Extended use of systemic hormone therapy represents one area that clinicians commonly encounter. However, because randomized trial data are not available, helping women make decisions regarding long-term use of hormone therapy is controversial. When it is finalized, the 2016 hormone therapy position statement from the North American Menopause Society will address this topic.

Here I’m referring to the patient who likely started systemic hormone therapy when she was a younger, or more recently menopausal, woman (perhaps in her early 50s), but now she’s in her 60s. In my practice, a patient in this age range would likely be on a lower-than-standard dose of hormone therapy than what she began with originally.

And now the question is, Should she continue, or should she stop, hormone therapy? The median duration of bothersome symptoms is about 10 or 11 years, from the best available data – far longer than what many physicians assume.

References

1. Menopause. 2014 Jun;21(6):679-81.

Dr. Kaunitz is a professor and associate chair of the department of obstetrics and gynecology, University of Florida in Jacksonville. He is on the board of trustees of the North American Menopause Society. He reports being a consultant or on the advisory board or review panel of several pharmaceutical companies, and receiving grant support from several pharmaceutical companies. He receives royalties from UpToDate.

Extended use of systemic hormone therapy represents one area that clinicians commonly encounter. However, because randomized trial data are not available, helping women make decisions regarding long-term use of hormone therapy is controversial. When it is finalized, the 2016 hormone therapy position statement from the North American Menopause Society will address this topic.

Here I’m referring to the patient who likely started systemic hormone therapy when she was a younger, or more recently menopausal, woman (perhaps in her early 50s), but now she’s in her 60s. In my practice, a patient in this age range would likely be on a lower-than-standard dose of hormone therapy than what she began with originally.

And now the question is, Should she continue, or should she stop, hormone therapy? The median duration of bothersome symptoms is about 10 or 11 years, from the best available data – far longer than what many physicians assume.

References

1. Menopause. 2014 Jun;21(6):679-81.

Dr. Kaunitz is a professor and associate chair of the department of obstetrics and gynecology, University of Florida in Jacksonville. He is on the board of trustees of the North American Menopause Society. He reports being a consultant or on the advisory board or review panel of several pharmaceutical companies, and receiving grant support from several pharmaceutical companies. He receives royalties from UpToDate.

Extended use of systemic hormone therapy represents one area that clinicians commonly encounter. However, because randomized trial data are not available, helping women make decisions regarding long-term use of hormone therapy is controversial. When it is finalized, the 2016 hormone therapy position statement from the North American Menopause Society will address this topic.

Here I’m referring to the patient who likely started systemic hormone therapy when she was a younger, or more recently menopausal, woman (perhaps in her early 50s), but now she’s in her 60s. In my practice, a patient in this age range would likely be on a lower-than-standard dose of hormone therapy than what she began with originally.

And now the question is, Should she continue, or should she stop, hormone therapy? The median duration of bothersome symptoms is about 10 or 11 years, from the best available data – far longer than what many physicians assume.

References

1. Menopause. 2014 Jun;21(6):679-81.

Dr. Kaunitz is a professor and associate chair of the department of obstetrics and gynecology, University of Florida in Jacksonville. He is on the board of trustees of the North American Menopause Society. He reports being a consultant or on the advisory board or review panel of several pharmaceutical companies, and receiving grant support from several pharmaceutical companies. He receives royalties from UpToDate.

First, I want to correct a misstatement I made in a recent column regarding incident to billing by an extender (Dermatology News, July 2016, p. 1) When an extender sees a patient for an established problem, they can bill at 100% if there is a supervising physician in the house, AND it should be under that supervising physician’s number – NOT necessarily by the physician who saw the original problem. This change was promulgated by the Centers for Medicare & Medicaid Services in the proposed rule, and everyone thought it was a done deal, but the billing remained unchanged in the final rule. Apologies for any confusion.

Coding

As all of you know, in 2010, the Centers for Medicare & Medicaid Services stopped recognizing the Current Procedural Terminology (CPT) consultation codes for Medicare Part B payment CMS decided (after an Office of Inspector General study) that consultations were really just new patient visits and stopped paying for consultations. Visits are now coded with new or follow-up patient evaluation and management codes. This is unfortunate, because a consultation pays more, and importantly, does not establish the patient as a patient in your practice for the next three years. If originally billed as a consultation, the patient can be seen back for another problem in the next three years, and be billed for a consultation, or a new patient as appropriate. Therefore, it is a big advantage to be able to bill for a consultation, assuming another doctor has asked your opinion and you call with or send them a report of your findings.

Just because Medicare says you cannot bill for consultations does not mean that all insurers are the same. The consultation codes are still in the CPT code book and your contracts with private insurers probably stipulate that the insurers must comply with CPT convention. In this case, you can bill your private insurers (including Medicare Advantage Plans, which are private insurers) for consultations when your documentation supports it. Be aware, that some of the more popular electronic health records that perform billing automatically default to a new patient visit, when a new patient consultation might be more appropriate.

While discussing evaluation and management coding, you should be aware that 97% of visits billed by dermatologists are level 3 or lower. This means that, even if your EHR can propel you to heights unimagined before, that it could become a problem. You cannot bill a higher level beyond what is medically appropriate. For example, you don’t usually need to do a full-body skin exam during an acne follow-up.

I’ll never forget the poor soul who explained to me that she was being audited “because all my visits were level 4 or 5, and the software agreed with it.” The software company (or the consultant) will not be sharing the joys of an audit with you. You can do a quick and easy check of your evaluation and management patterns, compared with others by checking either of the online Medicare databases, the Wall Street Journal’s “Medicare Unmasked” site or the “Treatment Tracker” for Doctors and Services in Medicare Part B, on the ProPublica website.

While you are there, check your procedure numbers against others. Are you a freeze-y king? Are you the shave master? There are often valid and justifiable reasons for unusual billing patterns. If you are an outlier, make sure you have a good reason to be there. For example, I am in the top 10% paid per patient visit in the state of Ohio. The reason is that I treat only skin cancer, and it usually involves surgery. The world is looking at these data. So should you.

Dr. Coldiron is a past president of the American Academy of Dermatology. He is currently in private practice, but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. Write to him at [email protected].

First, I want to correct a misstatement I made in a recent column regarding incident to billing by an extender (Dermatology News, July 2016, p. 1) When an extender sees a patient for an established problem, they can bill at 100% if there is a supervising physician in the house, AND it should be under that supervising physician’s number – NOT necessarily by the physician who saw the original problem. This change was promulgated by the Centers for Medicare & Medicaid Services in the proposed rule, and everyone thought it was a done deal, but the billing remained unchanged in the final rule. Apologies for any confusion.

Coding

As all of you know, in 2010, the Centers for Medicare & Medicaid Services stopped recognizing the Current Procedural Terminology (CPT) consultation codes for Medicare Part B payment CMS decided (after an Office of Inspector General study) that consultations were really just new patient visits and stopped paying for consultations. Visits are now coded with new or follow-up patient evaluation and management codes. This is unfortunate, because a consultation pays more, and importantly, does not establish the patient as a patient in your practice for the next three years. If originally billed as a consultation, the patient can be seen back for another problem in the next three years, and be billed for a consultation, or a new patient as appropriate. Therefore, it is a big advantage to be able to bill for a consultation, assuming another doctor has asked your opinion and you call with or send them a report of your findings.

Just because Medicare says you cannot bill for consultations does not mean that all insurers are the same. The consultation codes are still in the CPT code book and your contracts with private insurers probably stipulate that the insurers must comply with CPT convention. In this case, you can bill your private insurers (including Medicare Advantage Plans, which are private insurers) for consultations when your documentation supports it. Be aware, that some of the more popular electronic health records that perform billing automatically default to a new patient visit, when a new patient consultation might be more appropriate.

While discussing evaluation and management coding, you should be aware that 97% of visits billed by dermatologists are level 3 or lower. This means that, even if your EHR can propel you to heights unimagined before, that it could become a problem. You cannot bill a higher level beyond what is medically appropriate. For example, you don’t usually need to do a full-body skin exam during an acne follow-up.

I’ll never forget the poor soul who explained to me that she was being audited “because all my visits were level 4 or 5, and the software agreed with it.” The software company (or the consultant) will not be sharing the joys of an audit with you. You can do a quick and easy check of your evaluation and management patterns, compared with others by checking either of the online Medicare databases, the Wall Street Journal’s “Medicare Unmasked” site or the “Treatment Tracker” for Doctors and Services in Medicare Part B, on the ProPublica website.

While you are there, check your procedure numbers against others. Are you a freeze-y king? Are you the shave master? There are often valid and justifiable reasons for unusual billing patterns. If you are an outlier, make sure you have a good reason to be there. For example, I am in the top 10% paid per patient visit in the state of Ohio. The reason is that I treat only skin cancer, and it usually involves surgery. The world is looking at these data. So should you.

Dr. Coldiron is a past president of the American Academy of Dermatology. He is currently in private practice, but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. Write to him at [email protected].

First, I want to correct a misstatement I made in a recent column regarding incident to billing by an extender (Dermatology News, July 2016, p. 1) When an extender sees a patient for an established problem, they can bill at 100% if there is a supervising physician in the house, AND it should be under that supervising physician’s number – NOT necessarily by the physician who saw the original problem. This change was promulgated by the Centers for Medicare & Medicaid Services in the proposed rule, and everyone thought it was a done deal, but the billing remained unchanged in the final rule. Apologies for any confusion.

Coding

As all of you know, in 2010, the Centers for Medicare & Medicaid Services stopped recognizing the Current Procedural Terminology (CPT) consultation codes for Medicare Part B payment CMS decided (after an Office of Inspector General study) that consultations were really just new patient visits and stopped paying for consultations. Visits are now coded with new or follow-up patient evaluation and management codes. This is unfortunate, because a consultation pays more, and importantly, does not establish the patient as a patient in your practice for the next three years. If originally billed as a consultation, the patient can be seen back for another problem in the next three years, and be billed for a consultation, or a new patient as appropriate. Therefore, it is a big advantage to be able to bill for a consultation, assuming another doctor has asked your opinion and you call with or send them a report of your findings.

Just because Medicare says you cannot bill for consultations does not mean that all insurers are the same. The consultation codes are still in the CPT code book and your contracts with private insurers probably stipulate that the insurers must comply with CPT convention. In this case, you can bill your private insurers (including Medicare Advantage Plans, which are private insurers) for consultations when your documentation supports it. Be aware, that some of the more popular electronic health records that perform billing automatically default to a new patient visit, when a new patient consultation might be more appropriate.

While discussing evaluation and management coding, you should be aware that 97% of visits billed by dermatologists are level 3 or lower. This means that, even if your EHR can propel you to heights unimagined before, that it could become a problem. You cannot bill a higher level beyond what is medically appropriate. For example, you don’t usually need to do a full-body skin exam during an acne follow-up.

I’ll never forget the poor soul who explained to me that she was being audited “because all my visits were level 4 or 5, and the software agreed with it.” The software company (or the consultant) will not be sharing the joys of an audit with you. You can do a quick and easy check of your evaluation and management patterns, compared with others by checking either of the online Medicare databases, the Wall Street Journal’s “Medicare Unmasked” site or the “Treatment Tracker” for Doctors and Services in Medicare Part B, on the ProPublica website.

While you are there, check your procedure numbers against others. Are you a freeze-y king? Are you the shave master? There are often valid and justifiable reasons for unusual billing patterns. If you are an outlier, make sure you have a good reason to be there. For example, I am in the top 10% paid per patient visit in the state of Ohio. The reason is that I treat only skin cancer, and it usually involves surgery. The world is looking at these data. So should you.

Dr. Coldiron is a past president of the American Academy of Dermatology. He is currently in private practice, but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. Write to him at [email protected].

Officials at the Centers for Medicare & Medicaid Services are launching a new initiative aimed at reducing administrative burdens for physicians who participate in certain value-based payment models.

Under an 18-month pilot, providers practicing within certain Advanced Alternative Payment Models (Advanced APMs) will be relieved of additional documentation scrutiny under Medicare medical review programs, according to an Oct. 13 CMS announcement. As part of the effort, the agency will direct Medicare Administrative Contractors and Recovery Audit Contractors to consider doctors participating in Advanced APMs as a low-priority for postpayment claim reviews.

Courtesy American College of Physicians

[email protected]

On Twitter @legal_med

Officials at the Centers for Medicare & Medicaid Services are launching a new initiative aimed at reducing administrative burdens for physicians who participate in certain value-based payment models.

Under an 18-month pilot, providers practicing within certain Advanced Alternative Payment Models (Advanced APMs) will be relieved of additional documentation scrutiny under Medicare medical review programs, according to an Oct. 13 CMS announcement. As part of the effort, the agency will direct Medicare Administrative Contractors and Recovery Audit Contractors to consider doctors participating in Advanced APMs as a low-priority for postpayment claim reviews.

Courtesy American College of Physicians

[email protected]

On Twitter @legal_med

Officials at the Centers for Medicare & Medicaid Services are launching a new initiative aimed at reducing administrative burdens for physicians who participate in certain value-based payment models.

Under an 18-month pilot, providers practicing within certain Advanced Alternative Payment Models (Advanced APMs) will be relieved of additional documentation scrutiny under Medicare medical review programs, according to an Oct. 13 CMS announcement. As part of the effort, the agency will direct Medicare Administrative Contractors and Recovery Audit Contractors to consider doctors participating in Advanced APMs as a low-priority for postpayment claim reviews.

Courtesy American College of Physicians

[email protected]

On Twitter @legal_med

Micrograph showing

sickle cell disease

Image by Graham Beards

Researchers have described a gene-editing technique that can correct the sickle cell mutation in hematopoietic stem and progenitor cells (HSPCs) isolated from patients with sickle cell disease (SCD).

The investigators said these edited HSPCs produced wild-type adult and fetal hemoglobin.

The HSPCs were also able to engraft in mice and maintained their SCD gene edits long-term without showing any signs of side effects.

“This is an important advance because, for the first time, we show a level of correction in stem cells that should be sufficient for a clinical benefit in persons with sickle cell anemia,” said Mark Walters, MD, of UCSF Benioff Children’s Hospital Oakland in California.

Dr Walters and his colleagues described this work in Science Translational Medicine.

The researchers said they used a ribonucleoprotein complex consisting of Cas9 protein and unmodified single guide RNA, together with a single-stranded DNA oligonucleotide donor, to enable efficient replacement of the SCD mutation in human HSPCs.

The team then differentiated pools of these HSPCs into enucleated erythrocytes and late-stage erythroblasts to measure hemoglobin production.

They said the edited HSPCs produced “substantial amounts” of adult wild-type hemoglobin. The cells also showed a decrease in sickle hemoglobin and an increase in fetal hemoglobin.

When implanted in mice, the edited HSPCs repopulated and maintained their SCD gene edits for 16 weeks, with no signs of side effects. (The mice were sacrificed at 16 weeks.)

“We’re very excited about the promise of this technology,” said study author Jacob Corn, PhD, of the University of California, Berkeley.

“There is still a lot of work to be done before this approach might be used in the clinic, but we’re hopeful that it will pave the way for new kinds of treatment for patients with sickle cell disease.”

In fact, Dr Corn and his lab have joined with Dr Walters to initiate an early phase clinical trial to test this gene-editing approach within the next 5 years.

The investigators also noted that the approach might be effective for treating other disorders, such as β-thalassemia, Wiskott-Aldrich syndrome, and Fanconi anemia.

“Sickle cell disease is just one of many blood disorders caused by a single mutation in the genome,” Dr Corn said. “It’s very possible that other researchers and clinicians could use this type of gene editing to explore ways to cure a large number of diseases.”

Micrograph showing

sickle cell disease

Image by Graham Beards

Researchers have described a gene-editing technique that can correct the sickle cell mutation in hematopoietic stem and progenitor cells (HSPCs) isolated from patients with sickle cell disease (SCD).

The investigators said these edited HSPCs produced wild-type adult and fetal hemoglobin.

The HSPCs were also able to engraft in mice and maintained their SCD gene edits long-term without showing any signs of side effects.

“This is an important advance because, for the first time, we show a level of correction in stem cells that should be sufficient for a clinical benefit in persons with sickle cell anemia,” said Mark Walters, MD, of UCSF Benioff Children’s Hospital Oakland in California.

Dr Walters and his colleagues described this work in Science Translational Medicine.

The researchers said they used a ribonucleoprotein complex consisting of Cas9 protein and unmodified single guide RNA, together with a single-stranded DNA oligonucleotide donor, to enable efficient replacement of the SCD mutation in human HSPCs.

The team then differentiated pools of these HSPCs into enucleated erythrocytes and late-stage erythroblasts to measure hemoglobin production.

They said the edited HSPCs produced “substantial amounts” of adult wild-type hemoglobin. The cells also showed a decrease in sickle hemoglobin and an increase in fetal hemoglobin.

When implanted in mice, the edited HSPCs repopulated and maintained their SCD gene edits for 16 weeks, with no signs of side effects. (The mice were sacrificed at 16 weeks.)

“We’re very excited about the promise of this technology,” said study author Jacob Corn, PhD, of the University of California, Berkeley.

“There is still a lot of work to be done before this approach might be used in the clinic, but we’re hopeful that it will pave the way for new kinds of treatment for patients with sickle cell disease.”

In fact, Dr Corn and his lab have joined with Dr Walters to initiate an early phase clinical trial to test this gene-editing approach within the next 5 years.

The investigators also noted that the approach might be effective for treating other disorders, such as β-thalassemia, Wiskott-Aldrich syndrome, and Fanconi anemia.

“Sickle cell disease is just one of many blood disorders caused by a single mutation in the genome,” Dr Corn said. “It’s very possible that other researchers and clinicians could use this type of gene editing to explore ways to cure a large number of diseases.”

Micrograph showing

sickle cell disease

Image by Graham Beards

Researchers have described a gene-editing technique that can correct the sickle cell mutation in hematopoietic stem and progenitor cells (HSPCs) isolated from patients with sickle cell disease (SCD).

The investigators said these edited HSPCs produced wild-type adult and fetal hemoglobin.

The HSPCs were also able to engraft in mice and maintained their SCD gene edits long-term without showing any signs of side effects.

“This is an important advance because, for the first time, we show a level of correction in stem cells that should be sufficient for a clinical benefit in persons with sickle cell anemia,” said Mark Walters, MD, of UCSF Benioff Children’s Hospital Oakland in California.

Dr Walters and his colleagues described this work in Science Translational Medicine.

The researchers said they used a ribonucleoprotein complex consisting of Cas9 protein and unmodified single guide RNA, together with a single-stranded DNA oligonucleotide donor, to enable efficient replacement of the SCD mutation in human HSPCs.

The team then differentiated pools of these HSPCs into enucleated erythrocytes and late-stage erythroblasts to measure hemoglobin production.

They said the edited HSPCs produced “substantial amounts” of adult wild-type hemoglobin. The cells also showed a decrease in sickle hemoglobin and an increase in fetal hemoglobin.

When implanted in mice, the edited HSPCs repopulated and maintained their SCD gene edits for 16 weeks, with no signs of side effects. (The mice were sacrificed at 16 weeks.)

“We’re very excited about the promise of this technology,” said study author Jacob Corn, PhD, of the University of California, Berkeley.

“There is still a lot of work to be done before this approach might be used in the clinic, but we’re hopeful that it will pave the way for new kinds of treatment for patients with sickle cell disease.”

In fact, Dr Corn and his lab have joined with Dr Walters to initiate an early phase clinical trial to test this gene-editing approach within the next 5 years.

The investigators also noted that the approach might be effective for treating other disorders, such as β-thalassemia, Wiskott-Aldrich syndrome, and Fanconi anemia.

“Sickle cell disease is just one of many blood disorders caused by a single mutation in the genome,” Dr Corn said. “It’s very possible that other researchers and clinicians could use this type of gene editing to explore ways to cure a large number of diseases.”

Clinical Question: Can a collaborative quality improvement project improve the quality and efficiency of pediatric hospital discharges?

Background: Transitions of care, including at the time of hospital discharge, are a potential source of risk and can be associated with adverse events including medication errors and preventable readmissions. Some studies have shown that 10–20% of patients had an adverse event after discharge, and half of those were preventable; one adult study found nearly half of the discharged patients had at least one medication error.1,2 Although multiple projects to improve the discharge process have been published in adult literature, few have focused on the pediatric population. In this study, the Children’s Hospital Association (CHA) formed a pediatric quality improvement collaborative across multiple facilities to examine whether shared improvement strategies would affect failures of discharge-related care, parent-reported readiness for discharge, and readmission rates.

Study Design: Multicenter quality improvement collaborative.

Setting: 11 freestanding tertiary-care children’s hospitals in the United States.

Synopsis: Each of the 11 participating sites chose a specific target population, such as patients with sickle cell disease, asthma, or all discharged pediatric patients. Populations were selected at the discretion of the sites. A multidisciplinary expert advisory panel reviewed literature and developed a change package that included being proactive about discharge planning during hospitalization; improving throughput; arranging post-discharge treatment and support; and communicating post-discharge plan with patients, families, and providers. Each site selected elements of the change package to implement based on individual needs and preferences and incorporated via plan-do-study-act cycles during three action periods. Elements that were implemented by most or all sites included family education on diagnosis and discharge plans, use of discharge checklists, improvement of written discharge instructions, post-discharge follow-up phone calls to reinforce discharge instructions, and identifying and obtaining medications. Virtual learning conferences and monthly Web conferences were held for participants in the collaborative, and experienced improvement coaches guided teams through implementation.

The primary aim of the study was to reduce discharge-related care failures by 50% in 12 months. Failures were measured by phone calls to families two to seven days following discharge, and if any problem related to discharge occurred, the discharge was considered a failure (all-or-none measure). Components of this measure included understanding the diagnosis, receiving discharge instructions and education, complying with instructions, receiving necessary equipment, planning for follow-up pending tests, receiving help with appointments, and not requiring a related unplanned medical visit. Other measures evaluated in this study included patient/family readiness for discharge and unplanned readmission rates (72 hours and 30 days).

Overall, the rate of failures of discharge care was 34% at baseline, which decreased to 21% at the end of the collaborative, for a reduction of 40%. Some individual hospitals exceeded this mark as well. Among the hospitals reporting data on family readiness for discharge, there was a statistically significant improvement, with 85% of families at baseline rating readiness in the highest category and 91% in the last quarter of the study. There was no improvement in rates of unplanned readmission, with 72-hour readmission rates steady across the project (0.7% at onset, 1.1% at end of study; P = 0.29) and slight worsening of the 30-day rate (4.5% to 6.3%; P = 0.05).

Potential explanations for the findings related to readmission rates include seasonal variability in readmissions as well as high variability in patients included in the study. For example, one site focused on patients with sickle cell disease, another on patients with asthma, and others included all diagnoses. Overall, unplanned readmission rates were low (around 1% for 72-hour, 5% for 30-day), which is consistent with other pediatric studies.

Bottom Line: In this study, institutions using a collaborative approach improved the quality of inpatient discharges by using an intervention bundle in pediatric hospital settings. There was no improvement noted in readmission rates, although these rates were low.

Citation: Wu S, Tyler A, Logsdon T, et al. A quality improvement collaborative to improve the discharge process for hospitalized children. Pediatrics. 2016;138(2). pii:e20143604.

References:

1. Moore C, Wisnivesky J, Williams S, McGinn T. Medical errors related to discontinuity of care from an inpatient to an outpatient setting. J Gen Intern Med. 2003;18(8):646-651.
2. Forster AJ, Clark HD, Menard A, et al. Adverse events among medical patients after discharge from hospital. CMAJ. 2004;170(3):345-349.

Clinical Question: Can a collaborative quality improvement project improve the quality and efficiency of pediatric hospital discharges?

Background: Transitions of care, including at the time of hospital discharge, are a potential source of risk and can be associated with adverse events including medication errors and preventable readmissions. Some studies have shown that 10–20% of patients had an adverse event after discharge, and half of those were preventable; one adult study found nearly half of the discharged patients had at least one medication error.1,2 Although multiple projects to improve the discharge process have been published in adult literature, few have focused on the pediatric population. In this study, the Children’s Hospital Association (CHA) formed a pediatric quality improvement collaborative across multiple facilities to examine whether shared improvement strategies would affect failures of discharge-related care, parent-reported readiness for discharge, and readmission rates.

Study Design: Multicenter quality improvement collaborative.

Setting: 11 freestanding tertiary-care children’s hospitals in the United States.

Synopsis: Each of the 11 participating sites chose a specific target population, such as patients with sickle cell disease, asthma, or all discharged pediatric patients. Populations were selected at the discretion of the sites. A multidisciplinary expert advisory panel reviewed literature and developed a change package that included being proactive about discharge planning during hospitalization; improving throughput; arranging post-discharge treatment and support; and communicating post-discharge plan with patients, families, and providers. Each site selected elements of the change package to implement based on individual needs and preferences and incorporated via plan-do-study-act cycles during three action periods. Elements that were implemented by most or all sites included family education on diagnosis and discharge plans, use of discharge checklists, improvement of written discharge instructions, post-discharge follow-up phone calls to reinforce discharge instructions, and identifying and obtaining medications. Virtual learning conferences and monthly Web conferences were held for participants in the collaborative, and experienced improvement coaches guided teams through implementation.

The primary aim of the study was to reduce discharge-related care failures by 50% in 12 months. Failures were measured by phone calls to families two to seven days following discharge, and if any problem related to discharge occurred, the discharge was considered a failure (all-or-none measure). Components of this measure included understanding the diagnosis, receiving discharge instructions and education, complying with instructions, receiving necessary equipment, planning for follow-up pending tests, receiving help with appointments, and not requiring a related unplanned medical visit. Other measures evaluated in this study included patient/family readiness for discharge and unplanned readmission rates (72 hours and 30 days).

Overall, the rate of failures of discharge care was 34% at baseline, which decreased to 21% at the end of the collaborative, for a reduction of 40%. Some individual hospitals exceeded this mark as well. Among the hospitals reporting data on family readiness for discharge, there was a statistically significant improvement, with 85% of families at baseline rating readiness in the highest category and 91% in the last quarter of the study. There was no improvement in rates of unplanned readmission, with 72-hour readmission rates steady across the project (0.7% at onset, 1.1% at end of study; P = 0.29) and slight worsening of the 30-day rate (4.5% to 6.3%; P = 0.05).

Potential explanations for the findings related to readmission rates include seasonal variability in readmissions as well as high variability in patients included in the study. For example, one site focused on patients with sickle cell disease, another on patients with asthma, and others included all diagnoses. Overall, unplanned readmission rates were low (around 1% for 72-hour, 5% for 30-day), which is consistent with other pediatric studies.

Bottom Line: In this study, institutions using a collaborative approach improved the quality of inpatient discharges by using an intervention bundle in pediatric hospital settings. There was no improvement noted in readmission rates, although these rates were low.

Citation: Wu S, Tyler A, Logsdon T, et al. A quality improvement collaborative to improve the discharge process for hospitalized children. Pediatrics. 2016;138(2). pii:e20143604.

References:

1. Moore C, Wisnivesky J, Williams S, McGinn T. Medical errors related to discontinuity of care from an inpatient to an outpatient setting. J Gen Intern Med. 2003;18(8):646-651.
2. Forster AJ, Clark HD, Menard A, et al. Adverse events among medical patients after discharge from hospital. CMAJ. 2004;170(3):345-349.

Clinical Question: Can a collaborative quality improvement project improve the quality and efficiency of pediatric hospital discharges?

Background: Transitions of care, including at the time of hospital discharge, are a potential source of risk and can be associated with adverse events including medication errors and preventable readmissions. Some studies have shown that 10–20% of patients had an adverse event after discharge, and half of those were preventable; one adult study found nearly half of the discharged patients had at least one medication error.1,2 Although multiple projects to improve the discharge process have been published in adult literature, few have focused on the pediatric population. In this study, the Children’s Hospital Association (CHA) formed a pediatric quality improvement collaborative across multiple facilities to examine whether shared improvement strategies would affect failures of discharge-related care, parent-reported readiness for discharge, and readmission rates.

Study Design: Multicenter quality improvement collaborative.

Setting: 11 freestanding tertiary-care children’s hospitals in the United States.

Synopsis: Each of the 11 participating sites chose a specific target population, such as patients with sickle cell disease, asthma, or all discharged pediatric patients. Populations were selected at the discretion of the sites. A multidisciplinary expert advisory panel reviewed literature and developed a change package that included being proactive about discharge planning during hospitalization; improving throughput; arranging post-discharge treatment and support; and communicating post-discharge plan with patients, families, and providers. Each site selected elements of the change package to implement based on individual needs and preferences and incorporated via plan-do-study-act cycles during three action periods. Elements that were implemented by most or all sites included family education on diagnosis and discharge plans, use of discharge checklists, improvement of written discharge instructions, post-discharge follow-up phone calls to reinforce discharge instructions, and identifying and obtaining medications. Virtual learning conferences and monthly Web conferences were held for participants in the collaborative, and experienced improvement coaches guided teams through implementation.

The primary aim of the study was to reduce discharge-related care failures by 50% in 12 months. Failures were measured by phone calls to families two to seven days following discharge, and if any problem related to discharge occurred, the discharge was considered a failure (all-or-none measure). Components of this measure included understanding the diagnosis, receiving discharge instructions and education, complying with instructions, receiving necessary equipment, planning for follow-up pending tests, receiving help with appointments, and not requiring a related unplanned medical visit. Other measures evaluated in this study included patient/family readiness for discharge and unplanned readmission rates (72 hours and 30 days).

Overall, the rate of failures of discharge care was 34% at baseline, which decreased to 21% at the end of the collaborative, for a reduction of 40%. Some individual hospitals exceeded this mark as well. Among the hospitals reporting data on family readiness for discharge, there was a statistically significant improvement, with 85% of families at baseline rating readiness in the highest category and 91% in the last quarter of the study. There was no improvement in rates of unplanned readmission, with 72-hour readmission rates steady across the project (0.7% at onset, 1.1% at end of study; P = 0.29) and slight worsening of the 30-day rate (4.5% to 6.3%; P = 0.05).

Potential explanations for the findings related to readmission rates include seasonal variability in readmissions as well as high variability in patients included in the study. For example, one site focused on patients with sickle cell disease, another on patients with asthma, and others included all diagnoses. Overall, unplanned readmission rates were low (around 1% for 72-hour, 5% for 30-day), which is consistent with other pediatric studies.

Bottom Line: In this study, institutions using a collaborative approach improved the quality of inpatient discharges by using an intervention bundle in pediatric hospital settings. There was no improvement noted in readmission rates, although these rates were low.

Citation: Wu S, Tyler A, Logsdon T, et al. A quality improvement collaborative to improve the discharge process for hospitalized children. Pediatrics. 2016;138(2). pii:e20143604.

References:

1. Moore C, Wisnivesky J, Williams S, McGinn T. Medical errors related to discontinuity of care from an inpatient to an outpatient setting. J Gen Intern Med. 2003;18(8):646-651.
2. Forster AJ, Clark HD, Menard A, et al. Adverse events among medical patients after discharge from hospital. CMAJ. 2004;170(3):345-349.

Clinical Question: What is the performance of the Step-by-Step approach to evaluate febrile infants, and how does it compare to other existing criteria?

Background: Multiple studies have been performed to find the best set of criteria to identify febrile infants at low risk for bacterial infection in order to manage them in a less invasive manner. Common criteria used in the United States include Rochester, Philadelphia, and Boston criteria, initially published in the early 1990s. Since that time, management has evolved with the introduction of newer biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT), and epidemiology has changed with immunizations and improvement in intrapartum antibiotic prophylaxis.

A new algorithm, Step-by-Step, has been developed by a group of European pediatric emergency physicians and has been shown retrospectively to accurately identify groups of patients according to risk of noninvasive or invasive bacterial infection (IBI). This algorithm uses a sequential approach, evaluating the general appearance, age of the patient, urinalysis, and then other lab findings including CRP, PCT, and absolute neutrophil count (ANC). In this study, the authors sought to validate this algorithm prospectively in a larger multicenter population.

Study Design: Multicenter prospective study.

Setting: 11 European pediatric emergency departments in Spain, Italy, and Switzerland.

Synopsis: This study included infants ≤90 days of age presenting to the pediatric emergency department (PED) between September 2012 and August 2014 with fever without source (defined as temperature ≥38°C measured by thermometer at home or in the PED, with normal physical examination and no respiratory signs or symptoms or diarrheal process). Labs obtained for each patient included urinalysis, urine culture (obtained by bladder catheterization or suprapubic aspiration), white blood cell count, PCT, CRP, and blood culture. Further testing and management were determined by the treating physician and management protocols of each center.

Exclusion criteria included:

• Clear source of fever by history or physical examination.
• No fever in the PED and fever assessed only subjectively by parents prior to presentation without the use of a thermometer.
• Absence of one or more of the above lab tests.
• Refusal of parents to participate.

The study included 2,185 infants. Of these, 504 were diagnosed with bacterial infection, including 87 (3.9%) with IBI (defined as positive blood or cerebrospinal fluid culture) and 417 (19.1%) with non-IBI (409 of which were urinary tract infections). Following the first part of the Step-by-Step approach, which uses general appearance (well-appearing versus ill-appearing), age (older or younger than 21 days), and leukocyturia, identified 79.3% of patients with IBI and 98.5% of non-IBI. Adding the next steps in the approach, with PCT, CRP, and ANC, identified 991 low-risk patients (45.3% of the studied population). In this low-risk group, seven patients were subsequently identified as having IBI (0.7% of this group). Using the Step-by-Step approach led to a negative predictive value (NPV) of 99.3 for identifying IBI, with a negative likelihood ratio (LR) of 0.17.

In evaluation of the seven low-risk patients with IBI, three of these were noted to present to the PED within one hour of onset of fever, and three more patients had fever first detected on arrival in the PED. This short duration of fever, and the lack of time for a rise in biomarkers, is likely why these patients were missed in the initial assessment.

When the Rochester criteria were used for this group of 2,185 patients, 949 patients were identified as low risk, with 1.6% of the low-risk patients found to have IBI, leading to an NPV of 98.3 and negative LR of 0.41. The authors chose to compare their approach to the Rochester criteria because the other commonly used approaches (Boston, Philadelphia) recommend lumbar puncture in all febrile infants while Rochester does not, and more recent literature suggests an individualized approach rather than recommending the test systematically.

Limitations included:

• Prevalence of bacterial infection was similar to other European publications but higher than in many studies in the United States, primarily due to an increased rate of UTI. (In this study, the authors used a definition of leukocyturia and culture with ≥10,000 cfu/mL.)
• Band count, although part of the Rochester criteria, was not available in some of the centers and not included in analysis. Inclusion of this lab study could have changed the performance of the Rochester criteria.
• The Step-by-Step approach was not compared to other existing criteria.

Bottom Line: In this study, the Step-by-Step approach was very accurate in identifying febrile infants at low risk for invasive bacterial infection, performing better than the Rochester criteria, and may be helpful in evaluation of infants with fever in the emergency department. A cautious approach is warranted for patients with very short fever duration, as they may be missed by ancillary test results.

Citation: Gomez B, Mintegi S, Bressan S, et al. Validation of the “step-by-step” approach in the management of young febrile infants. Pediatrics. 2016;138(2). pic:e20154381.

Carl Galloway, MD, is a hospitalist at Sanford Children’s Hospital in Sioux Falls, S.D.

Clinical Question: What is the performance of the Step-by-Step approach to evaluate febrile infants, and how does it compare to other existing criteria?

Background: Multiple studies have been performed to find the best set of criteria to identify febrile infants at low risk for bacterial infection in order to manage them in a less invasive manner. Common criteria used in the United States include Rochester, Philadelphia, and Boston criteria, initially published in the early 1990s. Since that time, management has evolved with the introduction of newer biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT), and epidemiology has changed with immunizations and improvement in intrapartum antibiotic prophylaxis.

A new algorithm, Step-by-Step, has been developed by a group of European pediatric emergency physicians and has been shown retrospectively to accurately identify groups of patients according to risk of noninvasive or invasive bacterial infection (IBI). This algorithm uses a sequential approach, evaluating the general appearance, age of the patient, urinalysis, and then other lab findings including CRP, PCT, and absolute neutrophil count (ANC). In this study, the authors sought to validate this algorithm prospectively in a larger multicenter population.

Study Design: Multicenter prospective study.

Setting: 11 European pediatric emergency departments in Spain, Italy, and Switzerland.

Synopsis: This study included infants ≤90 days of age presenting to the pediatric emergency department (PED) between September 2012 and August 2014 with fever without source (defined as temperature ≥38°C measured by thermometer at home or in the PED, with normal physical examination and no respiratory signs or symptoms or diarrheal process). Labs obtained for each patient included urinalysis, urine culture (obtained by bladder catheterization or suprapubic aspiration), white blood cell count, PCT, CRP, and blood culture. Further testing and management were determined by the treating physician and management protocols of each center.

Exclusion criteria included:

• Clear source of fever by history or physical examination.
• No fever in the PED and fever assessed only subjectively by parents prior to presentation without the use of a thermometer.
• Absence of one or more of the above lab tests.
• Refusal of parents to participate.

The study included 2,185 infants. Of these, 504 were diagnosed with bacterial infection, including 87 (3.9%) with IBI (defined as positive blood or cerebrospinal fluid culture) and 417 (19.1%) with non-IBI (409 of which were urinary tract infections). Following the first part of the Step-by-Step approach, which uses general appearance (well-appearing versus ill-appearing), age (older or younger than 21 days), and leukocyturia, identified 79.3% of patients with IBI and 98.5% of non-IBI. Adding the next steps in the approach, with PCT, CRP, and ANC, identified 991 low-risk patients (45.3% of the studied population). In this low-risk group, seven patients were subsequently identified as having IBI (0.7% of this group). Using the Step-by-Step approach led to a negative predictive value (NPV) of 99.3 for identifying IBI, with a negative likelihood ratio (LR) of 0.17.

In evaluation of the seven low-risk patients with IBI, three of these were noted to present to the PED within one hour of onset of fever, and three more patients had fever first detected on arrival in the PED. This short duration of fever, and the lack of time for a rise in biomarkers, is likely why these patients were missed in the initial assessment.

When the Rochester criteria were used for this group of 2,185 patients, 949 patients were identified as low risk, with 1.6% of the low-risk patients found to have IBI, leading to an NPV of 98.3 and negative LR of 0.41. The authors chose to compare their approach to the Rochester criteria because the other commonly used approaches (Boston, Philadelphia) recommend lumbar puncture in all febrile infants while Rochester does not, and more recent literature suggests an individualized approach rather than recommending the test systematically.

Limitations included:

• Prevalence of bacterial infection was similar to other European publications but higher than in many studies in the United States, primarily due to an increased rate of UTI. (In this study, the authors used a definition of leukocyturia and culture with ≥10,000 cfu/mL.)
• Band count, although part of the Rochester criteria, was not available in some of the centers and not included in analysis. Inclusion of this lab study could have changed the performance of the Rochester criteria.
• The Step-by-Step approach was not compared to other existing criteria.

Bottom Line: In this study, the Step-by-Step approach was very accurate in identifying febrile infants at low risk for invasive bacterial infection, performing better than the Rochester criteria, and may be helpful in evaluation of infants with fever in the emergency department. A cautious approach is warranted for patients with very short fever duration, as they may be missed by ancillary test results.

Citation: Gomez B, Mintegi S, Bressan S, et al. Validation of the “step-by-step” approach in the management of young febrile infants. Pediatrics. 2016;138(2). pic:e20154381.

Carl Galloway, MD, is a hospitalist at Sanford Children’s Hospital in Sioux Falls, S.D.

Clinical Question: What is the performance of the Step-by-Step approach to evaluate febrile infants, and how does it compare to other existing criteria?

Background: Multiple studies have been performed to find the best set of criteria to identify febrile infants at low risk for bacterial infection in order to manage them in a less invasive manner. Common criteria used in the United States include Rochester, Philadelphia, and Boston criteria, initially published in the early 1990s. Since that time, management has evolved with the introduction of newer biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT), and epidemiology has changed with immunizations and improvement in intrapartum antibiotic prophylaxis.

A new algorithm, Step-by-Step, has been developed by a group of European pediatric emergency physicians and has been shown retrospectively to accurately identify groups of patients according to risk of noninvasive or invasive bacterial infection (IBI). This algorithm uses a sequential approach, evaluating the general appearance, age of the patient, urinalysis, and then other lab findings including CRP, PCT, and absolute neutrophil count (ANC). In this study, the authors sought to validate this algorithm prospectively in a larger multicenter population.

Study Design: Multicenter prospective study.

Setting: 11 European pediatric emergency departments in Spain, Italy, and Switzerland.

Synopsis: This study included infants ≤90 days of age presenting to the pediatric emergency department (PED) between September 2012 and August 2014 with fever without source (defined as temperature ≥38°C measured by thermometer at home or in the PED, with normal physical examination and no respiratory signs or symptoms or diarrheal process). Labs obtained for each patient included urinalysis, urine culture (obtained by bladder catheterization or suprapubic aspiration), white blood cell count, PCT, CRP, and blood culture. Further testing and management were determined by the treating physician and management protocols of each center.

Exclusion criteria included:

• Clear source of fever by history or physical examination.
• No fever in the PED and fever assessed only subjectively by parents prior to presentation without the use of a thermometer.
• Absence of one or more of the above lab tests.
• Refusal of parents to participate.

The study included 2,185 infants. Of these, 504 were diagnosed with bacterial infection, including 87 (3.9%) with IBI (defined as positive blood or cerebrospinal fluid culture) and 417 (19.1%) with non-IBI (409 of which were urinary tract infections). Following the first part of the Step-by-Step approach, which uses general appearance (well-appearing versus ill-appearing), age (older or younger than 21 days), and leukocyturia, identified 79.3% of patients with IBI and 98.5% of non-IBI. Adding the next steps in the approach, with PCT, CRP, and ANC, identified 991 low-risk patients (45.3% of the studied population). In this low-risk group, seven patients were subsequently identified as having IBI (0.7% of this group). Using the Step-by-Step approach led to a negative predictive value (NPV) of 99.3 for identifying IBI, with a negative likelihood ratio (LR) of 0.17.

In evaluation of the seven low-risk patients with IBI, three of these were noted to present to the PED within one hour of onset of fever, and three more patients had fever first detected on arrival in the PED. This short duration of fever, and the lack of time for a rise in biomarkers, is likely why these patients were missed in the initial assessment.

When the Rochester criteria were used for this group of 2,185 patients, 949 patients were identified as low risk, with 1.6% of the low-risk patients found to have IBI, leading to an NPV of 98.3 and negative LR of 0.41. The authors chose to compare their approach to the Rochester criteria because the other commonly used approaches (Boston, Philadelphia) recommend lumbar puncture in all febrile infants while Rochester does not, and more recent literature suggests an individualized approach rather than recommending the test systematically.

Limitations included:

• Prevalence of bacterial infection was similar to other European publications but higher than in many studies in the United States, primarily due to an increased rate of UTI. (In this study, the authors used a definition of leukocyturia and culture with ≥10,000 cfu/mL.)
• Band count, although part of the Rochester criteria, was not available in some of the centers and not included in analysis. Inclusion of this lab study could have changed the performance of the Rochester criteria.
• The Step-by-Step approach was not compared to other existing criteria.

Bottom Line: In this study, the Step-by-Step approach was very accurate in identifying febrile infants at low risk for invasive bacterial infection, performing better than the Rochester criteria, and may be helpful in evaluation of infants with fever in the emergency department. A cautious approach is warranted for patients with very short fever duration, as they may be missed by ancillary test results.

Citation: Gomez B, Mintegi S, Bressan S, et al. Validation of the “step-by-step” approach in the management of young febrile infants. Pediatrics. 2016;138(2). pic:e20154381.

Carl Galloway, MD, is a hospitalist at Sanford Children’s Hospital in Sioux Falls, S.D.

Mefloquine is a synthetic antimalarial drug structurally related to quinine. The drug was developed by the Walter Reed Army Institute of Research during a decades-long program that started during the Vietnam War in response to concerns of rising resistance to chloroquine.¹

The prelicensing clinical testing of mefloquine, originally known as WR 142,490, was conducted in part among U.S. military service members.^2,3 Soon after receiving FDA approval in 1989, under the brand name Lariam, it was recommended for use within the U.S. military.⁴ Over the following 2 decades, mefloquine was a common exposure during military deployments to malaria endemic areas.

Although the original U.S. mefloquine drug label noted that neuropsychiatric reactions could occur with use, changes to the drug label mandated by the FDA in July 2013, including a black box warning, described a potential for these to persist long after the drug has been discontinued.^5,6 These changes have served to reinforce earlier U.S. military policy changes beginning in 2009 that deprioritized use of the drug in favor of safer and better-tolerated antimalarials. Consequently, more than a quarter century after its introduction, mefloquine now is only rarely prescribed to members of the U.S. military.⁷

In addition to limiting current use of the drug, the recent boxed warning may have important implications for service-connected disability claims adjudication by the VA for veterans previously exposed to the drug. This report presents a case of a nondeployed veteran exposed to mefloquine during an early military postmarketing study who developed chronic neuropsychiatric symptoms linked to the drug that were recently deemed service-connected. This report concludes with some comments on the likely implications of this case for future similar disability claims.

Case Presentation

In 2014, a 56-year-old nondeployed U.S. Marine Corps veteran submitted a claim to the VA for disabling conditions. The veteran alleged these conditions were due to his exposure to mefloquine while in military service more than 2 decades earlier. The veteran enlisted in 1975 and experienced a motor vehicle accident with prolonged loss of consciousness in 1978 but had no other significant medical history.

Thirteen years later, stationed in Hawaii in 1991, he was encouraged to volunteer for a double-blinded postmarketing study, evaluating the adverse effects (AEs) of chloroquine and mefloquine.⁸ As documentation following the trial revealed, he was randomly assigned to the mefloquine arm and received a loading dose of 250 mg daily for 3 days, followed by 250 mg per week for 11 weeks.

During the study he experienced insomnia, abnormal dreams, and nightmares. He also developed symptoms of anxiety, depression, cognitive dysfunction, and changes in personality—including anger and irritability—that were severe enough to be noted by his family members. The patient had not been advised of the significance of these symptoms and therefore did not report them during the clinical trial, nor did he report their intermittent presence after the study’s conclusion through his retirement in 1996, fearing adverse career consequences. Subsequent exacerbations of these chronic symptoms later contributed to the patient’s loss of civilian employment in 2010.

After becoming aware of the 2013 boxed warning that these chronic symptoms could be due to his earlier exposure to mefloquine, the veteran sought evaluation by a VA clinician. On evaluation, the clinician noted no history of deployment, and no history of posttraumatic stress disorder (PTSD) criteria A stressors, and posited that the veteran’s chronic neuropsychiatric symptoms were most likely a consequence of his earlier use of mefloquine. The VA subsequently awarded the veteran 50% disability for an anxiety disorder characterized by chronic sleep impairment and frequent panic attacks, attributing these to his service-connected use of the drug.

Discussion

Although the original 1989 FDA-approved mefloquine label had warned to discontinue the drug if specific prodromal symptoms of “anxiety, depression, restlessness or confusion” were noted,as illustrated by this case, this guidance was not always consistently communicated to service members.⁵ Indeed, few service members in the 1991 military postmarketing study discontinued the medication even after reporting such symptoms.⁸ Vivid dreams, often described as “terrifying nightmares with technicolor clarity” were reported by 7% of study participants. Similarly, concentration problems were reported in 5%; irritability in 4%; anger and moodiness each in 1%; and insomnia in 25%. Two study participants, after failing to discontinue mefloquine at the onset of severe insomnia, were later hospitalized for severe depression and suicidal thoughts, later deemed due to preexisting conditions. Despite these seemingly unfavorable results, mefloquine was nonetheless deemed well tolerated.⁸

Military Use of Mefloquine

Beginning in 1992, use of mefloquine for prophylaxis of malaria was then widely directed within the U.S. military during operations in Somalia. There, a majority of personnel received mefloquine under conditions of command-directed and directly observed administration of the drug.^9,10 Again, drug label guidance describing the prodromal psychiatric symptoms that should have prompted discontinuation of mefloquine were either not consistently adhered to or not communicated. In one Somalia-era study, only 1 in 344 service members, or 0.3%, discontinued the drug.¹¹

Throughout the remainder of the 1990s, mefloquine remained the antimalarial drug of choice for most U.S. military operations, and when combat began in Afghanistan in 2001, widespread use was also directed there.^12,13 The following year, after national attention was directed to concerns of severe behavioral toxicity from the drug among personnel returning from Afghanistan, the manufacturer issued subtle changes to the mefloquine label warnings.^5,14

These label changes adjusted the previously exclusive list of prodromal symptoms to an illustrative list, emphasizing that “if psychiatric symptoms such as [emphasis added] acute anxiety, depression, restlessness or confusion occur, these may be considered prodromal to a more serious event. In these cases, the drug must be discontinued and an alternative medication should be substituted.”⁵

In 2001 a randomized double-blinded trial demonstrated that symptoms of anxiety and depression occurred in at least 4% of mefloquine users, insomnia in 13%, and abnormal dreams in 14%. Nevertheless, an Army memorandum issued soon after the labeling change significantly understated the known risks of developing such psychiatric symptoms, erroneously claiming that these occurred from mefloquine only “at a rate of one per 2,000 to 13,000 persons.”^15,16

Updated FDA Guidelines

In 2003, with widespread use of the drug being again directed during operations in Iraq, the FDA required that all mefloquine prescriptions be accompanied by a patient medication guide with warnings echoing those of the drug label that users seek medical attention should “possible signs of more serious mental problems” develop.^5,17 However, surveys suggested that few U.S. service members received these warnings or even verbal instructions to that effect.^17-19 During later congressional testimony, a service member who had experienced 3 weeks of nightmares prior to self-discontinuing the drug testified “every soldier I know has problems with it.”²⁰

In response, a senior military medical leader—failing to recognize that the nightmares the soldier reported were in fact psychiatric symptoms and possible signs of more serious mental problems that required the drug’s discontinuation—may have undermined the FDA-directed warnings by dismissing the soldier’s testimony as “perception,” maintaining instead “that perceptions can become realities” should it become “held that this medication is widely problematic.”²⁰

Given that certain preexisting conditions, including anxiety and depression, were known to confound recognition of incident psychiatric symptoms that required discontinuation of the drug, the original 1989 mefloquine label had noted that the drug should be used with caution in such patients. In subsequent years, this language was strengthened, and such patients were formally contraindicated the drug.²¹

Citing formal policy, senior military medical leaders provided assurance during congressional testimony that service members with these conditions would not be prescribed mefloquine.^16,18,20 However, later analysis of a large group of deployed service members revealed that 1 in 7 with contraindications to mefloquine had been prescribed the drug contrary to drug label guidance.²¹

Black Box Warning

With growing recognition of the challenges in using mefloquine as directed by the drug label, a 2009 Army policy memorandum prioritized the use of safer and better-tolerated daily medications, such as doxycycline and atovaquone-proguanil, and stated that “[m]efloquine should only be used for personnel with contraindications to doxycycline.”²² This policy was extended throughout the other military services later that year.²³ After concerns were raised that service members were still being prescribed the drug contrary to policy, further restrictions were formalized in early 2013 prior to the boxed warning, with mefloquine reserved for those only “with intolerance or contraindications” to the first-line drugs.^24,25

In a later memorandum announcing the July 2013 boxed warning, the military revealed that the number of active-duty personnel prescribed mefloquine had steadily decreased in prior years from 17,361 in 2008 to only 2,040 in 2012.⁷ Although the military has not released precise figures on the number of U.S. military personnel exposed to mefloquine since the drug’s introduction, based on a variety of sources, the total is likely to far exceed 100,000.^7,26

The major changes to the mefloquine label in 2013, including the boxed warning, clarified that neurologic and psychiatric effects from mefloquine could “persist after mefloquine has been discontinued.” The accompanying FDA Drug Safety Communication noted neurologic AEs from the drug, which include but are not limited to “dizziness, loss of balance, or ringing in the ears,” could “occur at any time during drug use, and can last for months to years after the drug is stopped or can be permanent.”⁶ Other neurologic symptoms listed in the drug label include vertigo, hearing impairment, headache, visual disturbances, sensory and motor neuropathies, including paresthesia, tremor, ataxia, convulsions, and encephalopathy.⁶

The updated drug label also made clear that psychiatric AEs from mefloquine, such as anxiety, paranoia, and depression to hallucinations and psychotic behavior, “have been reported to continue for months or years after mefloquine has been stopped.” Other psychiatric symptoms listed in the drug label include memory impairment, confusion, somnolence, insomnia, abnormal dreams, aggression, agitation, restlessness, mood swings, panic attacks, psychosis, and suicidal ideation.⁶

The 2013 boxed warning also served to reemphasize guidance first articulated in 2002 that any psychiatric symptom—presumably including abnormal dreams and insomnia—occurring during mefloquine use should be considered prodromal, prompting the drug’s immediate discontinuation.⁵ Specifically, the boxed warning explicitly cautioned that given the risk for serious psychiatric disturbances or neurologic AEs when used for malaria prophylaxis, “if psychiatric or neurologic symptoms occur, the drug should be discontinued and an alternative medication should be substituted.”⁶

Drug of Last Resort

By late 2013, partially on the basis of the boxed warning, the U.S. military declared mefloquine a “drug of last resort.”^7,27 The U.S. Army Special Operations Command (USASOC) took the further step of prohibiting use of mefloquine altogether and, according to news reports, directed that medical and command staff assess whether certain personnel experiencing AEs from the drug may mistakenly have been thought to be malingering, have PTSD, or have other psychological problems.²⁸

As the boxed warning and the USASOC order suggest, veterans exposed to mefloquine may have incurred a broad range of neurologic or psychiatric disorders or had others aggravated during military service as a result of their use of the drug. The effects of mefloquine may have confounded the diagnosis of neurologic or psychiatric disorders related to military service.^26,29 As these AEs may be a direct result of mefloquine prescribed during military service, those with disabling diagnoses consistent with these effects may be entitled to claim disability compensation through the VA.

Of potential significant relevance to this adjudication process is a memorandum written in early 2012, in which the military conceded:

Some deploying Service members have been provided mefloquine for malaria prophylaxis without appropriate documentation in their medical records and without proper screening for contraindications. In addition, not all individuals have been provided the required mefloquine medication guide and wallet information card, as required by the Food and Drug Administration. ²⁴

Veterans claiming a service-connected disability as a result of their use of mefloquine should therefore not always be expected to have documentation of prescribing in their military medical records. Although the VA could consider denying such claims for absence of proof of a nexus to military service, in light of this memorandum, the VA may need to consider other evidence of plausible exposure, including veteran testimony and deployment history.

It is also conceivable that the VA could consider denying such claims by arguing that the veteran directly contributed to the disability through willful misconduct by not adhering to mefloquine label guidance. However, as this memorandum establishes that mefloquine use was frequently directed without communication of the drug label precautions and warnings, the VA should consider that veterans claiming a service-connected disability frequently will not have known or otherwise been unable to discontinue the medication at the onset of prodromal symptoms.

It is also possible that the VA might deny claims on the basis that the claimed disabilities reflect preexisting conditions. However, as the memorandum establishes, use of mefloquine also was occasionally inappropriately directed to those with documented contraindications to the medication, who would have increased risk of AEs. As a result, veterans with preexisting neurologic or psychiatric conditions or disorders who nonetheless were prescribed mefloquine may reasonably claim these were aggravated during military service.

Conclusion

As this case suggests, in the coming years, as awareness of the chronic AEs of mefloquine increases among the veteran population, claims related to prior use of the drug are likely to increase and become of significant interest to the VA. Veterans with plausible exposure to mefloquine with neuropsychiatric disabilities who have yet to file a claim may be able to do so, and those veterans whose claims for service-connection were unfavorably adjudicated may be able to reopen their claims on the basis of the new material evidence in the 2012 military memorandum and the 2013 boxed warning.

This case report also suggests that service-connected disability claims arising from chronic neuropsychiatric AEs from mefloquine may prove to be of significant financial consequence. Further research to better define both the extent of prior mefloquine use among U.S. military personnel and the nature and prevalence of those chronic neurologic and psychiatric disorders caused by the drug would be helpful in informing improvements in the efficient and fair adjudication of such service-connected disability claims.

Mefloquine is a synthetic antimalarial drug structurally related to quinine. The drug was developed by the Walter Reed Army Institute of Research during a decades-long program that started during the Vietnam War in response to concerns of rising resistance to chloroquine.¹

The prelicensing clinical testing of mefloquine, originally known as WR 142,490, was conducted in part among U.S. military service members.^2,3 Soon after receiving FDA approval in 1989, under the brand name Lariam, it was recommended for use within the U.S. military.⁴ Over the following 2 decades, mefloquine was a common exposure during military deployments to malaria endemic areas.

Although the original U.S. mefloquine drug label noted that neuropsychiatric reactions could occur with use, changes to the drug label mandated by the FDA in July 2013, including a black box warning, described a potential for these to persist long after the drug has been discontinued.^5,6 These changes have served to reinforce earlier U.S. military policy changes beginning in 2009 that deprioritized use of the drug in favor of safer and better-tolerated antimalarials. Consequently, more than a quarter century after its introduction, mefloquine now is only rarely prescribed to members of the U.S. military.⁷

In addition to limiting current use of the drug, the recent boxed warning may have important implications for service-connected disability claims adjudication by the VA for veterans previously exposed to the drug. This report presents a case of a nondeployed veteran exposed to mefloquine during an early military postmarketing study who developed chronic neuropsychiatric symptoms linked to the drug that were recently deemed service-connected. This report concludes with some comments on the likely implications of this case for future similar disability claims.

Case Presentation

In 2014, a 56-year-old nondeployed U.S. Marine Corps veteran submitted a claim to the VA for disabling conditions. The veteran alleged these conditions were due to his exposure to mefloquine while in military service more than 2 decades earlier. The veteran enlisted in 1975 and experienced a motor vehicle accident with prolonged loss of consciousness in 1978 but had no other significant medical history.

Thirteen years later, stationed in Hawaii in 1991, he was encouraged to volunteer for a double-blinded postmarketing study, evaluating the adverse effects (AEs) of chloroquine and mefloquine.⁸ As documentation following the trial revealed, he was randomly assigned to the mefloquine arm and received a loading dose of 250 mg daily for 3 days, followed by 250 mg per week for 11 weeks.

During the study he experienced insomnia, abnormal dreams, and nightmares. He also developed symptoms of anxiety, depression, cognitive dysfunction, and changes in personality—including anger and irritability—that were severe enough to be noted by his family members. The patient had not been advised of the significance of these symptoms and therefore did not report them during the clinical trial, nor did he report their intermittent presence after the study’s conclusion through his retirement in 1996, fearing adverse career consequences. Subsequent exacerbations of these chronic symptoms later contributed to the patient’s loss of civilian employment in 2010.

After becoming aware of the 2013 boxed warning that these chronic symptoms could be due to his earlier exposure to mefloquine, the veteran sought evaluation by a VA clinician. On evaluation, the clinician noted no history of deployment, and no history of posttraumatic stress disorder (PTSD) criteria A stressors, and posited that the veteran’s chronic neuropsychiatric symptoms were most likely a consequence of his earlier use of mefloquine. The VA subsequently awarded the veteran 50% disability for an anxiety disorder characterized by chronic sleep impairment and frequent panic attacks, attributing these to his service-connected use of the drug.

Discussion

Although the original 1989 FDA-approved mefloquine label had warned to discontinue the drug if specific prodromal symptoms of “anxiety, depression, restlessness or confusion” were noted,as illustrated by this case, this guidance was not always consistently communicated to service members.⁵ Indeed, few service members in the 1991 military postmarketing study discontinued the medication even after reporting such symptoms.⁸ Vivid dreams, often described as “terrifying nightmares with technicolor clarity” were reported by 7% of study participants. Similarly, concentration problems were reported in 5%; irritability in 4%; anger and moodiness each in 1%; and insomnia in 25%. Two study participants, after failing to discontinue mefloquine at the onset of severe insomnia, were later hospitalized for severe depression and suicidal thoughts, later deemed due to preexisting conditions. Despite these seemingly unfavorable results, mefloquine was nonetheless deemed well tolerated.⁸

Military Use of Mefloquine

Beginning in 1992, use of mefloquine for prophylaxis of malaria was then widely directed within the U.S. military during operations in Somalia. There, a majority of personnel received mefloquine under conditions of command-directed and directly observed administration of the drug.^9,10 Again, drug label guidance describing the prodromal psychiatric symptoms that should have prompted discontinuation of mefloquine were either not consistently adhered to or not communicated. In one Somalia-era study, only 1 in 344 service members, or 0.3%, discontinued the drug.¹¹

Throughout the remainder of the 1990s, mefloquine remained the antimalarial drug of choice for most U.S. military operations, and when combat began in Afghanistan in 2001, widespread use was also directed there.^12,13 The following year, after national attention was directed to concerns of severe behavioral toxicity from the drug among personnel returning from Afghanistan, the manufacturer issued subtle changes to the mefloquine label warnings.^5,14

These label changes adjusted the previously exclusive list of prodromal symptoms to an illustrative list, emphasizing that “if psychiatric symptoms such as [emphasis added] acute anxiety, depression, restlessness or confusion occur, these may be considered prodromal to a more serious event. In these cases, the drug must be discontinued and an alternative medication should be substituted.”⁵

In 2001 a randomized double-blinded trial demonstrated that symptoms of anxiety and depression occurred in at least 4% of mefloquine users, insomnia in 13%, and abnormal dreams in 14%. Nevertheless, an Army memorandum issued soon after the labeling change significantly understated the known risks of developing such psychiatric symptoms, erroneously claiming that these occurred from mefloquine only “at a rate of one per 2,000 to 13,000 persons.”^15,16

Updated FDA Guidelines

In 2003, with widespread use of the drug being again directed during operations in Iraq, the FDA required that all mefloquine prescriptions be accompanied by a patient medication guide with warnings echoing those of the drug label that users seek medical attention should “possible signs of more serious mental problems” develop.^5,17 However, surveys suggested that few U.S. service members received these warnings or even verbal instructions to that effect.^17-19 During later congressional testimony, a service member who had experienced 3 weeks of nightmares prior to self-discontinuing the drug testified “every soldier I know has problems with it.”²⁰

In response, a senior military medical leader—failing to recognize that the nightmares the soldier reported were in fact psychiatric symptoms and possible signs of more serious mental problems that required the drug’s discontinuation—may have undermined the FDA-directed warnings by dismissing the soldier’s testimony as “perception,” maintaining instead “that perceptions can become realities” should it become “held that this medication is widely problematic.”²⁰

Given that certain preexisting conditions, including anxiety and depression, were known to confound recognition of incident psychiatric symptoms that required discontinuation of the drug, the original 1989 mefloquine label had noted that the drug should be used with caution in such patients. In subsequent years, this language was strengthened, and such patients were formally contraindicated the drug.²¹

Citing formal policy, senior military medical leaders provided assurance during congressional testimony that service members with these conditions would not be prescribed mefloquine.^16,18,20 However, later analysis of a large group of deployed service members revealed that 1 in 7 with contraindications to mefloquine had been prescribed the drug contrary to drug label guidance.²¹

Black Box Warning

With growing recognition of the challenges in using mefloquine as directed by the drug label, a 2009 Army policy memorandum prioritized the use of safer and better-tolerated daily medications, such as doxycycline and atovaquone-proguanil, and stated that “[m]efloquine should only be used for personnel with contraindications to doxycycline.”²² This policy was extended throughout the other military services later that year.²³ After concerns were raised that service members were still being prescribed the drug contrary to policy, further restrictions were formalized in early 2013 prior to the boxed warning, with mefloquine reserved for those only “with intolerance or contraindications” to the first-line drugs.^24,25

In a later memorandum announcing the July 2013 boxed warning, the military revealed that the number of active-duty personnel prescribed mefloquine had steadily decreased in prior years from 17,361 in 2008 to only 2,040 in 2012.⁷ Although the military has not released precise figures on the number of U.S. military personnel exposed to mefloquine since the drug’s introduction, based on a variety of sources, the total is likely to far exceed 100,000.^7,26

The major changes to the mefloquine label in 2013, including the boxed warning, clarified that neurologic and psychiatric effects from mefloquine could “persist after mefloquine has been discontinued.” The accompanying FDA Drug Safety Communication noted neurologic AEs from the drug, which include but are not limited to “dizziness, loss of balance, or ringing in the ears,” could “occur at any time during drug use, and can last for months to years after the drug is stopped or can be permanent.”⁶ Other neurologic symptoms listed in the drug label include vertigo, hearing impairment, headache, visual disturbances, sensory and motor neuropathies, including paresthesia, tremor, ataxia, convulsions, and encephalopathy.⁶

The updated drug label also made clear that psychiatric AEs from mefloquine, such as anxiety, paranoia, and depression to hallucinations and psychotic behavior, “have been reported to continue for months or years after mefloquine has been stopped.” Other psychiatric symptoms listed in the drug label include memory impairment, confusion, somnolence, insomnia, abnormal dreams, aggression, agitation, restlessness, mood swings, panic attacks, psychosis, and suicidal ideation.⁶

The 2013 boxed warning also served to reemphasize guidance first articulated in 2002 that any psychiatric symptom—presumably including abnormal dreams and insomnia—occurring during mefloquine use should be considered prodromal, prompting the drug’s immediate discontinuation.⁵ Specifically, the boxed warning explicitly cautioned that given the risk for serious psychiatric disturbances or neurologic AEs when used for malaria prophylaxis, “if psychiatric or neurologic symptoms occur, the drug should be discontinued and an alternative medication should be substituted.”⁶

Drug of Last Resort

By late 2013, partially on the basis of the boxed warning, the U.S. military declared mefloquine a “drug of last resort.”^7,27 The U.S. Army Special Operations Command (USASOC) took the further step of prohibiting use of mefloquine altogether and, according to news reports, directed that medical and command staff assess whether certain personnel experiencing AEs from the drug may mistakenly have been thought to be malingering, have PTSD, or have other psychological problems.²⁸

As the boxed warning and the USASOC order suggest, veterans exposed to mefloquine may have incurred a broad range of neurologic or psychiatric disorders or had others aggravated during military service as a result of their use of the drug. The effects of mefloquine may have confounded the diagnosis of neurologic or psychiatric disorders related to military service.^26,29 As these AEs may be a direct result of mefloquine prescribed during military service, those with disabling diagnoses consistent with these effects may be entitled to claim disability compensation through the VA.

Of potential significant relevance to this adjudication process is a memorandum written in early 2012, in which the military conceded:

Some deploying Service members have been provided mefloquine for malaria prophylaxis without appropriate documentation in their medical records and without proper screening for contraindications. In addition, not all individuals have been provided the required mefloquine medication guide and wallet information card, as required by the Food and Drug Administration. ²⁴

Veterans claiming a service-connected disability as a result of their use of mefloquine should therefore not always be expected to have documentation of prescribing in their military medical records. Although the VA could consider denying such claims for absence of proof of a nexus to military service, in light of this memorandum, the VA may need to consider other evidence of plausible exposure, including veteran testimony and deployment history.

It is also conceivable that the VA could consider denying such claims by arguing that the veteran directly contributed to the disability through willful misconduct by not adhering to mefloquine label guidance. However, as this memorandum establishes that mefloquine use was frequently directed without communication of the drug label precautions and warnings, the VA should consider that veterans claiming a service-connected disability frequently will not have known or otherwise been unable to discontinue the medication at the onset of prodromal symptoms.

It is also possible that the VA might deny claims on the basis that the claimed disabilities reflect preexisting conditions. However, as the memorandum establishes, use of mefloquine also was occasionally inappropriately directed to those with documented contraindications to the medication, who would have increased risk of AEs. As a result, veterans with preexisting neurologic or psychiatric conditions or disorders who nonetheless were prescribed mefloquine may reasonably claim these were aggravated during military service.

Conclusion

As this case suggests, in the coming years, as awareness of the chronic AEs of mefloquine increases among the veteran population, claims related to prior use of the drug are likely to increase and become of significant interest to the VA. Veterans with plausible exposure to mefloquine with neuropsychiatric disabilities who have yet to file a claim may be able to do so, and those veterans whose claims for service-connection were unfavorably adjudicated may be able to reopen their claims on the basis of the new material evidence in the 2012 military memorandum and the 2013 boxed warning.

This case report also suggests that service-connected disability claims arising from chronic neuropsychiatric AEs from mefloquine may prove to be of significant financial consequence. Further research to better define both the extent of prior mefloquine use among U.S. military personnel and the nature and prevalence of those chronic neurologic and psychiatric disorders caused by the drug would be helpful in informing improvements in the efficient and fair adjudication of such service-connected disability claims.

Mefloquine is a synthetic antimalarial drug structurally related to quinine. The drug was developed by the Walter Reed Army Institute of Research during a decades-long program that started during the Vietnam War in response to concerns of rising resistance to chloroquine.¹

The prelicensing clinical testing of mefloquine, originally known as WR 142,490, was conducted in part among U.S. military service members.^2,3 Soon after receiving FDA approval in 1989, under the brand name Lariam, it was recommended for use within the U.S. military.⁴ Over the following 2 decades, mefloquine was a common exposure during military deployments to malaria endemic areas.

Although the original U.S. mefloquine drug label noted that neuropsychiatric reactions could occur with use, changes to the drug label mandated by the FDA in July 2013, including a black box warning, described a potential for these to persist long after the drug has been discontinued.^5,6 These changes have served to reinforce earlier U.S. military policy changes beginning in 2009 that deprioritized use of the drug in favor of safer and better-tolerated antimalarials. Consequently, more than a quarter century after its introduction, mefloquine now is only rarely prescribed to members of the U.S. military.⁷

In addition to limiting current use of the drug, the recent boxed warning may have important implications for service-connected disability claims adjudication by the VA for veterans previously exposed to the drug. This report presents a case of a nondeployed veteran exposed to mefloquine during an early military postmarketing study who developed chronic neuropsychiatric symptoms linked to the drug that were recently deemed service-connected. This report concludes with some comments on the likely implications of this case for future similar disability claims.

Case Presentation

In 2014, a 56-year-old nondeployed U.S. Marine Corps veteran submitted a claim to the VA for disabling conditions. The veteran alleged these conditions were due to his exposure to mefloquine while in military service more than 2 decades earlier. The veteran enlisted in 1975 and experienced a motor vehicle accident with prolonged loss of consciousness in 1978 but had no other significant medical history.

Thirteen years later, stationed in Hawaii in 1991, he was encouraged to volunteer for a double-blinded postmarketing study, evaluating the adverse effects (AEs) of chloroquine and mefloquine.⁸ As documentation following the trial revealed, he was randomly assigned to the mefloquine arm and received a loading dose of 250 mg daily for 3 days, followed by 250 mg per week for 11 weeks.

During the study he experienced insomnia, abnormal dreams, and nightmares. He also developed symptoms of anxiety, depression, cognitive dysfunction, and changes in personality—including anger and irritability—that were severe enough to be noted by his family members. The patient had not been advised of the significance of these symptoms and therefore did not report them during the clinical trial, nor did he report their intermittent presence after the study’s conclusion through his retirement in 1996, fearing adverse career consequences. Subsequent exacerbations of these chronic symptoms later contributed to the patient’s loss of civilian employment in 2010.

After becoming aware of the 2013 boxed warning that these chronic symptoms could be due to his earlier exposure to mefloquine, the veteran sought evaluation by a VA clinician. On evaluation, the clinician noted no history of deployment, and no history of posttraumatic stress disorder (PTSD) criteria A stressors, and posited that the veteran’s chronic neuropsychiatric symptoms were most likely a consequence of his earlier use of mefloquine. The VA subsequently awarded the veteran 50% disability for an anxiety disorder characterized by chronic sleep impairment and frequent panic attacks, attributing these to his service-connected use of the drug.

Discussion

Although the original 1989 FDA-approved mefloquine label had warned to discontinue the drug if specific prodromal symptoms of “anxiety, depression, restlessness or confusion” were noted,as illustrated by this case, this guidance was not always consistently communicated to service members.⁵ Indeed, few service members in the 1991 military postmarketing study discontinued the medication even after reporting such symptoms.⁸ Vivid dreams, often described as “terrifying nightmares with technicolor clarity” were reported by 7% of study participants. Similarly, concentration problems were reported in 5%; irritability in 4%; anger and moodiness each in 1%; and insomnia in 25%. Two study participants, after failing to discontinue mefloquine at the onset of severe insomnia, were later hospitalized for severe depression and suicidal thoughts, later deemed due to preexisting conditions. Despite these seemingly unfavorable results, mefloquine was nonetheless deemed well tolerated.⁸

Military Use of Mefloquine

Beginning in 1992, use of mefloquine for prophylaxis of malaria was then widely directed within the U.S. military during operations in Somalia. There, a majority of personnel received mefloquine under conditions of command-directed and directly observed administration of the drug.^9,10 Again, drug label guidance describing the prodromal psychiatric symptoms that should have prompted discontinuation of mefloquine were either not consistently adhered to or not communicated. In one Somalia-era study, only 1 in 344 service members, or 0.3%, discontinued the drug.¹¹

Throughout the remainder of the 1990s, mefloquine remained the antimalarial drug of choice for most U.S. military operations, and when combat began in Afghanistan in 2001, widespread use was also directed there.^12,13 The following year, after national attention was directed to concerns of severe behavioral toxicity from the drug among personnel returning from Afghanistan, the manufacturer issued subtle changes to the mefloquine label warnings.^5,14

These label changes adjusted the previously exclusive list of prodromal symptoms to an illustrative list, emphasizing that “if psychiatric symptoms such as [emphasis added] acute anxiety, depression, restlessness or confusion occur, these may be considered prodromal to a more serious event. In these cases, the drug must be discontinued and an alternative medication should be substituted.”⁵

In 2001 a randomized double-blinded trial demonstrated that symptoms of anxiety and depression occurred in at least 4% of mefloquine users, insomnia in 13%, and abnormal dreams in 14%. Nevertheless, an Army memorandum issued soon after the labeling change significantly understated the known risks of developing such psychiatric symptoms, erroneously claiming that these occurred from mefloquine only “at a rate of one per 2,000 to 13,000 persons.”^15,16

Updated FDA Guidelines

In 2003, with widespread use of the drug being again directed during operations in Iraq, the FDA required that all mefloquine prescriptions be accompanied by a patient medication guide with warnings echoing those of the drug label that users seek medical attention should “possible signs of more serious mental problems” develop.^5,17 However, surveys suggested that few U.S. service members received these warnings or even verbal instructions to that effect.^17-19 During later congressional testimony, a service member who had experienced 3 weeks of nightmares prior to self-discontinuing the drug testified “every soldier I know has problems with it.”²⁰

In response, a senior military medical leader—failing to recognize that the nightmares the soldier reported were in fact psychiatric symptoms and possible signs of more serious mental problems that required the drug’s discontinuation—may have undermined the FDA-directed warnings by dismissing the soldier’s testimony as “perception,” maintaining instead “that perceptions can become realities” should it become “held that this medication is widely problematic.”²⁰

Given that certain preexisting conditions, including anxiety and depression, were known to confound recognition of incident psychiatric symptoms that required discontinuation of the drug, the original 1989 mefloquine label had noted that the drug should be used with caution in such patients. In subsequent years, this language was strengthened, and such patients were formally contraindicated the drug.²¹

Citing formal policy, senior military medical leaders provided assurance during congressional testimony that service members with these conditions would not be prescribed mefloquine.^16,18,20 However, later analysis of a large group of deployed service members revealed that 1 in 7 with contraindications to mefloquine had been prescribed the drug contrary to drug label guidance.²¹

Black Box Warning

With growing recognition of the challenges in using mefloquine as directed by the drug label, a 2009 Army policy memorandum prioritized the use of safer and better-tolerated daily medications, such as doxycycline and atovaquone-proguanil, and stated that “[m]efloquine should only be used for personnel with contraindications to doxycycline.”²² This policy was extended throughout the other military services later that year.²³ After concerns were raised that service members were still being prescribed the drug contrary to policy, further restrictions were formalized in early 2013 prior to the boxed warning, with mefloquine reserved for those only “with intolerance or contraindications” to the first-line drugs.^24,25

In a later memorandum announcing the July 2013 boxed warning, the military revealed that the number of active-duty personnel prescribed mefloquine had steadily decreased in prior years from 17,361 in 2008 to only 2,040 in 2012.⁷ Although the military has not released precise figures on the number of U.S. military personnel exposed to mefloquine since the drug’s introduction, based on a variety of sources, the total is likely to far exceed 100,000.^7,26

The major changes to the mefloquine label in 2013, including the boxed warning, clarified that neurologic and psychiatric effects from mefloquine could “persist after mefloquine has been discontinued.” The accompanying FDA Drug Safety Communication noted neurologic AEs from the drug, which include but are not limited to “dizziness, loss of balance, or ringing in the ears,” could “occur at any time during drug use, and can last for months to years after the drug is stopped or can be permanent.”⁶ Other neurologic symptoms listed in the drug label include vertigo, hearing impairment, headache, visual disturbances, sensory and motor neuropathies, including paresthesia, tremor, ataxia, convulsions, and encephalopathy.⁶

The updated drug label also made clear that psychiatric AEs from mefloquine, such as anxiety, paranoia, and depression to hallucinations and psychotic behavior, “have been reported to continue for months or years after mefloquine has been stopped.” Other psychiatric symptoms listed in the drug label include memory impairment, confusion, somnolence, insomnia, abnormal dreams, aggression, agitation, restlessness, mood swings, panic attacks, psychosis, and suicidal ideation.⁶

The 2013 boxed warning also served to reemphasize guidance first articulated in 2002 that any psychiatric symptom—presumably including abnormal dreams and insomnia—occurring during mefloquine use should be considered prodromal, prompting the drug’s immediate discontinuation.⁵ Specifically, the boxed warning explicitly cautioned that given the risk for serious psychiatric disturbances or neurologic AEs when used for malaria prophylaxis, “if psychiatric or neurologic symptoms occur, the drug should be discontinued and an alternative medication should be substituted.”⁶

Drug of Last Resort

By late 2013, partially on the basis of the boxed warning, the U.S. military declared mefloquine a “drug of last resort.”^7,27 The U.S. Army Special Operations Command (USASOC) took the further step of prohibiting use of mefloquine altogether and, according to news reports, directed that medical and command staff assess whether certain personnel experiencing AEs from the drug may mistakenly have been thought to be malingering, have PTSD, or have other psychological problems.²⁸

As the boxed warning and the USASOC order suggest, veterans exposed to mefloquine may have incurred a broad range of neurologic or psychiatric disorders or had others aggravated during military service as a result of their use of the drug. The effects of mefloquine may have confounded the diagnosis of neurologic or psychiatric disorders related to military service.^26,29 As these AEs may be a direct result of mefloquine prescribed during military service, those with disabling diagnoses consistent with these effects may be entitled to claim disability compensation through the VA.

Of potential significant relevance to this adjudication process is a memorandum written in early 2012, in which the military conceded:

Some deploying Service members have been provided mefloquine for malaria prophylaxis without appropriate documentation in their medical records and without proper screening for contraindications. In addition, not all individuals have been provided the required mefloquine medication guide and wallet information card, as required by the Food and Drug Administration. ²⁴

Veterans claiming a service-connected disability as a result of their use of mefloquine should therefore not always be expected to have documentation of prescribing in their military medical records. Although the VA could consider denying such claims for absence of proof of a nexus to military service, in light of this memorandum, the VA may need to consider other evidence of plausible exposure, including veteran testimony and deployment history.

It is also conceivable that the VA could consider denying such claims by arguing that the veteran directly contributed to the disability through willful misconduct by not adhering to mefloquine label guidance. However, as this memorandum establishes that mefloquine use was frequently directed without communication of the drug label precautions and warnings, the VA should consider that veterans claiming a service-connected disability frequently will not have known or otherwise been unable to discontinue the medication at the onset of prodromal symptoms.

It is also possible that the VA might deny claims on the basis that the claimed disabilities reflect preexisting conditions. However, as the memorandum establishes, use of mefloquine also was occasionally inappropriately directed to those with documented contraindications to the medication, who would have increased risk of AEs. As a result, veterans with preexisting neurologic or psychiatric conditions or disorders who nonetheless were prescribed mefloquine may reasonably claim these were aggravated during military service.

Conclusion

As this case suggests, in the coming years, as awareness of the chronic AEs of mefloquine increases among the veteran population, claims related to prior use of the drug are likely to increase and become of significant interest to the VA. Veterans with plausible exposure to mefloquine with neuropsychiatric disabilities who have yet to file a claim may be able to do so, and those veterans whose claims for service-connection were unfavorably adjudicated may be able to reopen their claims on the basis of the new material evidence in the 2012 military memorandum and the 2013 boxed warning.

This case report also suggests that service-connected disability claims arising from chronic neuropsychiatric AEs from mefloquine may prove to be of significant financial consequence. Further research to better define both the extent of prior mefloquine use among U.S. military personnel and the nature and prevalence of those chronic neurologic and psychiatric disorders caused by the drug would be helpful in informing improvements in the efficient and fair adjudication of such service-connected disability claims.

AML cells

A novel combination has shown promise for treating acute myeloid leukemia (AML) and other cancers, according to preclinical research published in Cancer Cell.

Researchers found that combining a DNMT inhibitor and a PARP inhibitor greatly increases the drugs’ anti-tumor activity, and the combination could be effective in malignancies that are not responsive to PARP inhibitors or DNMT inhibitors alone.

Experiments showed that, when combined, the 2 types of inhibitors cause interactions that significantly disrupt cancer cells’ ability to survive DNA damage.

“Our preclinical data suggest that combining low doses of these inhibitors will enhance the clinical effects of both drugs as a potential treatment for patients with AML,” said study author Feyruz V. Rassool, PhD, of the University of Maryland School of Medicine in Baltimore.

“Moreover, our initial data suggest that subtypes of AML with a poor prognosis are likely to be sensitive to this new therapeutic approach.”

Dr Rassool and her colleagues assessed the activity of a DNMT inhibitor—decitabine or 5-azacytidine—in combination with a PARP inhibitor—veliparib or talazoparib—against AML and breast cancer.

In both AML and breast cancer cells, combination treatment increased cytotoxicity and decreased clonogenicity, compared to treatment with either type of inhibitor alone.

The combination of 5-azacytidine and talazoparib produced “very robust responses” in 2 mouse models of AML (MV411 and MOLM14), according to the researchers.

“[It was] somewhat of a surprise that leukemia cells were this sensitive to the combination treatment,” said study author Stephen B. Baylin, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions in Baltimore.

“And if further research confirms our findings, it looks like it also could be useful for breast cancer and ovarian cancers for which PARP inhibitors have not been useful as yet.”

How the inhibitors work together

Dr Baylin noted that PARP helps repair naturally occurring breaks in strands of DNA, and some cancers rely more frequently on PARP than others.

“[PARP inhibitors] work according to how intensely and durably the PARP enzyme is trapped at certain DNA damage sites,” he explained. “If you can ramp up the duration and intensity of this trapping, you could potentially increase the efficacy of the drug[s].”

“We figured that if we pair 5-azacytidine and a PARP inhibitor like talazoparib, we may be able to increase PARP trapping at DNA damage sites.”

That’s because 5-azacytidine blocks proteins that attach gene-regulating methyl groups to DNA and traps those proteins on DNA. The proteins blocked by 5-azacytidine also interact with PARP enzymes at DNA damage sites.

In fact, the researchers did find that combining 5-azacytidine and talazoparib increased the time that PARP was trapped at sites of DNA damage in cancer cells. The time was extended from 30 minutes to 3-6 hours after treatment.

Next steps

Based on the results of this research, a clinical trial is planned to test whether low doses of decitabine and talazoparib can be safely combined and whether this therapy will be effective in AML patients.

The researchers are especially interested in testing the combination in patients who cannot receive intensive chemotherapy, whose leukemia is resistant to treatment, or who have relapsed after treatment.

“This is really a new paradigm mechanism that is being translated into a clinical trial,” Dr Rassool said. “It’s not just putting 2 drugs together.”

“We have shown in the laboratory that the proteins that these inhibitors target actually interact, so the effects of these inhibitors are enhanced through this interaction. Therein lies the novelty of this new approach.”

AML cells

A novel combination has shown promise for treating acute myeloid leukemia (AML) and other cancers, according to preclinical research published in Cancer Cell.

Researchers found that combining a DNMT inhibitor and a PARP inhibitor greatly increases the drugs’ anti-tumor activity, and the combination could be effective in malignancies that are not responsive to PARP inhibitors or DNMT inhibitors alone.

Experiments showed that, when combined, the 2 types of inhibitors cause interactions that significantly disrupt cancer cells’ ability to survive DNA damage.

“Our preclinical data suggest that combining low doses of these inhibitors will enhance the clinical effects of both drugs as a potential treatment for patients with AML,” said study author Feyruz V. Rassool, PhD, of the University of Maryland School of Medicine in Baltimore.

“Moreover, our initial data suggest that subtypes of AML with a poor prognosis are likely to be sensitive to this new therapeutic approach.”

Dr Rassool and her colleagues assessed the activity of a DNMT inhibitor—decitabine or 5-azacytidine—in combination with a PARP inhibitor—veliparib or talazoparib—against AML and breast cancer.

In both AML and breast cancer cells, combination treatment increased cytotoxicity and decreased clonogenicity, compared to treatment with either type of inhibitor alone.

The combination of 5-azacytidine and talazoparib produced “very robust responses” in 2 mouse models of AML (MV411 and MOLM14), according to the researchers.

“[It was] somewhat of a surprise that leukemia cells were this sensitive to the combination treatment,” said study author Stephen B. Baylin, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions in Baltimore.

“And if further research confirms our findings, it looks like it also could be useful for breast cancer and ovarian cancers for which PARP inhibitors have not been useful as yet.”

How the inhibitors work together

Dr Baylin noted that PARP helps repair naturally occurring breaks in strands of DNA, and some cancers rely more frequently on PARP than others.

“[PARP inhibitors] work according to how intensely and durably the PARP enzyme is trapped at certain DNA damage sites,” he explained. “If you can ramp up the duration and intensity of this trapping, you could potentially increase the efficacy of the drug[s].”

“We figured that if we pair 5-azacytidine and a PARP inhibitor like talazoparib, we may be able to increase PARP trapping at DNA damage sites.”

That’s because 5-azacytidine blocks proteins that attach gene-regulating methyl groups to DNA and traps those proteins on DNA. The proteins blocked by 5-azacytidine also interact with PARP enzymes at DNA damage sites.

In fact, the researchers did find that combining 5-azacytidine and talazoparib increased the time that PARP was trapped at sites of DNA damage in cancer cells. The time was extended from 30 minutes to 3-6 hours after treatment.

Next steps

Based on the results of this research, a clinical trial is planned to test whether low doses of decitabine and talazoparib can be safely combined and whether this therapy will be effective in AML patients.

The researchers are especially interested in testing the combination in patients who cannot receive intensive chemotherapy, whose leukemia is resistant to treatment, or who have relapsed after treatment.

“This is really a new paradigm mechanism that is being translated into a clinical trial,” Dr Rassool said. “It’s not just putting 2 drugs together.”

“We have shown in the laboratory that the proteins that these inhibitors target actually interact, so the effects of these inhibitors are enhanced through this interaction. Therein lies the novelty of this new approach.”

AML cells

A novel combination has shown promise for treating acute myeloid leukemia (AML) and other cancers, according to preclinical research published in Cancer Cell.

Researchers found that combining a DNMT inhibitor and a PARP inhibitor greatly increases the drugs’ anti-tumor activity, and the combination could be effective in malignancies that are not responsive to PARP inhibitors or DNMT inhibitors alone.

Experiments showed that, when combined, the 2 types of inhibitors cause interactions that significantly disrupt cancer cells’ ability to survive DNA damage.

“Our preclinical data suggest that combining low doses of these inhibitors will enhance the clinical effects of both drugs as a potential treatment for patients with AML,” said study author Feyruz V. Rassool, PhD, of the University of Maryland School of Medicine in Baltimore.

“Moreover, our initial data suggest that subtypes of AML with a poor prognosis are likely to be sensitive to this new therapeutic approach.”

Dr Rassool and her colleagues assessed the activity of a DNMT inhibitor—decitabine or 5-azacytidine—in combination with a PARP inhibitor—veliparib or talazoparib—against AML and breast cancer.

In both AML and breast cancer cells, combination treatment increased cytotoxicity and decreased clonogenicity, compared to treatment with either type of inhibitor alone.

The combination of 5-azacytidine and talazoparib produced “very robust responses” in 2 mouse models of AML (MV411 and MOLM14), according to the researchers.

“[It was] somewhat of a surprise that leukemia cells were this sensitive to the combination treatment,” said study author Stephen B. Baylin, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions in Baltimore.

“And if further research confirms our findings, it looks like it also could be useful for breast cancer and ovarian cancers for which PARP inhibitors have not been useful as yet.”

How the inhibitors work together

Dr Baylin noted that PARP helps repair naturally occurring breaks in strands of DNA, and some cancers rely more frequently on PARP than others.

“[PARP inhibitors] work according to how intensely and durably the PARP enzyme is trapped at certain DNA damage sites,” he explained. “If you can ramp up the duration and intensity of this trapping, you could potentially increase the efficacy of the drug[s].”

“We figured that if we pair 5-azacytidine and a PARP inhibitor like talazoparib, we may be able to increase PARP trapping at DNA damage sites.”

That’s because 5-azacytidine blocks proteins that attach gene-regulating methyl groups to DNA and traps those proteins on DNA. The proteins blocked by 5-azacytidine also interact with PARP enzymes at DNA damage sites.

In fact, the researchers did find that combining 5-azacytidine and talazoparib increased the time that PARP was trapped at sites of DNA damage in cancer cells. The time was extended from 30 minutes to 3-6 hours after treatment.

Next steps

Based on the results of this research, a clinical trial is planned to test whether low doses of decitabine and talazoparib can be safely combined and whether this therapy will be effective in AML patients.

The researchers are especially interested in testing the combination in patients who cannot receive intensive chemotherapy, whose leukemia is resistant to treatment, or who have relapsed after treatment.

“This is really a new paradigm mechanism that is being translated into a clinical trial,” Dr Rassool said. “It’s not just putting 2 drugs together.”

“We have shown in the laboratory that the proteins that these inhibitors target actually interact, so the effects of these inhibitors are enhanced through this interaction. Therein lies the novelty of this new approach.”

Zebrafish embryos

Image by Ian Johnston

Results of preclinical research explain the role endoglin plays in hematopoietic cell fate during embryogenesis.

Previous research showed that endoglin, a cell surface protein belonging to the TGF-beta receptor complex, is required for early hematopoietic lineage specification.

A new study shows that endoglin modulates the BMP and Wnt signaling pathways to encourage progenitor cells to develop into blood cells rather than cardiac cells.

This study was published in Nature Communications.

“During the early stages of development, cells have to make decisions very quickly,” said study author Rita Perlingeiro, PhD, of the University of Minnesota in Minneapolis.

“Fine-tuning of these early cell fate decisions can be easily disrupted by levels of key proteins within these cells. When one cell type is favored, this implies less of another. In this case, high levels of endoglin expression enhance the cell differentiation into blood cells, whereas cardiac cells are in deficit.”

Dr Perlingeiro and her colleagues made this discovery studying zebrafish and mouse models. The team wanted to pinpoint the mechanism underlying the dual function of endoglin in blood cell and cardiac cell fate.

The researchers found that endoglin is expressed in early mesoderm, and it marks both hematopoietic and cardiac progenitors.

Experiments showed that high levels of endoglin increase hematopoiesis while inhibiting cardiogenesis. And the levels of endoglin determine the activation of the BMP and Wnt signaling pathways.

With further investigation, the researchers identified JDP2, a member of the AP-1 transcription factor family, as an endoglin-dependent downstream target of Wnt signaling.

The team found that JDP2 expression is sufficient to establish blood cell fate when BMP and Wnt crosstalk is disturbed.

“The blood and heart systems are the first organs to develop in mammals, but the mechanisms regulating these earliest cell fate decisions are poorly understood,” Dr Perlingeiro said.

“By using multiple model systems, combined with specialized cell sorting technology and sequencing tools, our findings help uncover mechanisms previously unseen in the few cells engaged in these early development decisions.”

Zebrafish embryos

Image by Ian Johnston

Results of preclinical research explain the role endoglin plays in hematopoietic cell fate during embryogenesis.

Previous research showed that endoglin, a cell surface protein belonging to the TGF-beta receptor complex, is required for early hematopoietic lineage specification.

A new study shows that endoglin modulates the BMP and Wnt signaling pathways to encourage progenitor cells to develop into blood cells rather than cardiac cells.

This study was published in Nature Communications.

“During the early stages of development, cells have to make decisions very quickly,” said study author Rita Perlingeiro, PhD, of the University of Minnesota in Minneapolis.

“Fine-tuning of these early cell fate decisions can be easily disrupted by levels of key proteins within these cells. When one cell type is favored, this implies less of another. In this case, high levels of endoglin expression enhance the cell differentiation into blood cells, whereas cardiac cells are in deficit.”

Dr Perlingeiro and her colleagues made this discovery studying zebrafish and mouse models. The team wanted to pinpoint the mechanism underlying the dual function of endoglin in blood cell and cardiac cell fate.

The researchers found that endoglin is expressed in early mesoderm, and it marks both hematopoietic and cardiac progenitors.

Experiments showed that high levels of endoglin increase hematopoiesis while inhibiting cardiogenesis. And the levels of endoglin determine the activation of the BMP and Wnt signaling pathways.

With further investigation, the researchers identified JDP2, a member of the AP-1 transcription factor family, as an endoglin-dependent downstream target of Wnt signaling.

The team found that JDP2 expression is sufficient to establish blood cell fate when BMP and Wnt crosstalk is disturbed.

“The blood and heart systems are the first organs to develop in mammals, but the mechanisms regulating these earliest cell fate decisions are poorly understood,” Dr Perlingeiro said.

“By using multiple model systems, combined with specialized cell sorting technology and sequencing tools, our findings help uncover mechanisms previously unseen in the few cells engaged in these early development decisions.”

Zebrafish embryos

Image by Ian Johnston

Results of preclinical research explain the role endoglin plays in hematopoietic cell fate during embryogenesis.

Previous research showed that endoglin, a cell surface protein belonging to the TGF-beta receptor complex, is required for early hematopoietic lineage specification.

A new study shows that endoglin modulates the BMP and Wnt signaling pathways to encourage progenitor cells to develop into blood cells rather than cardiac cells.

This study was published in Nature Communications.

“During the early stages of development, cells have to make decisions very quickly,” said study author Rita Perlingeiro, PhD, of the University of Minnesota in Minneapolis.

“Fine-tuning of these early cell fate decisions can be easily disrupted by levels of key proteins within these cells. When one cell type is favored, this implies less of another. In this case, high levels of endoglin expression enhance the cell differentiation into blood cells, whereas cardiac cells are in deficit.”

Dr Perlingeiro and her colleagues made this discovery studying zebrafish and mouse models. The team wanted to pinpoint the mechanism underlying the dual function of endoglin in blood cell and cardiac cell fate.

The researchers found that endoglin is expressed in early mesoderm, and it marks both hematopoietic and cardiac progenitors.

Experiments showed that high levels of endoglin increase hematopoiesis while inhibiting cardiogenesis. And the levels of endoglin determine the activation of the BMP and Wnt signaling pathways.

With further investigation, the researchers identified JDP2, a member of the AP-1 transcription factor family, as an endoglin-dependent downstream target of Wnt signaling.

The team found that JDP2 expression is sufficient to establish blood cell fate when BMP and Wnt crosstalk is disturbed.

“The blood and heart systems are the first organs to develop in mammals, but the mechanisms regulating these earliest cell fate decisions are poorly understood,” Dr Perlingeiro said.

“By using multiple model systems, combined with specialized cell sorting technology and sequencing tools, our findings help uncover mechanisms previously unseen in the few cells engaged in these early development decisions.”

Beta-blockers were associated with less pain and lower opioid consumption in a case-control study of nearly 900 patients with osteoarthritis, Ana Valdes, PhD, and her colleagues reported in Arthritis Care & Research.

There is some mechanistic support for the association, which has been observed in other pain disorders, noted Dr. Valdes of the University of Nottingham (England) and her coauthors (Arthritis Care Res. 2016 Oct 1. doi: 10.1002/acr.23091).

©KatarzynaBialasiewicz/Thinkstock.com

[email protected]

Beta-blockers were associated with less pain and lower opioid consumption in a case-control study of nearly 900 patients with osteoarthritis, Ana Valdes, PhD, and her colleagues reported in Arthritis Care & Research.

There is some mechanistic support for the association, which has been observed in other pain disorders, noted Dr. Valdes of the University of Nottingham (England) and her coauthors (Arthritis Care Res. 2016 Oct 1. doi: 10.1002/acr.23091).

©KatarzynaBialasiewicz/Thinkstock.com

[email protected]

Beta-blockers were associated with less pain and lower opioid consumption in a case-control study of nearly 900 patients with osteoarthritis, Ana Valdes, PhD, and her colleagues reported in Arthritis Care & Research.

There is some mechanistic support for the association, which has been observed in other pain disorders, noted Dr. Valdes of the University of Nottingham (England) and her coauthors (Arthritis Care Res. 2016 Oct 1. doi: 10.1002/acr.23091).

©KatarzynaBialasiewicz/Thinkstock.com

[email protected]