Table 3.
Study 2 Intervention Sample
This sample of 28 veterans was mostly male (96.4%) with a mean (SD) age of 69.2 (10.9) years (range, 57-87). The majority (89.3%) described their race as White, followed by Black/African American (10.7%); no participants self-identified in other categories for race/ethnicity. Twelve veterans (42.9%) had no more than a high school education. The most common cancer diagnosis was genitourinary (35.7%) and the AJCC stage ranged from I to IV.
We employed information learned in study 1 to enhance access in study 2. We mailed letters to 278 veterans diagnosed with cancer in the previous 3 years that provided education about yoga based on study 1 findings. Of 207 veterans reached by phone, 133 (64%) stated they were not interested in coming to a yoga class; 74 (36%) were interested, but 30 felt they were unable to attend due to obstacles such as illness or travel. Ultimately 37 (18%) veterans agreed and consented to the class, and 28 (14%) completed postclass surveys.
In multivariate regression, higher expected health benefits of yoga were associated with higher physical function, lower concern about expected discomfort was also associated with higher physical function as well as higher education; similarly, lower concern about expected social norms was associated with higher physical function. Age was not associated with any of the BAYS factors.
Beliefs about yoga improved from before to after class for all 3 domains with greater expected benefit and lower concerns about discomfort or social norms:
Discussion
Yoga is an effective clinical intervention for addressing some long-term adverse effects in cancer survivors, although the body of research focuses predominantly on middle aged, female, White, college-educated breast cancer survivors. There is no evidence to suggest yoga would be less effective in other groups, but it has not been extensively studied in survivors from diverse subgroups. Beliefs about yoga are a factor that may enhance interest in yoga interventions and research, and measures aimed at addressing potential beliefs and fears may capture information that can be used to support older cancer survivors in holistic health. The aims of this study were to examine beliefs about yoga in 2 samples of older cancer survivors who received VHA care. The main findings are (1) interest in yoga was initially low and lower than that of other complementary or exercise-based interventions, but increased when participants were provided brief education about yoga; (2) interest in yoga was associated with beliefs about yoga with qualitative comments illuminating these beliefs; (3) demographic characteristics (education, race) and physical function were associated with beliefs about yoga; and (4) positive beliefs about yoga increased following a brief yoga intervention and was associated with improvements in physical function.
Willingness to consider a class appeared to shift for some older veterans when they were presented brief information about yoga that explained what is involved, how it might help, and that it could be done from a chair if needed. These findings clearly indicated that when trying to enhance participation in yoga in clinical or research programs, it will be important that recruitment materials provide such information. This finding is consistent with the qualitative findings that reflected a lack of knowledge or skepticism about benefits of yoga among some participants. Given the finding that physical function was associated with beliefs about yoga and was also a prominent theme in qualitative analyses,
Age was not associated with beliefs about yoga in either study. Importantly, in a more detailed study 1 follow-up analysis, beliefs about yoga were equivalent for aged > 70 years compared with those aged 40 to 69 years. It is not entirely clear why older adults have been underrepresented in studies of yoga in cancer survivors. However, older adults are vastly underrepresented in clinical trials for many health conditions, even though they are more likely to experience many diseases, including cancer.37 A new National Institutes of Health policy requires that individuals of all ages, including older adults, must be included in all human subjects research unless there are scientific reasons not to include them.38 It is therefore imperative to consider strategies to address underrepresentation of older adults.
Qualitative findings here suggest it will be important to consider logistical barriers including transportation and affordability as well as adaptations requested by older adults (eg, preferences for older teachers).18
Although our sample was small, we also found that adults from diverse racial and ethnic backgrounds had more positive beliefs about yoga, such that this finding should be interpreted with caution. Similar to older adults, individuals from diverse racial and ethnic groups are also underrepresented in clinical trials and may have lower access to complementary treatments. Cultural and linguistic adaptations and building community partnerships should be considered in both recruitment and intervention delivery strategies.40We learned that education about yoga may increase interest and that it is possible to recruit older veterans to yoga class. Nevertheless, in study 2, our rate of full participation was low, with only about 1 in 10 participating. Additional efforts to enhance beliefs about yoga and to addresslogistical barriers (offering telehealth yoga) are needed to best reach older veterans.
Limitations
These findings have several limitations. First, participants were homogeneous in age, gender, race/ethnicity and veteran status, which provides a window into this understudied population but limits generalizability and our ability to control across populations. Second, the sample size limited the ability to conduct subgroup and interaction analyses, such as examining potential differential effects of cancer type, treatment, and PTSD on yoga beliefs or to consider the relationship of yoga beliefs with changes in quality of life before and after the yoga intervention in study 2. Additionally, age was not associated with beliefs about yoga in these samples that of mostly older adults. We were able to compare middle-aged and older adults but could not compare beliefs about yoga to adults aged in their 20s and 30s. Last, our study excluded people with dementia and psychotic disorders. Further research is needed to examine yoga for older cancer survivors who have these conditions.
Conclusions
Education that specifically informs potential participants about yoga practice, potential modifications, and potential benefits, as well as adaptations to programs that address physical and logistical barriers may be useful in increasing access to and participation in yoga for older Veterans who are cancer survivors.
Acknowledgments/Funding
The authors have no financial or personal relationships to disclose. This work was supported by the US Department of Veterans Affairs (VA) Rehabilitation Research and Development Service. This material is the result of work supported with resources and the use of facilities at the VA Boston Healthcare System, Bedford VA Medical Center, and Michael E. DeBakey VA Medical Center in Houston, Texas. We thank the members of the Veterans Cancer Rehabilitation Study (Vetcares) Research teams in Boston and in Houston and the veterans who have participated in our research studies and allow us to contribute to their health care.
1. Mustian KM, Sprod LK, Janelsins M, et al. Multicenter, randomized controlled trial of yoga for sleep quality among cancer survivors. J Clin Oncol. 2013;31(26):3233-3241. doi:10.1200/JCO.2012.43.7707
2. Chandwani KD, Thornton B, Perkins GH, et al. Yoga improves quality of life and benefit finding in women undergoing radiotherapy for breast cancer. J Soc Integr Oncol. 2010;8(2):43-55.
3. Erratum: Primary follicular lymphoma of disguised as multiple miliary like lesions: A case report and review of literature. Indian J Pathol Microbiol. 2018;61(4):643. doi:10.4103/0377-4929.243009
4. Eyigor S, Uslu R, Apaydın S, Caramat I, Yesil H. Can yoga have any effect on shoulder and arm pain and quality of life in patients with breast cancer? A randomized, controlled, single-blind trial. Complement Ther Clin Pract. 2018;32:40-45. doi:10.1016/j.ctcp.2018.04.010
5. Loudon A, Barnett T, Piller N, Immink MA, Williams AD. Yoga management of breast cancer-related lymphoedema: a randomised controlled pilot-trial. BMC Complement Altern Med. 2014;14:214. Published 2014 Jul 1. doi:10.1186/1472-6882-14-214
6. Browning KK, Kue J, Lyons F, Overcash J. Feasibility of mind-body movement programs for cancer survivors. Oncol Nurs Forum. 2017;44(4):446-456. doi:10.1188/17.ONF.446-456
7. Rosenbaum MS, Velde J. The effects of yoga, massage, and reiki on patient well-being at a cancer resource center. Clin J Oncol Nurs. 2016;20(3):E77-E81. doi:10.1188/16.CJON.E77-E81
8. Yun H, Sun L, Mao JJ. Growth of integrative medicine at leading cancer centers between 2009 and 2016: a systematic analysis of NCI-designated comprehensive cancer center websites. J Natl Cancer Inst Monogr. 2017;2017(52):lgx004. doi:10.1093/jncimonographs/lgx004
9. Sanft T, Denlinger CS, Armenian S, et al. NCCN guidelines insights: survivorship, version 2.2019. J Natl Compr Canc Netw. 2019;17(7):784-794. doi:10.6004/jnccn.2019.0034
10. Lyman GH, Greenlee H, Bohlke K, et al. Integrative therapies during and after breast cancer treatment: ASCO endorsement of the SIO clinical practice guideline. J Clin Oncol. 2018;36(25):2647-2655. doi:10.1200/JCO.2018.79.2721
11. Culos-Reed SN, Mackenzie MJ, Sohl SJ, Jesse MT, Zahavich AN, Danhauer SC. Yoga & cancer interventions: a review of the clinical significance of patient reported outcomes for cancer survivors. Evid Based Complement Alternat Med. 2012;2012:642576. doi:10.1155/2012/642576
12. Danhauer SC, Addington EL, Cohen L, et al. Yoga for symptom management in oncology: a review of the evidence base and future directions for research. Cancer. 2019;125(12):1979-1989. doi:10.1002/cncr.31979
13. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34. doi:10.3322/caac.21551
14. US Department of Veterans Affairs. Veterans’ diseases associated with Agent Orange. Updated June 16, 2021. Accessed September 22, 2021. https://www.publichealth.va.gov/exposures/agentorange/conditions
15. Deimling GT, Arendt JA, Kypriotakis G, Bowman KF. Functioning of older, long-term cancer survivors: the role of cancer and comorbidities. J Am Geriatr Soc. 2009;57(suppl 2):S289-S292. doi:10.1111/j.1532-5415.2009.02515.x
16. King K, Gosian J, Doherty K, et al. Implementing yoga therapy adapted for older veterans who are cancer survivors. Int J Yoga Therap. 2014;24:87-96.
17. Wertman A, Wister AV, Mitchell BA. On and off the mat: yoga experiences of middle-aged and older adults. Can J Aging. 2016;35(2):190-205. doi:10.1017/S0714980816000155
18. Chen KM, Wang HH, Li CH, Chen MH. Community vs. institutional elders’ evaluations of and preferences for yoga exercises. J Clin Nurs. 2011;20(7-8):1000-1007. doi:10.1111/j.1365-2702.2010.03337.x
19. Saravanakumar P, Higgins IJ, Van Der Riet PJ, Sibbritt D. Tai chi and yoga in residential aged care: perspectives of participants: A qualitative study. J Clin Nurs. 2018;27(23-24):4390-4399. doi:10.1111/jocn.14590
20. Fan JT, Chen KM. Using silver yoga exercises to promote physical and mental health of elders with dementia in long-term care facilities. Int Psychogeriatr. 2011;23(8):1222-1230. doi:10.1017/S1041610211000287
21. Taylor TR, Barrow J, Makambi K, et al. A restorative yoga intervention for African-American breast cancer survivors: a pilot study. J Racial Ethn Health Disparities. 2018;5(1):62-72. doi:10.1007/s40615-017-0342-4
22. Moadel AB, Shah C, Wylie-Rosett J, et al. Randomized controlled trial of yoga among a multiethnic sample of breast cancer patients: effects on quality of life. J Clin Oncol. 2007;25(28):4387-4395. doi:10.1200/JCO.2006.06.6027
23. Smith SA, Whitehead MS, Sheats JQ, Chubb B, Alema-Mensah E, Ansa BE. Community engagement to address socio-ecological barriers to physical activity among African American breast cancer survivors. J Ga Public Health Assoc. 2017;6(3):393-397. doi:10.21633/jgpha.6.312
24. Cushing RE, Braun KL, Alden C-Iayt SW, Katz AR. Military-Tailored Yoga for Veterans with Post-traumatic Stress Disorder. Mil Med. 2018;183(5-6):e223-e231. doi:10.1093/milmed/usx071
25. Davis LW, Schmid AA, Daggy JK, et al. Symptoms improve after a yoga program designed for PTSD in a randomized controlled trial with veterans and civilians. Psychol Trauma. 2020;12(8):904-912. doi:10.1037/tra0000564
26. Chopin SM, Sheerin CM, Meyer BL. Yoga for warriors: An intervention for veterans with comorbid chronic pain and PTSD. Psychol Trauma. 2020;12(8):888-896. doi:10.1037/tra0000649
27. US Department of Veterans Affairs. Whole health. Updated September 13, 2021. Accessed September 22, 2021. https://www.va.gov/wholehealth
28. Sohl SJ, Schnur JB, Daly L, Suslov K, Montgomery GH. Development of the beliefs about yoga scale. Int J Yoga Therap. 2011;(21):85-91.
29. Cadmus-Bertram L, Littman AJ, Ulrich CM, et al. Predictors of adherence to a 26-week viniyoga intervention among post-treatment breast cancer survivors. J Altern Complement Med. 2013;19(9):751-758. doi:10.1089/acm.2012.0118
30. Mackenzie MJ, Carlson LE, Ekkekakis P, Paskevich DM, Culos-Reed SN. Affect and mindfulness as predictors of change in mood disturbance, stress symptoms, and quality of life in a community-based yoga program for cancer survivors. Evid Based Complement Alternat Med. 2013;2013:419496. doi:10.1155/2013/419496
31. Naik AD, Martin LA, Karel M, et al. Cancer survivor rehabilitation and recovery: protocol for the Veterans Cancer Rehabilitation Study (Vet-CaRes). BMC Health Serv Res. 2013;13:93. Published 2013 Mar 11. doi:10.1186/1472-6963-13-93
32. Northwestern University. PROMIS Health Organization and the PROMIS Cooperative Group. PROMIS Short Form v2.0 - Physical Function 6b. Accessed September 24, 2021. https://www.healthmeasures.net/index.php?option=com_instruments&view=measure&id=793&Itemid=992
33. Northwestern University. PROMIS Health Organization and the PROMIS Cooperative Group. PROMIS Short Form v1.0 - Anxiety 6a. Accessed September 24, 2021. https://www.healthmeasures.net/index.php?option=com_instruments&view=measure&id=145&Itemid=992
34. Northwestern University. PROMIS Health Organization and the PROMIS Cooperative Group. PROMIS-43 Profile v2.1. Accessed September 24, 2021. https://www.healthmeasures.net/index.php?option=com_instruments&view=measure&id=858&Itemid=992
35. Todd NJ, Jones SH, Lobban FA. “Recovery” in bipolar disorder: how can service users be supported through a self-management intervention? A qualitative focus group study. J Ment Health. 2012;21(2):114-126. doi:10.3109/09638237.2011.621471
36. Finlay L. “Outing” the researcher: the provenance, process, and practice of reflexivity. Qual Health Res. 2002;12(4):531-545. doi:10.1177/104973202129120052
37. Herrera AP, Snipes SA, King DW, Torres-Vigil I, Goldberg DS, Weinberg AD. Disparate inclusion of older adults in clinical trials: priorities and opportunities for policy and practice change. Am J Public Health. 2010;10(suppl 1):S105-S112. doi:10.2105/AJPH.2009.162982
38. National Institutes of Health. Revision: NIH policy and guidelines on the inclusion of individuals across the lifespan as participants in research involving human subjects. Published December 19, 2017. Accessed September 22, 2021. https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-116.html
39. Townsley CA, Selby R, Siu LL. Systematic review of barriers to the recruitment of older patients with cancer onto clinical trials. J Clin Oncol. 2005;23(13):3112-3124. doi:10.1200/JCO.2005.00.141
40. Vuong I, Wright J, Nolan MB, et al. Overcoming barriers: evidence-based strategies to increase enrollment of underrepresented populations in cancer therapeutic clinical trials-a narrative review. J Cancer Educ. 2020;35(5):841-849. doi:10.1007/s13187-019-01650-y
1. Mustian KM, Sprod LK, Janelsins M, et al. Multicenter, randomized controlled trial of yoga for sleep quality among cancer survivors. J Clin Oncol. 2013;31(26):3233-3241. doi:10.1200/JCO.2012.43.7707
2. Chandwani KD, Thornton B, Perkins GH, et al. Yoga improves quality of life and benefit finding in women undergoing radiotherapy for breast cancer. J Soc Integr Oncol. 2010;8(2):43-55.
3. Erratum: Primary follicular lymphoma of disguised as multiple miliary like lesions: A case report and review of literature. Indian J Pathol Microbiol. 2018;61(4):643. doi:10.4103/0377-4929.243009
4. Eyigor S, Uslu R, Apaydın S, Caramat I, Yesil H. Can yoga have any effect on shoulder and arm pain and quality of life in patients with breast cancer? A randomized, controlled, single-blind trial. Complement Ther Clin Pract. 2018;32:40-45. doi:10.1016/j.ctcp.2018.04.010
5. Loudon A, Barnett T, Piller N, Immink MA, Williams AD. Yoga management of breast cancer-related lymphoedema: a randomised controlled pilot-trial. BMC Complement Altern Med. 2014;14:214. Published 2014 Jul 1. doi:10.1186/1472-6882-14-214
6. Browning KK, Kue J, Lyons F, Overcash J. Feasibility of mind-body movement programs for cancer survivors. Oncol Nurs Forum. 2017;44(4):446-456. doi:10.1188/17.ONF.446-456
7. Rosenbaum MS, Velde J. The effects of yoga, massage, and reiki on patient well-being at a cancer resource center. Clin J Oncol Nurs. 2016;20(3):E77-E81. doi:10.1188/16.CJON.E77-E81
8. Yun H, Sun L, Mao JJ. Growth of integrative medicine at leading cancer centers between 2009 and 2016: a systematic analysis of NCI-designated comprehensive cancer center websites. J Natl Cancer Inst Monogr. 2017;2017(52):lgx004. doi:10.1093/jncimonographs/lgx004
9. Sanft T, Denlinger CS, Armenian S, et al. NCCN guidelines insights: survivorship, version 2.2019. J Natl Compr Canc Netw. 2019;17(7):784-794. doi:10.6004/jnccn.2019.0034
10. Lyman GH, Greenlee H, Bohlke K, et al. Integrative therapies during and after breast cancer treatment: ASCO endorsement of the SIO clinical practice guideline. J Clin Oncol. 2018;36(25):2647-2655. doi:10.1200/JCO.2018.79.2721
11. Culos-Reed SN, Mackenzie MJ, Sohl SJ, Jesse MT, Zahavich AN, Danhauer SC. Yoga & cancer interventions: a review of the clinical significance of patient reported outcomes for cancer survivors. Evid Based Complement Alternat Med. 2012;2012:642576. doi:10.1155/2012/642576
12. Danhauer SC, Addington EL, Cohen L, et al. Yoga for symptom management in oncology: a review of the evidence base and future directions for research. Cancer. 2019;125(12):1979-1989. doi:10.1002/cncr.31979
13. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34. doi:10.3322/caac.21551
14. US Department of Veterans Affairs. Veterans’ diseases associated with Agent Orange. Updated June 16, 2021. Accessed September 22, 2021. https://www.publichealth.va.gov/exposures/agentorange/conditions
15. Deimling GT, Arendt JA, Kypriotakis G, Bowman KF. Functioning of older, long-term cancer survivors: the role of cancer and comorbidities. J Am Geriatr Soc. 2009;57(suppl 2):S289-S292. doi:10.1111/j.1532-5415.2009.02515.x
16. King K, Gosian J, Doherty K, et al. Implementing yoga therapy adapted for older veterans who are cancer survivors. Int J Yoga Therap. 2014;24:87-96.
17. Wertman A, Wister AV, Mitchell BA. On and off the mat: yoga experiences of middle-aged and older adults. Can J Aging. 2016;35(2):190-205. doi:10.1017/S0714980816000155
18. Chen KM, Wang HH, Li CH, Chen MH. Community vs. institutional elders’ evaluations of and preferences for yoga exercises. J Clin Nurs. 2011;20(7-8):1000-1007. doi:10.1111/j.1365-2702.2010.03337.x
19. Saravanakumar P, Higgins IJ, Van Der Riet PJ, Sibbritt D. Tai chi and yoga in residential aged care: perspectives of participants: A qualitative study. J Clin Nurs. 2018;27(23-24):4390-4399. doi:10.1111/jocn.14590
20. Fan JT, Chen KM. Using silver yoga exercises to promote physical and mental health of elders with dementia in long-term care facilities. Int Psychogeriatr. 2011;23(8):1222-1230. doi:10.1017/S1041610211000287
21. Taylor TR, Barrow J, Makambi K, et al. A restorative yoga intervention for African-American breast cancer survivors: a pilot study. J Racial Ethn Health Disparities. 2018;5(1):62-72. doi:10.1007/s40615-017-0342-4
22. Moadel AB, Shah C, Wylie-Rosett J, et al. Randomized controlled trial of yoga among a multiethnic sample of breast cancer patients: effects on quality of life. J Clin Oncol. 2007;25(28):4387-4395. doi:10.1200/JCO.2006.06.6027
23. Smith SA, Whitehead MS, Sheats JQ, Chubb B, Alema-Mensah E, Ansa BE. Community engagement to address socio-ecological barriers to physical activity among African American breast cancer survivors. J Ga Public Health Assoc. 2017;6(3):393-397. doi:10.21633/jgpha.6.312
24. Cushing RE, Braun KL, Alden C-Iayt SW, Katz AR. Military-Tailored Yoga for Veterans with Post-traumatic Stress Disorder. Mil Med. 2018;183(5-6):e223-e231. doi:10.1093/milmed/usx071
25. Davis LW, Schmid AA, Daggy JK, et al. Symptoms improve after a yoga program designed for PTSD in a randomized controlled trial with veterans and civilians. Psychol Trauma. 2020;12(8):904-912. doi:10.1037/tra0000564
26. Chopin SM, Sheerin CM, Meyer BL. Yoga for warriors: An intervention for veterans with comorbid chronic pain and PTSD. Psychol Trauma. 2020;12(8):888-896. doi:10.1037/tra0000649
27. US Department of Veterans Affairs. Whole health. Updated September 13, 2021. Accessed September 22, 2021. https://www.va.gov/wholehealth
28. Sohl SJ, Schnur JB, Daly L, Suslov K, Montgomery GH. Development of the beliefs about yoga scale. Int J Yoga Therap. 2011;(21):85-91.
29. Cadmus-Bertram L, Littman AJ, Ulrich CM, et al. Predictors of adherence to a 26-week viniyoga intervention among post-treatment breast cancer survivors. J Altern Complement Med. 2013;19(9):751-758. doi:10.1089/acm.2012.0118
30. Mackenzie MJ, Carlson LE, Ekkekakis P, Paskevich DM, Culos-Reed SN. Affect and mindfulness as predictors of change in mood disturbance, stress symptoms, and quality of life in a community-based yoga program for cancer survivors. Evid Based Complement Alternat Med. 2013;2013:419496. doi:10.1155/2013/419496
31. Naik AD, Martin LA, Karel M, et al. Cancer survivor rehabilitation and recovery: protocol for the Veterans Cancer Rehabilitation Study (Vet-CaRes). BMC Health Serv Res. 2013;13:93. Published 2013 Mar 11. doi:10.1186/1472-6963-13-93
32. Northwestern University. PROMIS Health Organization and the PROMIS Cooperative Group. PROMIS Short Form v2.0 - Physical Function 6b. Accessed September 24, 2021. https://www.healthmeasures.net/index.php?option=com_instruments&view=measure&id=793&Itemid=992
33. Northwestern University. PROMIS Health Organization and the PROMIS Cooperative Group. PROMIS Short Form v1.0 - Anxiety 6a. Accessed September 24, 2021. https://www.healthmeasures.net/index.php?option=com_instruments&view=measure&id=145&Itemid=992
34. Northwestern University. PROMIS Health Organization and the PROMIS Cooperative Group. PROMIS-43 Profile v2.1. Accessed September 24, 2021. https://www.healthmeasures.net/index.php?option=com_instruments&view=measure&id=858&Itemid=992
35. Todd NJ, Jones SH, Lobban FA. “Recovery” in bipolar disorder: how can service users be supported through a self-management intervention? A qualitative focus group study. J Ment Health. 2012;21(2):114-126. doi:10.3109/09638237.2011.621471
36. Finlay L. “Outing” the researcher: the provenance, process, and practice of reflexivity. Qual Health Res. 2002;12(4):531-545. doi:10.1177/104973202129120052
37. Herrera AP, Snipes SA, King DW, Torres-Vigil I, Goldberg DS, Weinberg AD. Disparate inclusion of older adults in clinical trials: priorities and opportunities for policy and practice change. Am J Public Health. 2010;10(suppl 1):S105-S112. doi:10.2105/AJPH.2009.162982
38. National Institutes of Health. Revision: NIH policy and guidelines on the inclusion of individuals across the lifespan as participants in research involving human subjects. Published December 19, 2017. Accessed September 22, 2021. https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-116.html
39. Townsley CA, Selby R, Siu LL. Systematic review of barriers to the recruitment of older patients with cancer onto clinical trials. J Clin Oncol. 2005;23(13):3112-3124. doi:10.1200/JCO.2005.00.141
40. Vuong I, Wright J, Nolan MB, et al. Overcoming barriers: evidence-based strategies to increase enrollment of underrepresented populations in cancer therapeutic clinical trials-a narrative review. J Cancer Educ. 2020;35(5):841-849. doi:10.1007/s13187-019-01650-y
Cavitary Lung Lesion in a Tuberculosis-Negative Patient
A patient with worsening chronic cough, shortness of breath, and hemoptysis tested negative for tuberculosis; but a chest computed tomography scan showed an upper left lobe cavitary lesion.
A 71-year-old, currently homeless male veteran with a 29 pack-year history of smoking and history of alcohol abuse presented to the emergency department at Washington DC Veterans Affairs Medical Center with worsening chronic cough and shortness of breath. He had no history of HIV or immunosuppressant medications. Four weeks prior, he was treated at an outpatient urgent care for community acquired pneumonia with a 10-day course of oral amoxicillin/clavulanic acid 875 mg twice daily and azithromycin 500 mg day 1, then 250 mg days 2 through 5. Despite antibiotic therapy, his symptoms continued to worsen, and he developed hemoptysis. He also reported weight loss of 20 lb in the past 3 months despite a strong appetite and adequate oral intake. He reported no fevers and night sweats. A review of the patient’s systems was otherwise unremarkable.
On examination, the patient was afebrile at 37.2 °C but tachycardic at 108 beats/min. He also was tachypneic at 22 breaths/min with an oxygen saturation of 89% on room air. Decreased breath sounds in the left upper lobe were noted on auscultation of the lung fields. Laboratory test results were notable for a leukocytosis of 14.3 k/μL (reference range, 4-11k/μL) and an elevated erythrocyte sedimentation rate (ESR) of 25.08 mm/h (reference range, 0-16 mm/h) and C-reactive protein (CRP) of 4.75 mg/L (reference range, 0.00-3.00 mg/L). Liver-associated enzymes and a coagulation panel were within normal limits. His QuantiFERON-TB Gold tuberculosis (TB) blood test was negative. A computed tomography (CT) scan of the chest was obtained, which showed an interval increase of a known upper left lobe cavitary lesion compared with that of prior imaging and the presence of a ball-shaped lesion in the cavity (Figures 1 and 2).
In addition to the imaging, the patient underwent bronchoscopy with bronchoalveolar lavage (BAL) to further evaluate the upper left lobe cavitary lesion. The differential diagnosis for pulmonary cavities is described in the Table. The BAL aspirates were negative for acid-fast bacteria; however, periodic acid–Schiff stain and Grocott methenamine silver stain showed fungal elements. He was diagnosed with chronic cavitary pulmonary aspergillosis (CCPA), confirmed with serum antigen (galactomannan assay) and serum immunoglobulin G (IgG) positive for Aspergillus fumigatus (A fumigatus). Mycologic cultures were positive for A fumigatus.
Discussion
Aspergillomas are accumulations of Aspergillus spp hyphae, fibrin, and other inflammatory components that typically occur in preexisting pulmonary cavities.1 They are most frequently caused by A fumigatus, which is ubiquitous in the environment and acquired via inhalation of airborne spores in 90% of cases.2 The typical ball-shaped appearance forms when hyphae growing along the inside walls of the cavity ultimately fall inward, usually leaving a surrounding pocket of air that can be seen on diagnostic imaging. CCPA falls within the chronic pulmonary aspergillosis (CPA) category, which includes a spectrum of other subtypes to include single aspergillomas, Aspergillus nodules, and chronic fibrosing pulmonary aspergillosis (CFPA). The prevalence of CPA and its subtypes are limited to case reports and case series in the literature, with reported rates differing up to 40-fold based on region, treatment, and diagnosis criteria.3,4 Models developed by Denning and colleagues mirror those used by The World Health Organization and estimate 1.2 million people have CPA as a sequela to pulmonary TB globally.5
A single aspergilloma (simple aspergilloma) is typically not invasive, whereas CCPA (complex aspergilloma) is the most common CPA and can behave more invasively.6,7 Both can occur in immunocompetent hosts. One study followed 140 individuals with aspergillomas for more than 7 years and found that 60.8% of aspergillomas remained stable in size, while 25.9% increased and 13.3% decreased in size. Half of cases were complicated by hemoptysis, but only 4.2% of cases became invasive.8 Roughly 70% of aspergillomas occur in individuals with a previous history of TB, but any pulmonary cavity can put a patient at increased risk.
Cases have been observed in patients with pulmonary cysts, emphysema/chronic obstructive pulmonary disease, bullae, lung cancer, sarcoidosis, other fungal cavities, and previous lung surgeries.9 Because of its association with CPA, TB testing should be completed as part of the workup as was the case in our patient. Although QuantiFERON-TB Gold has an estimated sensitivity of 92% per the manufacturer’s package insert, results can vary depending on the setting and extent of the TB.10
Clinical features of Aspergillus infection in immunocompetent individuals include weight loss, chronic nonproductive cough, hemoptysis of variable severity, fatigue, and/or shortness of breath.11 CT is the imaging modality of choice and will typically show an upper-lobe cavitation with or without a fungal ball. For patients with suspicious imaging, laboratory testing with serum Aspergillus IgG antibodies should be performed. Aspergillus antigen testing is performed with galactomannan enzyme immunoassay, which detects galactomannan, a polysaccharide antigen that exists primarily in the cell walls of Aspergillus spp. This should be performed on BAL washings rather than serum, however, as serum testing has poor sensitivity.11 Sputum culture is not very sensitive, and although the polymerase chain reaction of sputum and BAL fluid are more sensitive than culture, false-positive results can occur with transient colonization or contamination of samples.11,12 Elevations of inflammatory markers, namely ESR and CRP, are commonly present but not specific for CPA.
Denning and colleagues propose the following criteria for diagnosing CCPA: one large cavity or 2 or more cavities on chest imaging with or without a fungal ball (aspergilloma) in one or more of the cavities (exclude patients with other chronic fungal cavitary lesions, eg, pulmonary histoplasmosis, coccidioidomycosis, and paracoccidioidomycosis); and at least one of the following symptoms for at least 3 months: fever, weight loss, fatigue, cough, sputum production, hemoptysis, or shortness of breath; and a positive Aspergillus IgG with or without culture of Aspergillus spp from the lungs.11Our case fulfills the diagnostic criteria for CCPA. The ≥ 3 months of weight loss was useful in differentiating this case from a single aspergilloma in which the role of antifungal treatment remains unclear especially in those who are asymptomatic.2 In those with single aspergillomas with significant hemoptysis, embolization may be required. In the management of localized CCPA, surgical excision is recommended and curative in many cases.6,11 If left untreated, CCPA carries a 5-year mortality rate as high as 80% and often is accompanied with progression to CFPA, the terminal fibrosing evolution of CCPA, resulting in major fibrotic lung destruction.6 Oral azoles with or without surgical management also are useful in preventing clinical and radiologic progression.6
A multidisciplinary team, including infectious disease and surgery carefully discussed treatment options with the patient. Surgery was offered and the patient declined. We then decided on a trial of medical management alone based on shared decision making. In accordance with the recommendations from our infectious disease colleagues, the patient was started on a voriconazole 200 mg orally twice daily. Duration of therapy was planned for 6 months, with close monitoring of hepatic function, serum electrolytes, and visual function.13
Conclusions
This case highlights important differences among the CPA subtypes and how management differs based on etiology. Diagnostic criteria for CCPA were discussed, and in any patient with the constellation of the symptoms described with one or more cavitary lesions noted on imaging, CCPA should be considered regardless of immunocompetence. A multidisciplinary treatment approach with medical and surgical considerations is crucial to prevent progression to CFPA.
1. Kon K, Rai M, eds. The Microbiology of Respiratory System Infections. Academic Press; 2016.
2. Alguire P, Chick D, eds. ACP MKSAP 18: Medical Knowledge Self-Assessment Program. American College of Physicians; 2018.
3. Tuberculosis Association. Aspergilloma and residual tuberculous cavities. The results of a resurvey. Tubercle. 1970;51(3):227-245.
4. Tuberculosis Association. Aspergillus in persistent lung cavities after tuberculosis. A report from the Research Committee of the British Tuberculosis Association. Tubercle. 968;49(1):1-11.
5. Denning DW, Pleuvry A, Cole DC. Global burden of chronic pulmonary aspergillosis as a sequel to pulmonary tuberculosis. Bull World Health Organ. 2011;89(12):864-872. doi:10.2471/BLT.11.089441
6. Page ID, Byanyima R, Hosmane S, et al. Chronic pulmonary aspergillosis commonly complicates treated pulmonary tuberculosis with residual cavitation. Eur Respir J. 2019;53(3):1801184. doi:10.1183/13993003.01184-2018
7. Kousha, M, Tadi R, Soubani AO. Pulmonary aspergillosis: a clinical review. Eur Respir Rev. 2011;20(121):156-174. doi:10.1183/09059180.00001011
8. Lee JK, Lee Y, Park SS, et al. Clinical course and prognostic factors of pulmonary aspergilloma. Respirology. 2014;19(7):1066-1072. doi:10.1111/resp.12344
9. Kawamura S, Maesaki S, Tomono K, Tashiro T, Kohno S. Clinical evaluation of 61 patients with pulmonary aspergilloma. Intern Med. 2000;39(3):209-212. doi:10.2169/internalmedicine.39.209
10. QuantiFERON-TB Gold ELISA. Package insert. Qiagen; November 2019.
11. Denning DW, Cadranel J, Beigelman-Aubry C, et al; European Society for Clinical Microbiology and Infectious Diseases and European Respiratory Society. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J. 2016;47(1):45-68. doi:10.1183/13993003.00583-2015. PMID: 26699723.
12. Denning DW, Park S, Lass-Florl C, et al. High-frequency triazole resistance found in nonculturable Aspergillus fumigatus from lungs of patients with chronic fungal disease. Clin Infect Dis. 2011;52(9):1123-9. doi:10.1093/cid/cir179
13. Patterson TF, Thompson GR III, Denning DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1-e60. doi:10.1093/cid/ciw326
A patient with worsening chronic cough, shortness of breath, and hemoptysis tested negative for tuberculosis; but a chest computed tomography scan showed an upper left lobe cavitary lesion.
A 71-year-old, currently homeless male veteran with a 29 pack-year history of smoking and history of alcohol abuse presented to the emergency department at Washington DC Veterans Affairs Medical Center with worsening chronic cough and shortness of breath. He had no history of HIV or immunosuppressant medications. Four weeks prior, he was treated at an outpatient urgent care for community acquired pneumonia with a 10-day course of oral amoxicillin/clavulanic acid 875 mg twice daily and azithromycin 500 mg day 1, then 250 mg days 2 through 5. Despite antibiotic therapy, his symptoms continued to worsen, and he developed hemoptysis. He also reported weight loss of 20 lb in the past 3 months despite a strong appetite and adequate oral intake. He reported no fevers and night sweats. A review of the patient’s systems was otherwise unremarkable.
On examination, the patient was afebrile at 37.2 °C but tachycardic at 108 beats/min. He also was tachypneic at 22 breaths/min with an oxygen saturation of 89% on room air. Decreased breath sounds in the left upper lobe were noted on auscultation of the lung fields. Laboratory test results were notable for a leukocytosis of 14.3 k/μL (reference range, 4-11k/μL) and an elevated erythrocyte sedimentation rate (ESR) of 25.08 mm/h (reference range, 0-16 mm/h) and C-reactive protein (CRP) of 4.75 mg/L (reference range, 0.00-3.00 mg/L). Liver-associated enzymes and a coagulation panel were within normal limits. His QuantiFERON-TB Gold tuberculosis (TB) blood test was negative. A computed tomography (CT) scan of the chest was obtained, which showed an interval increase of a known upper left lobe cavitary lesion compared with that of prior imaging and the presence of a ball-shaped lesion in the cavity (Figures 1 and 2).
In addition to the imaging, the patient underwent bronchoscopy with bronchoalveolar lavage (BAL) to further evaluate the upper left lobe cavitary lesion. The differential diagnosis for pulmonary cavities is described in the Table. The BAL aspirates were negative for acid-fast bacteria; however, periodic acid–Schiff stain and Grocott methenamine silver stain showed fungal elements. He was diagnosed with chronic cavitary pulmonary aspergillosis (CCPA), confirmed with serum antigen (galactomannan assay) and serum immunoglobulin G (IgG) positive for Aspergillus fumigatus (A fumigatus). Mycologic cultures were positive for A fumigatus.
Discussion
Aspergillomas are accumulations of Aspergillus spp hyphae, fibrin, and other inflammatory components that typically occur in preexisting pulmonary cavities.1 They are most frequently caused by A fumigatus, which is ubiquitous in the environment and acquired via inhalation of airborne spores in 90% of cases.2 The typical ball-shaped appearance forms when hyphae growing along the inside walls of the cavity ultimately fall inward, usually leaving a surrounding pocket of air that can be seen on diagnostic imaging. CCPA falls within the chronic pulmonary aspergillosis (CPA) category, which includes a spectrum of other subtypes to include single aspergillomas, Aspergillus nodules, and chronic fibrosing pulmonary aspergillosis (CFPA). The prevalence of CPA and its subtypes are limited to case reports and case series in the literature, with reported rates differing up to 40-fold based on region, treatment, and diagnosis criteria.3,4 Models developed by Denning and colleagues mirror those used by The World Health Organization and estimate 1.2 million people have CPA as a sequela to pulmonary TB globally.5
A single aspergilloma (simple aspergilloma) is typically not invasive, whereas CCPA (complex aspergilloma) is the most common CPA and can behave more invasively.6,7 Both can occur in immunocompetent hosts. One study followed 140 individuals with aspergillomas for more than 7 years and found that 60.8% of aspergillomas remained stable in size, while 25.9% increased and 13.3% decreased in size. Half of cases were complicated by hemoptysis, but only 4.2% of cases became invasive.8 Roughly 70% of aspergillomas occur in individuals with a previous history of TB, but any pulmonary cavity can put a patient at increased risk.
Cases have been observed in patients with pulmonary cysts, emphysema/chronic obstructive pulmonary disease, bullae, lung cancer, sarcoidosis, other fungal cavities, and previous lung surgeries.9 Because of its association with CPA, TB testing should be completed as part of the workup as was the case in our patient. Although QuantiFERON-TB Gold has an estimated sensitivity of 92% per the manufacturer’s package insert, results can vary depending on the setting and extent of the TB.10
Clinical features of Aspergillus infection in immunocompetent individuals include weight loss, chronic nonproductive cough, hemoptysis of variable severity, fatigue, and/or shortness of breath.11 CT is the imaging modality of choice and will typically show an upper-lobe cavitation with or without a fungal ball. For patients with suspicious imaging, laboratory testing with serum Aspergillus IgG antibodies should be performed. Aspergillus antigen testing is performed with galactomannan enzyme immunoassay, which detects galactomannan, a polysaccharide antigen that exists primarily in the cell walls of Aspergillus spp. This should be performed on BAL washings rather than serum, however, as serum testing has poor sensitivity.11 Sputum culture is not very sensitive, and although the polymerase chain reaction of sputum and BAL fluid are more sensitive than culture, false-positive results can occur with transient colonization or contamination of samples.11,12 Elevations of inflammatory markers, namely ESR and CRP, are commonly present but not specific for CPA.
Denning and colleagues propose the following criteria for diagnosing CCPA: one large cavity or 2 or more cavities on chest imaging with or without a fungal ball (aspergilloma) in one or more of the cavities (exclude patients with other chronic fungal cavitary lesions, eg, pulmonary histoplasmosis, coccidioidomycosis, and paracoccidioidomycosis); and at least one of the following symptoms for at least 3 months: fever, weight loss, fatigue, cough, sputum production, hemoptysis, or shortness of breath; and a positive Aspergillus IgG with or without culture of Aspergillus spp from the lungs.11Our case fulfills the diagnostic criteria for CCPA. The ≥ 3 months of weight loss was useful in differentiating this case from a single aspergilloma in which the role of antifungal treatment remains unclear especially in those who are asymptomatic.2 In those with single aspergillomas with significant hemoptysis, embolization may be required. In the management of localized CCPA, surgical excision is recommended and curative in many cases.6,11 If left untreated, CCPA carries a 5-year mortality rate as high as 80% and often is accompanied with progression to CFPA, the terminal fibrosing evolution of CCPA, resulting in major fibrotic lung destruction.6 Oral azoles with or without surgical management also are useful in preventing clinical and radiologic progression.6
A multidisciplinary team, including infectious disease and surgery carefully discussed treatment options with the patient. Surgery was offered and the patient declined. We then decided on a trial of medical management alone based on shared decision making. In accordance with the recommendations from our infectious disease colleagues, the patient was started on a voriconazole 200 mg orally twice daily. Duration of therapy was planned for 6 months, with close monitoring of hepatic function, serum electrolytes, and visual function.13
Conclusions
This case highlights important differences among the CPA subtypes and how management differs based on etiology. Diagnostic criteria for CCPA were discussed, and in any patient with the constellation of the symptoms described with one or more cavitary lesions noted on imaging, CCPA should be considered regardless of immunocompetence. A multidisciplinary treatment approach with medical and surgical considerations is crucial to prevent progression to CFPA.
A patient with worsening chronic cough, shortness of breath, and hemoptysis tested negative for tuberculosis; but a chest computed tomography scan showed an upper left lobe cavitary lesion.
A 71-year-old, currently homeless male veteran with a 29 pack-year history of smoking and history of alcohol abuse presented to the emergency department at Washington DC Veterans Affairs Medical Center with worsening chronic cough and shortness of breath. He had no history of HIV or immunosuppressant medications. Four weeks prior, he was treated at an outpatient urgent care for community acquired pneumonia with a 10-day course of oral amoxicillin/clavulanic acid 875 mg twice daily and azithromycin 500 mg day 1, then 250 mg days 2 through 5. Despite antibiotic therapy, his symptoms continued to worsen, and he developed hemoptysis. He also reported weight loss of 20 lb in the past 3 months despite a strong appetite and adequate oral intake. He reported no fevers and night sweats. A review of the patient’s systems was otherwise unremarkable.
On examination, the patient was afebrile at 37.2 °C but tachycardic at 108 beats/min. He also was tachypneic at 22 breaths/min with an oxygen saturation of 89% on room air. Decreased breath sounds in the left upper lobe were noted on auscultation of the lung fields. Laboratory test results were notable for a leukocytosis of 14.3 k/μL (reference range, 4-11k/μL) and an elevated erythrocyte sedimentation rate (ESR) of 25.08 mm/h (reference range, 0-16 mm/h) and C-reactive protein (CRP) of 4.75 mg/L (reference range, 0.00-3.00 mg/L). Liver-associated enzymes and a coagulation panel were within normal limits. His QuantiFERON-TB Gold tuberculosis (TB) blood test was negative. A computed tomography (CT) scan of the chest was obtained, which showed an interval increase of a known upper left lobe cavitary lesion compared with that of prior imaging and the presence of a ball-shaped lesion in the cavity (Figures 1 and 2).
In addition to the imaging, the patient underwent bronchoscopy with bronchoalveolar lavage (BAL) to further evaluate the upper left lobe cavitary lesion. The differential diagnosis for pulmonary cavities is described in the Table. The BAL aspirates were negative for acid-fast bacteria; however, periodic acid–Schiff stain and Grocott methenamine silver stain showed fungal elements. He was diagnosed with chronic cavitary pulmonary aspergillosis (CCPA), confirmed with serum antigen (galactomannan assay) and serum immunoglobulin G (IgG) positive for Aspergillus fumigatus (A fumigatus). Mycologic cultures were positive for A fumigatus.
Discussion
Aspergillomas are accumulations of Aspergillus spp hyphae, fibrin, and other inflammatory components that typically occur in preexisting pulmonary cavities.1 They are most frequently caused by A fumigatus, which is ubiquitous in the environment and acquired via inhalation of airborne spores in 90% of cases.2 The typical ball-shaped appearance forms when hyphae growing along the inside walls of the cavity ultimately fall inward, usually leaving a surrounding pocket of air that can be seen on diagnostic imaging. CCPA falls within the chronic pulmonary aspergillosis (CPA) category, which includes a spectrum of other subtypes to include single aspergillomas, Aspergillus nodules, and chronic fibrosing pulmonary aspergillosis (CFPA). The prevalence of CPA and its subtypes are limited to case reports and case series in the literature, with reported rates differing up to 40-fold based on region, treatment, and diagnosis criteria.3,4 Models developed by Denning and colleagues mirror those used by The World Health Organization and estimate 1.2 million people have CPA as a sequela to pulmonary TB globally.5
A single aspergilloma (simple aspergilloma) is typically not invasive, whereas CCPA (complex aspergilloma) is the most common CPA and can behave more invasively.6,7 Both can occur in immunocompetent hosts. One study followed 140 individuals with aspergillomas for more than 7 years and found that 60.8% of aspergillomas remained stable in size, while 25.9% increased and 13.3% decreased in size. Half of cases were complicated by hemoptysis, but only 4.2% of cases became invasive.8 Roughly 70% of aspergillomas occur in individuals with a previous history of TB, but any pulmonary cavity can put a patient at increased risk.
Cases have been observed in patients with pulmonary cysts, emphysema/chronic obstructive pulmonary disease, bullae, lung cancer, sarcoidosis, other fungal cavities, and previous lung surgeries.9 Because of its association with CPA, TB testing should be completed as part of the workup as was the case in our patient. Although QuantiFERON-TB Gold has an estimated sensitivity of 92% per the manufacturer’s package insert, results can vary depending on the setting and extent of the TB.10
Clinical features of Aspergillus infection in immunocompetent individuals include weight loss, chronic nonproductive cough, hemoptysis of variable severity, fatigue, and/or shortness of breath.11 CT is the imaging modality of choice and will typically show an upper-lobe cavitation with or without a fungal ball. For patients with suspicious imaging, laboratory testing with serum Aspergillus IgG antibodies should be performed. Aspergillus antigen testing is performed with galactomannan enzyme immunoassay, which detects galactomannan, a polysaccharide antigen that exists primarily in the cell walls of Aspergillus spp. This should be performed on BAL washings rather than serum, however, as serum testing has poor sensitivity.11 Sputum culture is not very sensitive, and although the polymerase chain reaction of sputum and BAL fluid are more sensitive than culture, false-positive results can occur with transient colonization or contamination of samples.11,12 Elevations of inflammatory markers, namely ESR and CRP, are commonly present but not specific for CPA.
Denning and colleagues propose the following criteria for diagnosing CCPA: one large cavity or 2 or more cavities on chest imaging with or without a fungal ball (aspergilloma) in one or more of the cavities (exclude patients with other chronic fungal cavitary lesions, eg, pulmonary histoplasmosis, coccidioidomycosis, and paracoccidioidomycosis); and at least one of the following symptoms for at least 3 months: fever, weight loss, fatigue, cough, sputum production, hemoptysis, or shortness of breath; and a positive Aspergillus IgG with or without culture of Aspergillus spp from the lungs.11Our case fulfills the diagnostic criteria for CCPA. The ≥ 3 months of weight loss was useful in differentiating this case from a single aspergilloma in which the role of antifungal treatment remains unclear especially in those who are asymptomatic.2 In those with single aspergillomas with significant hemoptysis, embolization may be required. In the management of localized CCPA, surgical excision is recommended and curative in many cases.6,11 If left untreated, CCPA carries a 5-year mortality rate as high as 80% and often is accompanied with progression to CFPA, the terminal fibrosing evolution of CCPA, resulting in major fibrotic lung destruction.6 Oral azoles with or without surgical management also are useful in preventing clinical and radiologic progression.6
A multidisciplinary team, including infectious disease and surgery carefully discussed treatment options with the patient. Surgery was offered and the patient declined. We then decided on a trial of medical management alone based on shared decision making. In accordance with the recommendations from our infectious disease colleagues, the patient was started on a voriconazole 200 mg orally twice daily. Duration of therapy was planned for 6 months, with close monitoring of hepatic function, serum electrolytes, and visual function.13
Conclusions
This case highlights important differences among the CPA subtypes and how management differs based on etiology. Diagnostic criteria for CCPA were discussed, and in any patient with the constellation of the symptoms described with one or more cavitary lesions noted on imaging, CCPA should be considered regardless of immunocompetence. A multidisciplinary treatment approach with medical and surgical considerations is crucial to prevent progression to CFPA.
1. Kon K, Rai M, eds. The Microbiology of Respiratory System Infections. Academic Press; 2016.
2. Alguire P, Chick D, eds. ACP MKSAP 18: Medical Knowledge Self-Assessment Program. American College of Physicians; 2018.
3. Tuberculosis Association. Aspergilloma and residual tuberculous cavities. The results of a resurvey. Tubercle. 1970;51(3):227-245.
4. Tuberculosis Association. Aspergillus in persistent lung cavities after tuberculosis. A report from the Research Committee of the British Tuberculosis Association. Tubercle. 968;49(1):1-11.
5. Denning DW, Pleuvry A, Cole DC. Global burden of chronic pulmonary aspergillosis as a sequel to pulmonary tuberculosis. Bull World Health Organ. 2011;89(12):864-872. doi:10.2471/BLT.11.089441
6. Page ID, Byanyima R, Hosmane S, et al. Chronic pulmonary aspergillosis commonly complicates treated pulmonary tuberculosis with residual cavitation. Eur Respir J. 2019;53(3):1801184. doi:10.1183/13993003.01184-2018
7. Kousha, M, Tadi R, Soubani AO. Pulmonary aspergillosis: a clinical review. Eur Respir Rev. 2011;20(121):156-174. doi:10.1183/09059180.00001011
8. Lee JK, Lee Y, Park SS, et al. Clinical course and prognostic factors of pulmonary aspergilloma. Respirology. 2014;19(7):1066-1072. doi:10.1111/resp.12344
9. Kawamura S, Maesaki S, Tomono K, Tashiro T, Kohno S. Clinical evaluation of 61 patients with pulmonary aspergilloma. Intern Med. 2000;39(3):209-212. doi:10.2169/internalmedicine.39.209
10. QuantiFERON-TB Gold ELISA. Package insert. Qiagen; November 2019.
11. Denning DW, Cadranel J, Beigelman-Aubry C, et al; European Society for Clinical Microbiology and Infectious Diseases and European Respiratory Society. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J. 2016;47(1):45-68. doi:10.1183/13993003.00583-2015. PMID: 26699723.
12. Denning DW, Park S, Lass-Florl C, et al. High-frequency triazole resistance found in nonculturable Aspergillus fumigatus from lungs of patients with chronic fungal disease. Clin Infect Dis. 2011;52(9):1123-9. doi:10.1093/cid/cir179
13. Patterson TF, Thompson GR III, Denning DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1-e60. doi:10.1093/cid/ciw326
1. Kon K, Rai M, eds. The Microbiology of Respiratory System Infections. Academic Press; 2016.
2. Alguire P, Chick D, eds. ACP MKSAP 18: Medical Knowledge Self-Assessment Program. American College of Physicians; 2018.
3. Tuberculosis Association. Aspergilloma and residual tuberculous cavities. The results of a resurvey. Tubercle. 1970;51(3):227-245.
4. Tuberculosis Association. Aspergillus in persistent lung cavities after tuberculosis. A report from the Research Committee of the British Tuberculosis Association. Tubercle. 968;49(1):1-11.
5. Denning DW, Pleuvry A, Cole DC. Global burden of chronic pulmonary aspergillosis as a sequel to pulmonary tuberculosis. Bull World Health Organ. 2011;89(12):864-872. doi:10.2471/BLT.11.089441
6. Page ID, Byanyima R, Hosmane S, et al. Chronic pulmonary aspergillosis commonly complicates treated pulmonary tuberculosis with residual cavitation. Eur Respir J. 2019;53(3):1801184. doi:10.1183/13993003.01184-2018
7. Kousha, M, Tadi R, Soubani AO. Pulmonary aspergillosis: a clinical review. Eur Respir Rev. 2011;20(121):156-174. doi:10.1183/09059180.00001011
8. Lee JK, Lee Y, Park SS, et al. Clinical course and prognostic factors of pulmonary aspergilloma. Respirology. 2014;19(7):1066-1072. doi:10.1111/resp.12344
9. Kawamura S, Maesaki S, Tomono K, Tashiro T, Kohno S. Clinical evaluation of 61 patients with pulmonary aspergilloma. Intern Med. 2000;39(3):209-212. doi:10.2169/internalmedicine.39.209
10. QuantiFERON-TB Gold ELISA. Package insert. Qiagen; November 2019.
11. Denning DW, Cadranel J, Beigelman-Aubry C, et al; European Society for Clinical Microbiology and Infectious Diseases and European Respiratory Society. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J. 2016;47(1):45-68. doi:10.1183/13993003.00583-2015. PMID: 26699723.
12. Denning DW, Park S, Lass-Florl C, et al. High-frequency triazole resistance found in nonculturable Aspergillus fumigatus from lungs of patients with chronic fungal disease. Clin Infect Dis. 2011;52(9):1123-9. doi:10.1093/cid/cir179
13. Patterson TF, Thompson GR III, Denning DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1-e60. doi:10.1093/cid/ciw326