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Cannabis and prenatal care
We know that the environment significantly impacts our health. People who live in areas prone to industrial waste, poor air or water quality, and crime have higher risks for cardiovascular disease, severe asthma, and stress-induced illnesses. Children who grow up under these conditions can experience a failure to thrive.
As ob.gyns., we also recognize that the intrauterine environment plays a key role in influencing embryonic and fetal development. For this reason, we counsel our pregnant patients to eat well-balanced diets, drink healthy amounts of water, get plenty of rest, and incorporate physical activity into their daily routines. Indeed, the seminal work by Sir David Barker demonstrated that the roots of chronic diseases – including hypertension, stroke, and type 2 diabetes – begin in utero. We truly are where we live – from before birth up through adulthood.
Because the womb environment, where we spend the first critical 9 months of life, dramatically affects our lifelong health, we advise against the use of certain medications and other substances during pregnancy. Some of these recommendations seem clear-cut: Don’t smoke and significantly reduce or abstain from alcohol consumption; illicit drugs – such as cocaine or heroin – should never be used. However, gray areas exist. For example, although anticonvulsants carry higher risks for congenital malformations, patients who experience seizures may need to continue taking antiepileptic drugs during pregnancy, especially those with long safety records.
One of the newer challenges the medical community in general must face is the broadened use and wider societal acceptance of cannabis. Currently legal in 33 U.S. states and Washington, D.C., medical marijuana now is viewed as another legitimate tool in the health care arsenal, rather than the off-limits, off-label substance it was less than a generation ago.
Although proponents may tout the health benefits of cannabis and related products like cannabidiol, it remains unclear what the long-term effects of routine use may have on development, especially fetal development. However, how we as ob.gyns. navigate conversations with our patients around substance use remains crucial to our delivery of the best possible prenatal care.
We have invited Katrina S. Mark, MD, associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, to examine use of cannabis in pregnancy and the need for maintaining trust in the patient-practitioner relationship when discussing substance use during prenatal counseling.
Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at [email protected].
We know that the environment significantly impacts our health. People who live in areas prone to industrial waste, poor air or water quality, and crime have higher risks for cardiovascular disease, severe asthma, and stress-induced illnesses. Children who grow up under these conditions can experience a failure to thrive.
As ob.gyns., we also recognize that the intrauterine environment plays a key role in influencing embryonic and fetal development. For this reason, we counsel our pregnant patients to eat well-balanced diets, drink healthy amounts of water, get plenty of rest, and incorporate physical activity into their daily routines. Indeed, the seminal work by Sir David Barker demonstrated that the roots of chronic diseases – including hypertension, stroke, and type 2 diabetes – begin in utero. We truly are where we live – from before birth up through adulthood.
Because the womb environment, where we spend the first critical 9 months of life, dramatically affects our lifelong health, we advise against the use of certain medications and other substances during pregnancy. Some of these recommendations seem clear-cut: Don’t smoke and significantly reduce or abstain from alcohol consumption; illicit drugs – such as cocaine or heroin – should never be used. However, gray areas exist. For example, although anticonvulsants carry higher risks for congenital malformations, patients who experience seizures may need to continue taking antiepileptic drugs during pregnancy, especially those with long safety records.
One of the newer challenges the medical community in general must face is the broadened use and wider societal acceptance of cannabis. Currently legal in 33 U.S. states and Washington, D.C., medical marijuana now is viewed as another legitimate tool in the health care arsenal, rather than the off-limits, off-label substance it was less than a generation ago.
Although proponents may tout the health benefits of cannabis and related products like cannabidiol, it remains unclear what the long-term effects of routine use may have on development, especially fetal development. However, how we as ob.gyns. navigate conversations with our patients around substance use remains crucial to our delivery of the best possible prenatal care.
We have invited Katrina S. Mark, MD, associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, to examine use of cannabis in pregnancy and the need for maintaining trust in the patient-practitioner relationship when discussing substance use during prenatal counseling.
Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at [email protected].
We know that the environment significantly impacts our health. People who live in areas prone to industrial waste, poor air or water quality, and crime have higher risks for cardiovascular disease, severe asthma, and stress-induced illnesses. Children who grow up under these conditions can experience a failure to thrive.
As ob.gyns., we also recognize that the intrauterine environment plays a key role in influencing embryonic and fetal development. For this reason, we counsel our pregnant patients to eat well-balanced diets, drink healthy amounts of water, get plenty of rest, and incorporate physical activity into their daily routines. Indeed, the seminal work by Sir David Barker demonstrated that the roots of chronic diseases – including hypertension, stroke, and type 2 diabetes – begin in utero. We truly are where we live – from before birth up through adulthood.
Because the womb environment, where we spend the first critical 9 months of life, dramatically affects our lifelong health, we advise against the use of certain medications and other substances during pregnancy. Some of these recommendations seem clear-cut: Don’t smoke and significantly reduce or abstain from alcohol consumption; illicit drugs – such as cocaine or heroin – should never be used. However, gray areas exist. For example, although anticonvulsants carry higher risks for congenital malformations, patients who experience seizures may need to continue taking antiepileptic drugs during pregnancy, especially those with long safety records.
One of the newer challenges the medical community in general must face is the broadened use and wider societal acceptance of cannabis. Currently legal in 33 U.S. states and Washington, D.C., medical marijuana now is viewed as another legitimate tool in the health care arsenal, rather than the off-limits, off-label substance it was less than a generation ago.
Although proponents may tout the health benefits of cannabis and related products like cannabidiol, it remains unclear what the long-term effects of routine use may have on development, especially fetal development. However, how we as ob.gyns. navigate conversations with our patients around substance use remains crucial to our delivery of the best possible prenatal care.
We have invited Katrina S. Mark, MD, associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, to examine use of cannabis in pregnancy and the need for maintaining trust in the patient-practitioner relationship when discussing substance use during prenatal counseling.
Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at [email protected].
Counseling on cannabis use in pregnancy
A flurry of research papers published this year has simultaneously documented a rise in the use of cannabis during pregnancy and offered more data about its potential harms. This confluence of findings is concerning and highlights the importance of screening our patients for cannabis use and engaging with them in a way in which we can maintain their trust and their commitment to prenatal care.
A retrospective cohort study involving 661,617 women in Ontario found a significant association between self-reported cannabis use in pregnancy and an increased risk of preterm birth (relative risk, 1.41), as well as a greater likelihood of small-for-gestational-age babies (RR, 1.53), placental abruption (RR, 1.72), and transfer to neonatal intensive care (RR, 1.40).1 The study, reported in JAMA in July 2019, carefully matched users with nonusers who had the same characteristics – for example, tobacco use or not.
This new information builds upon other meta-analyses that have demonstrated a decrease in birth weight and greater admittance to the neonatal ICU associated with cannabis use in pregnancy – and it supplements what some research suggests about long-term neurologic development and a potentially increased risk of attention and behavioral problems. Other outcomes that have been noted in long-term neurologic studies of children who were exposed to cannabis in utero include impaired visual acuity, verbal reasoning and comprehension, and short-term memory.2
Increases in use were recently documented in two studies. One, an analysis of data from the National Survey on Drug Use and Health (NSDUH) published in JAMA in June 2019, showed that, between 2002-2003 and 2016-2017, the use of cannabis “in the past month” increased from 3.4% to 7.0% among pregnant women overall, and from 6% to 12% during the first trimester.3
The use of cannabis on a daily or near-daily basis, moreover, increased from 0.9% to 3% among pregnant women overall and from 2% to 5% during the first trimester. The data were collected during face-to-face interviews and were adjusted for age, race/ethnicity, and family income.
In the second study – a cross-sectional study of 367,403 pregnancies among women who filled out a questionnaire on cannabis use during standard prenatal care at Kaiser Permanente Northern California – the adjusted prevalence of use in the year before pregnancy increased from 7% in 2009 to 13% in 2017, and the adjusted prevalence during pregnancy increased from 2% to 3%.4
As in the NSDUH analysis, daily use increased most rapidly (compared with weekly or monthly) such that, by 2017, 25% of those who reported using cannabis in the year before pregnancy – and 21% of those who used cannabis during pregnancy – were daily users. It is notable that Kaiser’s population is diverse in all respects, and that the annual relative rates of increase in cannabis use before and during pregnancy (at each level of frequency) were consistent across racial/ethnic and household income groups.
It’s also worth noting that, in earlier research covering a similar time period (2009-2016), the investigators found significant increases in use via urine toxicology testing that occurs at the first prenatal visit at Kaiser. The increase found through questionnaires, therefore, reflects more than a greater willingness to self-report.
Choosing a screening tool
Universal prenatal substance use screening is recommended by the American College of Obstetricians and Gynecologists and the Centers for Disease Control and Prevention, but we don’t have any specific recommendations on what this means. Who should be screening, and what should that screening look like? Should we use a biologic screen, a standardized screening tool, or simply ask patients whether they use illicit substances?
Screening tools seem advantageous in that they are low cost, noninvasive, potentially comprehensive, and not subject to false-positive results as biologic screens can be – but which tool or tools are best? There are several validated screening tools that can be used outside of pregnancy to determine an individual’s use of illicit substances and whether or not that use is problematic, but previous studies have not used biologic markers to validate substance use screeners in pregnancy. Nor have studies compared screeners in pregnancy.
In our prenatal population in Baltimore, we have not been getting the answers we want using various nonvalidated screening tools. Approximately 30% of patients are positive for cannabis by urine screen, but only half tell us about their use.
Through research in our two prenatal care practices (one serving mostly privately insured and the other serving primarily Medicaid-eligible patients), we assessed both the accuracy and the acceptability of three substance use screening tools that are brief and that have been validated (for the general population) by the World Health Organization for screening of multiple substances: the 4P’s Plus (Parents, Partner, Past, and Pregnancy), the National Institute on Drug Abuse Quick Screen–ASSIST (Modified Alcohol, Smoking and Substance Involvement Screening Test), and the SURP-P (Substance Use Risk Profile–Pregnancy) scale.
In one study, published in May 2019 in Obstetrics & Gynecology, we recruited 500 pregnant women and administered these three tests to each of them.5 We then compared results with those of urine and hair drug testing, and checked the test-retest reliability of each test by readministering them (albeit by telephone) a week later. Although hair testing is not an indicator of current substance use, we used it to validate the screening tools on less-recent use.
The tests with the highest sensitivity and negative predictive values – the qualities we most want for screening – were the SURP-P and the 4P’s Plus (sensitivity of 92.4% and 90.2%, respectively). Overall they were highly sensitive screening tools across all trimesters, races, and age groups, making them more ideal screening tests than the NIDA Quick Screen–ASSIST.
Of the two tests, the 4P’s Plus screening tool was the one preferred by staff from both practices. In a companion qualitative study, we conducted focus-group discussions with 40 practice staff who were responsible for administering or overseeing patient screening.6 The staff, who were unaware of the sensitivity findings, were asked what they thought about the acceptability to patients of each of the three tools and their usability in practice.
Most of the participating staff preferred the 4P’s Plus screening tool for several reasons: It is easy to understand, is brief and to the point, and it has nonjudgmental language and tone. The screener first asks the patient about her parents’ and her partner’s use of alcohol and drugs, and then asks the patient about her own use of alcohol and tobacco. Affirmative responses to these questions lead to additional questions.
The premise is that one’s genetics, history, and current exposures – as well as one’s own use of tobacco and alcohol – are significantly associated with the use of illicit substances. If the patient reports no parental history or partner usage, and has never drank or smoked before, it’s extremely unlikely that she is using other drugs. The progression of questions does indeed seem less judgmental than immediately asking: “Do you use drugs?”
For us, the insight from this staff perception study combined with the findings on accuracy mean that the 4P’s Plus may be the most useful and acceptable screening tool for routine use in prenatal care.
Talking with our patients
The increase in the use of cannabis before and after pregnancy parallels the movement toward state legalization and decriminalization. Historically, clinicians often have relied on illegality as their main focus of counseling when giving recommendations for cessation and abstinence in pregnancy.2 This approach not only leads to punitive counseling, which can fracture the doctor-patient relationship, but increasingly it is no longer valid. In our changing legal climate, we need to provide medically based counseling and be very clear with our patients that legalization does not equate to safety.
It is important that we neither minimize nor overstate the risks. The evidence base for adverse birth outcomes of cannabis use in pregnancy is quite robust, but the associations can be subtle and are moderated by other behaviors and environmental factors that continue to challenge researchers.
As with alcohol, there likely are dose-or trimester-dependent differences in perinatal outcomes, and it’s quite possible that different cannabis products and routes of consumption have different effects. At this point, however, we don’t know the full story, nor do we know the extent to which the literature is biased toward positive correlations – the reporting of adverse effects – compared with negative findings. It is our job as medical care providers to be comfortable in that gray area and to still counsel patients on what we do know, providing the best-possible medical advice based on the information available to us.
In talking with patients, I explain that cannabis may cause a spectrum of problems and that there certainly are risks. I also tell them that we’re uncertain about the conditions and magnitude of that risk and that some babies who are exposed to cannabis in utero may have no perceivable consequences. Such honesty is important for maintaining trust, especially as some patients may see friends and relatives who also are cannabis users have normal pregnancy outcomes.
Much of my concern about cannabis in pregnancy centers on its effect on the developing brain and on long-term neurologic development. I share this with patients – I tell them that cannabis crosses the placenta and may well affect their baby’s brain as it is developing. I explain that I do not know whether this effect would be big or small, but that it’s not a chance I’m willing to take for their baby.
It is also important to educate patients that cannabis products are untested and unregulated and that they may be contaminated with heavy metals, pesticides, and other toxins that may be harmful to themselves and their babies. Patients also should know that the potency of cannabis has been dramatically increasing; research shows that the tetrahydrocannabinol – the psychoactive component – concentration has tripled over the past 2 decades.7
Research tells us that women who use illicit drugs and alcohol categorically engage in some form of harm reduction once they learn they are pregnant, and the same is true for cannabis. This is seen in dramatically different rates of first- and third-trimester use in the new analysis of NSDUH data; third-trimester use is approximately halved.
Some women will not be able to discontinue use, however, or they may try to quit and fail in their attempts. As we should with substance use more broadly, we must meet patients where they are, view cannabis use as a chronic medical problem, offer our assistance in helping them reduce harms of their use, and understand that quitting is a process.
Screening for mental health disorders and trauma is, of course, especially important in patients who use cannabis and other substances recreationally. In cases of medical marijuana usage, I recommend, as ACOG and other have done, that we discuss the risks and benefits of continuing cannabis versus shifting to alternative medications if options exist.
All patients should be welcomed, congratulated on their pregnancy and on coming for prenatal care, and engaged in the overall process of optimizing their health and the health of their baby. Like any other health issue during pregnancy, cannabis use needs to be screened for and treated in an evidence-based manner, but it does not define the trajectory or success of a woman’s pregnancy or her ability to be a successful parent.
Dr. Mark is associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine.
References
1. JAMA. 2019 Jul 9;322(2):145-52.
2. Preventive Medicine 2017 May 18;104:46-9.
3. JAMA. 2019 Jul 9;322(2):167-9.
4. JAMA Netw Open. 2019 Jul 3;2(7):e196471.
5. Obstet Gynecol. 2019 May;133(5):952-61.
6. J. Addict Med. 2019 May 10. doi: 10.1097/ADM.0000000000000543.
7. Biol Psychiatry. 2016 Apr 1;79(7):613-9.
A flurry of research papers published this year has simultaneously documented a rise in the use of cannabis during pregnancy and offered more data about its potential harms. This confluence of findings is concerning and highlights the importance of screening our patients for cannabis use and engaging with them in a way in which we can maintain their trust and their commitment to prenatal care.
A retrospective cohort study involving 661,617 women in Ontario found a significant association between self-reported cannabis use in pregnancy and an increased risk of preterm birth (relative risk, 1.41), as well as a greater likelihood of small-for-gestational-age babies (RR, 1.53), placental abruption (RR, 1.72), and transfer to neonatal intensive care (RR, 1.40).1 The study, reported in JAMA in July 2019, carefully matched users with nonusers who had the same characteristics – for example, tobacco use or not.
This new information builds upon other meta-analyses that have demonstrated a decrease in birth weight and greater admittance to the neonatal ICU associated with cannabis use in pregnancy – and it supplements what some research suggests about long-term neurologic development and a potentially increased risk of attention and behavioral problems. Other outcomes that have been noted in long-term neurologic studies of children who were exposed to cannabis in utero include impaired visual acuity, verbal reasoning and comprehension, and short-term memory.2
Increases in use were recently documented in two studies. One, an analysis of data from the National Survey on Drug Use and Health (NSDUH) published in JAMA in June 2019, showed that, between 2002-2003 and 2016-2017, the use of cannabis “in the past month” increased from 3.4% to 7.0% among pregnant women overall, and from 6% to 12% during the first trimester.3
The use of cannabis on a daily or near-daily basis, moreover, increased from 0.9% to 3% among pregnant women overall and from 2% to 5% during the first trimester. The data were collected during face-to-face interviews and were adjusted for age, race/ethnicity, and family income.
In the second study – a cross-sectional study of 367,403 pregnancies among women who filled out a questionnaire on cannabis use during standard prenatal care at Kaiser Permanente Northern California – the adjusted prevalence of use in the year before pregnancy increased from 7% in 2009 to 13% in 2017, and the adjusted prevalence during pregnancy increased from 2% to 3%.4
As in the NSDUH analysis, daily use increased most rapidly (compared with weekly or monthly) such that, by 2017, 25% of those who reported using cannabis in the year before pregnancy – and 21% of those who used cannabis during pregnancy – were daily users. It is notable that Kaiser’s population is diverse in all respects, and that the annual relative rates of increase in cannabis use before and during pregnancy (at each level of frequency) were consistent across racial/ethnic and household income groups.
It’s also worth noting that, in earlier research covering a similar time period (2009-2016), the investigators found significant increases in use via urine toxicology testing that occurs at the first prenatal visit at Kaiser. The increase found through questionnaires, therefore, reflects more than a greater willingness to self-report.
Choosing a screening tool
Universal prenatal substance use screening is recommended by the American College of Obstetricians and Gynecologists and the Centers for Disease Control and Prevention, but we don’t have any specific recommendations on what this means. Who should be screening, and what should that screening look like? Should we use a biologic screen, a standardized screening tool, or simply ask patients whether they use illicit substances?
Screening tools seem advantageous in that they are low cost, noninvasive, potentially comprehensive, and not subject to false-positive results as biologic screens can be – but which tool or tools are best? There are several validated screening tools that can be used outside of pregnancy to determine an individual’s use of illicit substances and whether or not that use is problematic, but previous studies have not used biologic markers to validate substance use screeners in pregnancy. Nor have studies compared screeners in pregnancy.
In our prenatal population in Baltimore, we have not been getting the answers we want using various nonvalidated screening tools. Approximately 30% of patients are positive for cannabis by urine screen, but only half tell us about their use.
Through research in our two prenatal care practices (one serving mostly privately insured and the other serving primarily Medicaid-eligible patients), we assessed both the accuracy and the acceptability of three substance use screening tools that are brief and that have been validated (for the general population) by the World Health Organization for screening of multiple substances: the 4P’s Plus (Parents, Partner, Past, and Pregnancy), the National Institute on Drug Abuse Quick Screen–ASSIST (Modified Alcohol, Smoking and Substance Involvement Screening Test), and the SURP-P (Substance Use Risk Profile–Pregnancy) scale.
In one study, published in May 2019 in Obstetrics & Gynecology, we recruited 500 pregnant women and administered these three tests to each of them.5 We then compared results with those of urine and hair drug testing, and checked the test-retest reliability of each test by readministering them (albeit by telephone) a week later. Although hair testing is not an indicator of current substance use, we used it to validate the screening tools on less-recent use.
The tests with the highest sensitivity and negative predictive values – the qualities we most want for screening – were the SURP-P and the 4P’s Plus (sensitivity of 92.4% and 90.2%, respectively). Overall they were highly sensitive screening tools across all trimesters, races, and age groups, making them more ideal screening tests than the NIDA Quick Screen–ASSIST.
Of the two tests, the 4P’s Plus screening tool was the one preferred by staff from both practices. In a companion qualitative study, we conducted focus-group discussions with 40 practice staff who were responsible for administering or overseeing patient screening.6 The staff, who were unaware of the sensitivity findings, were asked what they thought about the acceptability to patients of each of the three tools and their usability in practice.
Most of the participating staff preferred the 4P’s Plus screening tool for several reasons: It is easy to understand, is brief and to the point, and it has nonjudgmental language and tone. The screener first asks the patient about her parents’ and her partner’s use of alcohol and drugs, and then asks the patient about her own use of alcohol and tobacco. Affirmative responses to these questions lead to additional questions.
The premise is that one’s genetics, history, and current exposures – as well as one’s own use of tobacco and alcohol – are significantly associated with the use of illicit substances. If the patient reports no parental history or partner usage, and has never drank or smoked before, it’s extremely unlikely that she is using other drugs. The progression of questions does indeed seem less judgmental than immediately asking: “Do you use drugs?”
For us, the insight from this staff perception study combined with the findings on accuracy mean that the 4P’s Plus may be the most useful and acceptable screening tool for routine use in prenatal care.
Talking with our patients
The increase in the use of cannabis before and after pregnancy parallels the movement toward state legalization and decriminalization. Historically, clinicians often have relied on illegality as their main focus of counseling when giving recommendations for cessation and abstinence in pregnancy.2 This approach not only leads to punitive counseling, which can fracture the doctor-patient relationship, but increasingly it is no longer valid. In our changing legal climate, we need to provide medically based counseling and be very clear with our patients that legalization does not equate to safety.
It is important that we neither minimize nor overstate the risks. The evidence base for adverse birth outcomes of cannabis use in pregnancy is quite robust, but the associations can be subtle and are moderated by other behaviors and environmental factors that continue to challenge researchers.
As with alcohol, there likely are dose-or trimester-dependent differences in perinatal outcomes, and it’s quite possible that different cannabis products and routes of consumption have different effects. At this point, however, we don’t know the full story, nor do we know the extent to which the literature is biased toward positive correlations – the reporting of adverse effects – compared with negative findings. It is our job as medical care providers to be comfortable in that gray area and to still counsel patients on what we do know, providing the best-possible medical advice based on the information available to us.
In talking with patients, I explain that cannabis may cause a spectrum of problems and that there certainly are risks. I also tell them that we’re uncertain about the conditions and magnitude of that risk and that some babies who are exposed to cannabis in utero may have no perceivable consequences. Such honesty is important for maintaining trust, especially as some patients may see friends and relatives who also are cannabis users have normal pregnancy outcomes.
Much of my concern about cannabis in pregnancy centers on its effect on the developing brain and on long-term neurologic development. I share this with patients – I tell them that cannabis crosses the placenta and may well affect their baby’s brain as it is developing. I explain that I do not know whether this effect would be big or small, but that it’s not a chance I’m willing to take for their baby.
It is also important to educate patients that cannabis products are untested and unregulated and that they may be contaminated with heavy metals, pesticides, and other toxins that may be harmful to themselves and their babies. Patients also should know that the potency of cannabis has been dramatically increasing; research shows that the tetrahydrocannabinol – the psychoactive component – concentration has tripled over the past 2 decades.7
Research tells us that women who use illicit drugs and alcohol categorically engage in some form of harm reduction once they learn they are pregnant, and the same is true for cannabis. This is seen in dramatically different rates of first- and third-trimester use in the new analysis of NSDUH data; third-trimester use is approximately halved.
Some women will not be able to discontinue use, however, or they may try to quit and fail in their attempts. As we should with substance use more broadly, we must meet patients where they are, view cannabis use as a chronic medical problem, offer our assistance in helping them reduce harms of their use, and understand that quitting is a process.
Screening for mental health disorders and trauma is, of course, especially important in patients who use cannabis and other substances recreationally. In cases of medical marijuana usage, I recommend, as ACOG and other have done, that we discuss the risks and benefits of continuing cannabis versus shifting to alternative medications if options exist.
All patients should be welcomed, congratulated on their pregnancy and on coming for prenatal care, and engaged in the overall process of optimizing their health and the health of their baby. Like any other health issue during pregnancy, cannabis use needs to be screened for and treated in an evidence-based manner, but it does not define the trajectory or success of a woman’s pregnancy or her ability to be a successful parent.
Dr. Mark is associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine.
References
1. JAMA. 2019 Jul 9;322(2):145-52.
2. Preventive Medicine 2017 May 18;104:46-9.
3. JAMA. 2019 Jul 9;322(2):167-9.
4. JAMA Netw Open. 2019 Jul 3;2(7):e196471.
5. Obstet Gynecol. 2019 May;133(5):952-61.
6. J. Addict Med. 2019 May 10. doi: 10.1097/ADM.0000000000000543.
7. Biol Psychiatry. 2016 Apr 1;79(7):613-9.
A flurry of research papers published this year has simultaneously documented a rise in the use of cannabis during pregnancy and offered more data about its potential harms. This confluence of findings is concerning and highlights the importance of screening our patients for cannabis use and engaging with them in a way in which we can maintain their trust and their commitment to prenatal care.
A retrospective cohort study involving 661,617 women in Ontario found a significant association between self-reported cannabis use in pregnancy and an increased risk of preterm birth (relative risk, 1.41), as well as a greater likelihood of small-for-gestational-age babies (RR, 1.53), placental abruption (RR, 1.72), and transfer to neonatal intensive care (RR, 1.40).1 The study, reported in JAMA in July 2019, carefully matched users with nonusers who had the same characteristics – for example, tobacco use or not.
This new information builds upon other meta-analyses that have demonstrated a decrease in birth weight and greater admittance to the neonatal ICU associated with cannabis use in pregnancy – and it supplements what some research suggests about long-term neurologic development and a potentially increased risk of attention and behavioral problems. Other outcomes that have been noted in long-term neurologic studies of children who were exposed to cannabis in utero include impaired visual acuity, verbal reasoning and comprehension, and short-term memory.2
Increases in use were recently documented in two studies. One, an analysis of data from the National Survey on Drug Use and Health (NSDUH) published in JAMA in June 2019, showed that, between 2002-2003 and 2016-2017, the use of cannabis “in the past month” increased from 3.4% to 7.0% among pregnant women overall, and from 6% to 12% during the first trimester.3
The use of cannabis on a daily or near-daily basis, moreover, increased from 0.9% to 3% among pregnant women overall and from 2% to 5% during the first trimester. The data were collected during face-to-face interviews and were adjusted for age, race/ethnicity, and family income.
In the second study – a cross-sectional study of 367,403 pregnancies among women who filled out a questionnaire on cannabis use during standard prenatal care at Kaiser Permanente Northern California – the adjusted prevalence of use in the year before pregnancy increased from 7% in 2009 to 13% in 2017, and the adjusted prevalence during pregnancy increased from 2% to 3%.4
As in the NSDUH analysis, daily use increased most rapidly (compared with weekly or monthly) such that, by 2017, 25% of those who reported using cannabis in the year before pregnancy – and 21% of those who used cannabis during pregnancy – were daily users. It is notable that Kaiser’s population is diverse in all respects, and that the annual relative rates of increase in cannabis use before and during pregnancy (at each level of frequency) were consistent across racial/ethnic and household income groups.
It’s also worth noting that, in earlier research covering a similar time period (2009-2016), the investigators found significant increases in use via urine toxicology testing that occurs at the first prenatal visit at Kaiser. The increase found through questionnaires, therefore, reflects more than a greater willingness to self-report.
Choosing a screening tool
Universal prenatal substance use screening is recommended by the American College of Obstetricians and Gynecologists and the Centers for Disease Control and Prevention, but we don’t have any specific recommendations on what this means. Who should be screening, and what should that screening look like? Should we use a biologic screen, a standardized screening tool, or simply ask patients whether they use illicit substances?
Screening tools seem advantageous in that they are low cost, noninvasive, potentially comprehensive, and not subject to false-positive results as biologic screens can be – but which tool or tools are best? There are several validated screening tools that can be used outside of pregnancy to determine an individual’s use of illicit substances and whether or not that use is problematic, but previous studies have not used biologic markers to validate substance use screeners in pregnancy. Nor have studies compared screeners in pregnancy.
In our prenatal population in Baltimore, we have not been getting the answers we want using various nonvalidated screening tools. Approximately 30% of patients are positive for cannabis by urine screen, but only half tell us about their use.
Through research in our two prenatal care practices (one serving mostly privately insured and the other serving primarily Medicaid-eligible patients), we assessed both the accuracy and the acceptability of three substance use screening tools that are brief and that have been validated (for the general population) by the World Health Organization for screening of multiple substances: the 4P’s Plus (Parents, Partner, Past, and Pregnancy), the National Institute on Drug Abuse Quick Screen–ASSIST (Modified Alcohol, Smoking and Substance Involvement Screening Test), and the SURP-P (Substance Use Risk Profile–Pregnancy) scale.
In one study, published in May 2019 in Obstetrics & Gynecology, we recruited 500 pregnant women and administered these three tests to each of them.5 We then compared results with those of urine and hair drug testing, and checked the test-retest reliability of each test by readministering them (albeit by telephone) a week later. Although hair testing is not an indicator of current substance use, we used it to validate the screening tools on less-recent use.
The tests with the highest sensitivity and negative predictive values – the qualities we most want for screening – were the SURP-P and the 4P’s Plus (sensitivity of 92.4% and 90.2%, respectively). Overall they were highly sensitive screening tools across all trimesters, races, and age groups, making them more ideal screening tests than the NIDA Quick Screen–ASSIST.
Of the two tests, the 4P’s Plus screening tool was the one preferred by staff from both practices. In a companion qualitative study, we conducted focus-group discussions with 40 practice staff who were responsible for administering or overseeing patient screening.6 The staff, who were unaware of the sensitivity findings, were asked what they thought about the acceptability to patients of each of the three tools and their usability in practice.
Most of the participating staff preferred the 4P’s Plus screening tool for several reasons: It is easy to understand, is brief and to the point, and it has nonjudgmental language and tone. The screener first asks the patient about her parents’ and her partner’s use of alcohol and drugs, and then asks the patient about her own use of alcohol and tobacco. Affirmative responses to these questions lead to additional questions.
The premise is that one’s genetics, history, and current exposures – as well as one’s own use of tobacco and alcohol – are significantly associated with the use of illicit substances. If the patient reports no parental history or partner usage, and has never drank or smoked before, it’s extremely unlikely that she is using other drugs. The progression of questions does indeed seem less judgmental than immediately asking: “Do you use drugs?”
For us, the insight from this staff perception study combined with the findings on accuracy mean that the 4P’s Plus may be the most useful and acceptable screening tool for routine use in prenatal care.
Talking with our patients
The increase in the use of cannabis before and after pregnancy parallels the movement toward state legalization and decriminalization. Historically, clinicians often have relied on illegality as their main focus of counseling when giving recommendations for cessation and abstinence in pregnancy.2 This approach not only leads to punitive counseling, which can fracture the doctor-patient relationship, but increasingly it is no longer valid. In our changing legal climate, we need to provide medically based counseling and be very clear with our patients that legalization does not equate to safety.
It is important that we neither minimize nor overstate the risks. The evidence base for adverse birth outcomes of cannabis use in pregnancy is quite robust, but the associations can be subtle and are moderated by other behaviors and environmental factors that continue to challenge researchers.
As with alcohol, there likely are dose-or trimester-dependent differences in perinatal outcomes, and it’s quite possible that different cannabis products and routes of consumption have different effects. At this point, however, we don’t know the full story, nor do we know the extent to which the literature is biased toward positive correlations – the reporting of adverse effects – compared with negative findings. It is our job as medical care providers to be comfortable in that gray area and to still counsel patients on what we do know, providing the best-possible medical advice based on the information available to us.
In talking with patients, I explain that cannabis may cause a spectrum of problems and that there certainly are risks. I also tell them that we’re uncertain about the conditions and magnitude of that risk and that some babies who are exposed to cannabis in utero may have no perceivable consequences. Such honesty is important for maintaining trust, especially as some patients may see friends and relatives who also are cannabis users have normal pregnancy outcomes.
Much of my concern about cannabis in pregnancy centers on its effect on the developing brain and on long-term neurologic development. I share this with patients – I tell them that cannabis crosses the placenta and may well affect their baby’s brain as it is developing. I explain that I do not know whether this effect would be big or small, but that it’s not a chance I’m willing to take for their baby.
It is also important to educate patients that cannabis products are untested and unregulated and that they may be contaminated with heavy metals, pesticides, and other toxins that may be harmful to themselves and their babies. Patients also should know that the potency of cannabis has been dramatically increasing; research shows that the tetrahydrocannabinol – the psychoactive component – concentration has tripled over the past 2 decades.7
Research tells us that women who use illicit drugs and alcohol categorically engage in some form of harm reduction once they learn they are pregnant, and the same is true for cannabis. This is seen in dramatically different rates of first- and third-trimester use in the new analysis of NSDUH data; third-trimester use is approximately halved.
Some women will not be able to discontinue use, however, or they may try to quit and fail in their attempts. As we should with substance use more broadly, we must meet patients where they are, view cannabis use as a chronic medical problem, offer our assistance in helping them reduce harms of their use, and understand that quitting is a process.
Screening for mental health disorders and trauma is, of course, especially important in patients who use cannabis and other substances recreationally. In cases of medical marijuana usage, I recommend, as ACOG and other have done, that we discuss the risks and benefits of continuing cannabis versus shifting to alternative medications if options exist.
All patients should be welcomed, congratulated on their pregnancy and on coming for prenatal care, and engaged in the overall process of optimizing their health and the health of their baby. Like any other health issue during pregnancy, cannabis use needs to be screened for and treated in an evidence-based manner, but it does not define the trajectory or success of a woman’s pregnancy or her ability to be a successful parent.
Dr. Mark is associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine.
References
1. JAMA. 2019 Jul 9;322(2):145-52.
2. Preventive Medicine 2017 May 18;104:46-9.
3. JAMA. 2019 Jul 9;322(2):167-9.
4. JAMA Netw Open. 2019 Jul 3;2(7):e196471.
5. Obstet Gynecol. 2019 May;133(5):952-61.
6. J. Addict Med. 2019 May 10. doi: 10.1097/ADM.0000000000000543.
7. Biol Psychiatry. 2016 Apr 1;79(7):613-9.
Caspofungin bests fluconazole for antifungal prophylaxis in young AML patients
Antifungal prophylaxis with caspofungin led to a lower incidence of invasive fungal disease, compared with fluconazole, in children and young adults with acute myeloid leukemia (AML), according to new study findings.
The results suggest caspofungin may be an appropriate prophylactic strategy to prevent invasive fungal disease in younger patients with newly diagnosed AML, reported Brian T. Fisher, DO, of the University of Pennsylvania, Philadelphia, and colleagues. The study was published in JAMA.
The randomized, open-label study included 517 children, adolescents, and young adults with de novo, relapsed, or secondary AML. Study patients received treatment in 115 centers throughout United States and Canada. The median age of patients in the study was 9 years (range, 0-26 years); 56% were male and approximately 69% were white.
Study subjects were randomly assigned to receive antifungal prophylaxis with 70 mg/m2 (maximum dose 70 mg/day) of intravenous caspofungin on day 1, followed by 50 mg/m2 per day (maximum dose 50 mg/day) thereafter, or age-dosed intravenous or oral fluconazole.
Prophylactic therapy was initiated 24-72 hours after the completion of each chemotherapy cycle, and was maintained until the end of the neutropenic period following each cycle.
At 5-month follow-up, the cumulative incidence rate of probable or proven invasive fungal disease was 3.1% (95% confidence interval, 1.3%-7.0%) in the caspofungin arm, compared with 7.2% (95% CI, 4.4%-11.8%) in the fluconazole arm (overall P = .03).
In addition, the 5-month cumulative incidence rate of probable or proven invasive aspergillosis infection was 0.5% (95%CI, 0.1%-3.5%) in patients who received caspofungin, compared with 3.1% (95% CI, 1.4%-6.9%) in patients who received fluconazole (overall P = .046).
“No statistically significant differences in empirical antifungal therapy or 2-year overall survival were observed,” they reported.
With respect to safety, the most frequently reported adverse events were hypokalemia (22 events in the caspofungin arm vs. 13 in the fluconazole arm), respiratory failure (6 events in the caspofungin arm vs. 9 in the fluconazole arm), and elevated alanine transaminase (4 events in the caspofungin arm vs. 8 in the fluconazole arm).
The researchers acknowledged a key limitation of the study was the short duration of follow-up. As a result, the precision of some comparative measures may have been reduced.
The National Cancer Institute funded the study. The authors reported financial affiliations with Astellas, Celgene, Leadiant Biosciences, Merck, Nabriva Therapeutics, Novartis, Pfizer, Shire, and T2 Biosystems.
SOURCE: Fisher BT et al. JAMA. 2019;322(17):1673-81.
Antifungal prophylaxis with caspofungin led to a lower incidence of invasive fungal disease, compared with fluconazole, in children and young adults with acute myeloid leukemia (AML), according to new study findings.
The results suggest caspofungin may be an appropriate prophylactic strategy to prevent invasive fungal disease in younger patients with newly diagnosed AML, reported Brian T. Fisher, DO, of the University of Pennsylvania, Philadelphia, and colleagues. The study was published in JAMA.
The randomized, open-label study included 517 children, adolescents, and young adults with de novo, relapsed, or secondary AML. Study patients received treatment in 115 centers throughout United States and Canada. The median age of patients in the study was 9 years (range, 0-26 years); 56% were male and approximately 69% were white.
Study subjects were randomly assigned to receive antifungal prophylaxis with 70 mg/m2 (maximum dose 70 mg/day) of intravenous caspofungin on day 1, followed by 50 mg/m2 per day (maximum dose 50 mg/day) thereafter, or age-dosed intravenous or oral fluconazole.
Prophylactic therapy was initiated 24-72 hours after the completion of each chemotherapy cycle, and was maintained until the end of the neutropenic period following each cycle.
At 5-month follow-up, the cumulative incidence rate of probable or proven invasive fungal disease was 3.1% (95% confidence interval, 1.3%-7.0%) in the caspofungin arm, compared with 7.2% (95% CI, 4.4%-11.8%) in the fluconazole arm (overall P = .03).
In addition, the 5-month cumulative incidence rate of probable or proven invasive aspergillosis infection was 0.5% (95%CI, 0.1%-3.5%) in patients who received caspofungin, compared with 3.1% (95% CI, 1.4%-6.9%) in patients who received fluconazole (overall P = .046).
“No statistically significant differences in empirical antifungal therapy or 2-year overall survival were observed,” they reported.
With respect to safety, the most frequently reported adverse events were hypokalemia (22 events in the caspofungin arm vs. 13 in the fluconazole arm), respiratory failure (6 events in the caspofungin arm vs. 9 in the fluconazole arm), and elevated alanine transaminase (4 events in the caspofungin arm vs. 8 in the fluconazole arm).
The researchers acknowledged a key limitation of the study was the short duration of follow-up. As a result, the precision of some comparative measures may have been reduced.
The National Cancer Institute funded the study. The authors reported financial affiliations with Astellas, Celgene, Leadiant Biosciences, Merck, Nabriva Therapeutics, Novartis, Pfizer, Shire, and T2 Biosystems.
SOURCE: Fisher BT et al. JAMA. 2019;322(17):1673-81.
Antifungal prophylaxis with caspofungin led to a lower incidence of invasive fungal disease, compared with fluconazole, in children and young adults with acute myeloid leukemia (AML), according to new study findings.
The results suggest caspofungin may be an appropriate prophylactic strategy to prevent invasive fungal disease in younger patients with newly diagnosed AML, reported Brian T. Fisher, DO, of the University of Pennsylvania, Philadelphia, and colleagues. The study was published in JAMA.
The randomized, open-label study included 517 children, adolescents, and young adults with de novo, relapsed, or secondary AML. Study patients received treatment in 115 centers throughout United States and Canada. The median age of patients in the study was 9 years (range, 0-26 years); 56% were male and approximately 69% were white.
Study subjects were randomly assigned to receive antifungal prophylaxis with 70 mg/m2 (maximum dose 70 mg/day) of intravenous caspofungin on day 1, followed by 50 mg/m2 per day (maximum dose 50 mg/day) thereafter, or age-dosed intravenous or oral fluconazole.
Prophylactic therapy was initiated 24-72 hours after the completion of each chemotherapy cycle, and was maintained until the end of the neutropenic period following each cycle.
At 5-month follow-up, the cumulative incidence rate of probable or proven invasive fungal disease was 3.1% (95% confidence interval, 1.3%-7.0%) in the caspofungin arm, compared with 7.2% (95% CI, 4.4%-11.8%) in the fluconazole arm (overall P = .03).
In addition, the 5-month cumulative incidence rate of probable or proven invasive aspergillosis infection was 0.5% (95%CI, 0.1%-3.5%) in patients who received caspofungin, compared with 3.1% (95% CI, 1.4%-6.9%) in patients who received fluconazole (overall P = .046).
“No statistically significant differences in empirical antifungal therapy or 2-year overall survival were observed,” they reported.
With respect to safety, the most frequently reported adverse events were hypokalemia (22 events in the caspofungin arm vs. 13 in the fluconazole arm), respiratory failure (6 events in the caspofungin arm vs. 9 in the fluconazole arm), and elevated alanine transaminase (4 events in the caspofungin arm vs. 8 in the fluconazole arm).
The researchers acknowledged a key limitation of the study was the short duration of follow-up. As a result, the precision of some comparative measures may have been reduced.
The National Cancer Institute funded the study. The authors reported financial affiliations with Astellas, Celgene, Leadiant Biosciences, Merck, Nabriva Therapeutics, Novartis, Pfizer, Shire, and T2 Biosystems.
SOURCE: Fisher BT et al. JAMA. 2019;322(17):1673-81.
FROM JAMA
Requests for crowd diagnoses of STDs common on social media
Requests for crowd diagnosis of sexually transmitted diseases were frequent on a social media website, new research found.
The social media website Reddit, which currently has 330 million monthly active users, is home to more than 230 health-related subreddits, including r/STD, a forum that allows users to publicly share “stories, concerns, and questions” about “anything and everything STD related,” Alicia L. Nobles, PhD, of the department of medicine at the University of California, San Diego, and associates wrote in a research letter published in JAMA.
Dr. Noble and associates conducted an analysis of all posts published to r/STD from the subreddit’s inception during November 2010–February 2019, a total of 16,979 posts. Three coauthors independently coded each post, recording whether or not a post requested a crowd diagnosis, and if so, whether that request was made to obtain a second opinion after a visit to a health care professional.
About 58% of posts requested a crowd diagnosis, 31% of which included an image of the physical signs. One-fifth of the requests for a crowd diagnosis were seeking a second opinion after a previous diagnosis by a health care professional. Nearly 90% of all crowd-diagnosis requests received at least one reply (mean responses, 1.7), with a median response time of 3.04 hours. About 80% of requests were answered in less than 1 day.
While crowd diagnoses do seem to be popular and have the benefits of anonymity, rapid response, and multiple opinions, the accuracy of crowd diagnoses is unknown given the limited information responders operate with and the potential lack of responder medical training, the study authors noted. Misdiagnosis could allow further disease transmission, and third parties viewing posts could incorrectly self-diagnose their own condition.
“Health care professionals could partner with social media outlets to promote the potential benefits of crowd diagnosis while suppressing potential harms, for example by having trained professionals respond to posts to better diagnose and make referrals to health care centers,” Dr. Nobles and associates concluded.
One coauthor reported receiving personal fees from Bloomberg and Good Analytics, and another reported receiving grants from the National Institutes of Health; no other disclosures were reported.
SOURCE: Nobles AL et al. JAMA. 2019 Nov 5;322(17):1712-3.
Requests for crowd diagnosis of sexually transmitted diseases were frequent on a social media website, new research found.
The social media website Reddit, which currently has 330 million monthly active users, is home to more than 230 health-related subreddits, including r/STD, a forum that allows users to publicly share “stories, concerns, and questions” about “anything and everything STD related,” Alicia L. Nobles, PhD, of the department of medicine at the University of California, San Diego, and associates wrote in a research letter published in JAMA.
Dr. Noble and associates conducted an analysis of all posts published to r/STD from the subreddit’s inception during November 2010–February 2019, a total of 16,979 posts. Three coauthors independently coded each post, recording whether or not a post requested a crowd diagnosis, and if so, whether that request was made to obtain a second opinion after a visit to a health care professional.
About 58% of posts requested a crowd diagnosis, 31% of which included an image of the physical signs. One-fifth of the requests for a crowd diagnosis were seeking a second opinion after a previous diagnosis by a health care professional. Nearly 90% of all crowd-diagnosis requests received at least one reply (mean responses, 1.7), with a median response time of 3.04 hours. About 80% of requests were answered in less than 1 day.
While crowd diagnoses do seem to be popular and have the benefits of anonymity, rapid response, and multiple opinions, the accuracy of crowd diagnoses is unknown given the limited information responders operate with and the potential lack of responder medical training, the study authors noted. Misdiagnosis could allow further disease transmission, and third parties viewing posts could incorrectly self-diagnose their own condition.
“Health care professionals could partner with social media outlets to promote the potential benefits of crowd diagnosis while suppressing potential harms, for example by having trained professionals respond to posts to better diagnose and make referrals to health care centers,” Dr. Nobles and associates concluded.
One coauthor reported receiving personal fees from Bloomberg and Good Analytics, and another reported receiving grants from the National Institutes of Health; no other disclosures were reported.
SOURCE: Nobles AL et al. JAMA. 2019 Nov 5;322(17):1712-3.
Requests for crowd diagnosis of sexually transmitted diseases were frequent on a social media website, new research found.
The social media website Reddit, which currently has 330 million monthly active users, is home to more than 230 health-related subreddits, including r/STD, a forum that allows users to publicly share “stories, concerns, and questions” about “anything and everything STD related,” Alicia L. Nobles, PhD, of the department of medicine at the University of California, San Diego, and associates wrote in a research letter published in JAMA.
Dr. Noble and associates conducted an analysis of all posts published to r/STD from the subreddit’s inception during November 2010–February 2019, a total of 16,979 posts. Three coauthors independently coded each post, recording whether or not a post requested a crowd diagnosis, and if so, whether that request was made to obtain a second opinion after a visit to a health care professional.
About 58% of posts requested a crowd diagnosis, 31% of which included an image of the physical signs. One-fifth of the requests for a crowd diagnosis were seeking a second opinion after a previous diagnosis by a health care professional. Nearly 90% of all crowd-diagnosis requests received at least one reply (mean responses, 1.7), with a median response time of 3.04 hours. About 80% of requests were answered in less than 1 day.
While crowd diagnoses do seem to be popular and have the benefits of anonymity, rapid response, and multiple opinions, the accuracy of crowd diagnoses is unknown given the limited information responders operate with and the potential lack of responder medical training, the study authors noted. Misdiagnosis could allow further disease transmission, and third parties viewing posts could incorrectly self-diagnose their own condition.
“Health care professionals could partner with social media outlets to promote the potential benefits of crowd diagnosis while suppressing potential harms, for example by having trained professionals respond to posts to better diagnose and make referrals to health care centers,” Dr. Nobles and associates concluded.
One coauthor reported receiving personal fees from Bloomberg and Good Analytics, and another reported receiving grants from the National Institutes of Health; no other disclosures were reported.
SOURCE: Nobles AL et al. JAMA. 2019 Nov 5;322(17):1712-3.
FROM JAMA
Key clinical point: Crowd-diagnosis requests of STDs are popular on a social media–based health forum.
Major finding: Nearly 60% of r/STD posts were a request for diagnosis, 87% of which received a reply (mean responses, 1.7; mean response time, 3.0 hours).
Study details: A review of 16,979 posts on the subreddit r/STD.
Disclosures: One coauthor reported receiving personal fees from Bloomberg and Good Analytics, and another reported receiving grants from the National Institutes of Health; no other disclosures were reported.Source: Nobles AL et al. JAMA. 2019 Nov 5;322(17):1712-3.
Moroccan Health Care: A Link to Radicalization and Proposed Solution
The relationship between the Kingdom of Morocco and the US began just after the US declared its own independence. It is one of the oldest of US partnerships with a foreign country, and since the end of the First Barbary War in 1805 it has remained one of the most stable. The Utah National Guard (UTNG) has an active state partnership program (SPP) with Morocco, which helps maintain that stability and fosters the relationship. The SPP provides the Kingdom of Morocco assistance in the areas of disaster medicine, prehospital medicine, and rural access to health care.
The objective of this review is to highlight the role the SPP plays in ensuring Morocco’s continued stability, enhancing its role as a leader among African nations, aiding its medically vulnerable rural populations to prevent recruitment by terrorist organizations, and maintaining its long-term relationship with the US.
Background
The Kingdom of Morocco resides in a geologically and politically unstable part of the world, yet it has been a stable constitutional monarchy. Like California, Morocco has a long coastline of more than 1,000 miles. It sits along an active earthquake fault line with a disaster response program that is only in its infancy. The Kingdom has a high youth unemployment rate and lacks adequate public education opportunities, which exacerbate feelings of government indifference. Morocco’s medical system is highly centralized, and large parts of the rural population lack access to basic medical care—potentially alienating the population. The Moroccan current disaster plan ORSEC (plan d’ Organization des Secours) was established in 1966 and updated in 2005 but does not provide a comprehensive, unified disaster response. The ORSEC plan is of French derivation and is not a list of actions but a general plan of organization and supply. 1
When governments fail to provide basic services—health care being just one—those services may be filled by groups seeking to influence the government and population by threatening acts of violence to achieve political, religious, and ideologic gain; for example, the Taliban in Afghanistan, the Muslim brotherhood in Egypt and in the West Bank, and the Islamic State in Iraq and Syria (ISIS) in Syria.2-5 These groups gain a foothold and legitimacy by providing mosques, youth groups, clinics, hospitals, and schools. 2-5
Identified Needs
Morocco is at risk of experiencing an earthquake and possible subsequent tsunami. In 1755, Morocco was impacted by the Great Lisbon earthquake and tsunami. Witnesses reported 15-meter waves with 24-meter crests.6 Building codes and architecture laws have changed little since the 1960 Agadir earthquake, which killed 12,000 people. The disaster response program—although improved since the 1960s—is still in the early stages of development, and another earthquake and possible subsequent tsunami would result in a disaster that could overwhelm the medical community of Morocco.
Perceived Government Indifference
The Moroccan constitutional monarchy is more stable than are the governments of its North African neighbors. King Mohammed VI presides over the government, and regular elections are held for members of Parliament, which names a prime minister. However, in August 2019, overall unemployment was at 8.5%, and youth unemployment was 22.3%.7 A United Nations report in August 2019 stated that literacy rates for Morocco were 71.7%. These data were from a 2015 census, the last year data were collected.8 These deficits in employment and education can foster anger toward the Moroccan government for not adequately providing these services and possibly introduce radicalization as a result of the population’s perceived government indifference and lack of economic mobility.
Access to Medical Care
Morocco has a 2-tiered medical system for providing services: urban and rural. In 2018 the Legatum Prosperity Index ranked Morocco 103 of 149 countries in health care. The prosperity index measures health variables, which include but were not limited to basic physical and mental health, health infrastructure, and preventive care.9 Outside the metropolitan areas, emergency medical care is nonexistent, primary care is sporadic, and there is little modern technology available.
Despite humanitarian efforts over many years, there is little to no medical care in the rural “medical desert.” A 2017 study from the University of Washington Institute for Health Metrics and Evaluation compared the global burden of disease in similar countries. The study found that Morocco was significantly higher than the mean in the prevalence of ischemic heart disease and Alzheimer disease, lower than the mean in the areas of neonatal disorders, lower respiratory infections, and tuberculosis, and statistically indistinct from the mean in stroke, congenital defects, road injuries, diabetes mellitus, and hypertensive heart disease compared with the disease prevalence of other countries of similar size and economic measures.10 The study also found a particularly acute disparity in access to health care in rural areas. In 2016, the Oxford Business Group reported staff shortages and disproportionate distribution of resources in the Moroccan health care system.11
Additionally, the lack of trained health care personnel has added to an already overstressed health care system. A chief stressor in a health care system is an insufficient replacement rate. Health employees working for the Moroccan Ministry of Health retire at a rate of 1,500 per year.10,11 These shortages may serve to further the feelings of frustration and government indifference. This frustration is momentarily decreased by humanitarian efforts that have taken place in the African continent in the past decades, but this band-aid approach to assisting the population that is medically underserved has done little to alleviate the long-term problem of access to care. And feelings of government abandonment can sow the seeds of discontent in the rural population, creating fertile ground for recruitment by terrorist organizations.2,3
Lack of Health Care and Radicalism
It has been postulated that there is a link between radicalization and lack of medical care. Depression and perceived government indifference are considered contributors to radicalization.12-16 In 2005, Victoroff suggested that there are certain psychological traits characteristic of “typical" terrorists: these include high affective valence regarding an ideologic issue, a personal stake (perceived oppression, persecution or humiliation, need for identity, glory, or vengeance), low cognitive ability, low tolerance for ambiguity, and a capacity to suppress instinctive and learned moral constraints against harming innocents.15 In 2009, Lafree and Ackerman suggested that terrorism feeds on the ability of groups to portray governments and their agents as illegitimate.16 It is possible that part of the illegitimacy campaign of radicalization and terrorist recruitment may be identification of the lack of health care by the government thus magnifying feelings of government abandonment in a vulnerable population.
In 2011, the new Moroccan constitution identified access to basic health care as a right of the Moroccan people.17 Additionally, in 2013, a government white paper was produced outlining the need to increase access to health care, particularly in rural areas, including a focus on infant and maternal mortality, diabetes mellitus (DM), heart disease, and respiratory problems.17,18
Proposed Solutions, A Beginning
A health outreach program with a regional health professional training center in a relatively stable country within the African Union (AU) would be a step toward delivering health care to Morocco and interested AU members. Interested nations have been and will continue to be invited to train at the Moroccan center and return to their countries and start training programs. This idea was echoed by the World Bank in a 2015 loan proposal to Morocco, which suggested that addressing disparities in access to health care is a social justice issue, with other benefits such as increased productivity, employment, lower out-of-pocket expenditures, and promotion of good governance.17
In 2012, Buhi reported that a positive regard for authorities and healthier influences seemed to be a protective factor against radicalization. He also suggested a public health approach to understanding and preventing violent radicalization.19 The solutions are complex, especially in rural areas and in vulnerable nations common to Africa.
Medical training efforts by the US Department of Defense (DoD), Medical Readiness Training Institute (DMRT), and international health specialists working with the military and civilian entities in neighboring African countries have improved response to regional disasters. However, to address the broader issues, a more permanent, cooperative possible solution may begin with the establishment in Morocco of a regional education center for disaster preparedness and for health care providers (HCPs). This would serve as a training program for disaster first responders. Graduates of the program would receive additional training to become HCPs similar to physician assistant (PA) and nurse practitioner (NP) programs in the US. Morocco is uniquely positioned to accomplish this due to its location, political stability, and ties with other African nations.
The goal of the Moroccan regional education center (within the King Mohammed V Hospital) is to bring together global health experts and increase the intellectual infrastructure of not only Morocco, but also offer this training program to interested countries within the AU. Advancement of the regional education center will require legislative changes to expand prescriptive privileges and scope of practice within each country. The medical element of the SPP as presently constituted without the regional education center will continue its humanitarian goals, but the proposed creation of the regional education center will educate participants to serve the rural communities within each participating country. Eventually the entire educational program will be the responsibility of the Moroccan military and the AU participants. This will require reprioritizing resources from the provision of humanitarian health care services to an HCP education approach.
Disaster Response
Deficits in disaster response capabilities have been identified by members of the Moroccan military with the assistance of the UTNG. The most glaring deficit identified was the disparity in training between military and civilian first responders. Thus, a training program was initiated by the Moroccan military and the UTNG that combined internationally recognized, durable, robust emergency training programs. These programs consisted of, but were not limited to, parts or entire programs of the following: basic disaster life support, advanced disaster life support, disaster casualty care, and advanced trauma life support. The goal of this training was to improve communication, reduce mortality, and create strike teams, which can quickly provide health care independent of a hospital during a disaster.
Patients can overwhelm hospitals in a disaster when need exceeds resources. In 1996, Mallonee reported that at least 67% of the patients who sought care at a hospital during the Oklahoma City bombing disaster did not need advanced medical treatment.20 Such patients could be seen at an identified casualty collection point by a strike team and treated and released rather than traveling to the hospital and using staff and resources that could be used more judiciously for the more seriously injured.21 These teams consist of trained first responders with an experienced HCP (physician, PA, NP) and a nurse and are trained to operate for up to 72 hours in a predetermined location and serve as a “filter” for the hospital. Their role is to treat and release the less severely injured and refer only the more severely injured to the hospital after basic stabilization, thus preserving precious resources necessary for the more seriously injured.
This disaster response training program was offered to the Moroccan military, ministry of health and ministry of tourism, and quickly turned into an Africa-wide interest. A regional training center was proposed. This was assisted with the cooperation of Weber State University in Ogden Utah, Utah Valley University in Orem, and private interests in a public/private/military state partnership. Program supplies and didactic instruction were and will be provided by the UTNG and supplemented through the DoD Africa command. Instruction will be a cooperative effort agreed on between the UTNG and the Moroccan military medical specialists within their specific area of expertise.
Underserved Communities
Finally, from this pool of interested strike team members, a health care provider school will be formed to educate, certify, and service the needs of the underserved communities in Morocco and interested AU countries. This program will be similar to the PA and NP programs in the US and will be geared to those graduates from the previous programs with intense classroom instruction for one year followed by a year of one-on-one preceptorship with an experienced physician. The goal of the program is to prepare individuals with patient care experience to fulfill a bigger role in health care in an underserved (usually austere, rural) area that currently has minimal health care presence. This fills a need identified by the World Bank in 2015 that the Moroccan government needs to respond to the demand for improved access to and quality of health care services—particularly to the rural poor.17
The Moroccan military has a presence in many medically underserved areas. The logical fit for the HCP program will be drawn from a pool of active-duty military individuals who express an interest and qualify through attendance in all phases of the training.
Conclusion
This program of disaster medical education, strike teams, and HCPs is currently training more than 200 students a year throughout Morocco. The proposed direction of this cooperative program to produce HCPs in rural areas will increase access to health care for the Moroccan people who are now underserved. Morocco, as a health care training hub in Africa, will increase access to health care for interested African countries. The goal politically will be to reduce feelings of government indifference in vulnerable populations and reduce recruitment into radical ideologies.
1. Nahon M, Michaloux M. L’organisation de la réponse de la sécurité civile: le dispositif ORSEC Organisation of civilian emergency services: The ORSEC plan. https://www.sciencedirect.com/science/article/pii/S2211423816300499#! Published July 2016. Accessed October 7, 2019.
2. Berman E. Hamas, Taliban and the Jewish underground: an economist's view of radical religious militias. NBER Working Paper No. w10004. https://ssrn.com/abstract=450885. Published September 2003. Accessed October 7, 2019.
3. Jordan J. Attacking the leader. Missing the mark; why terrorist groups survive decapitation strikes. Int Secur. 2014;38(4):7-38.
4. Grynkewich A. Welfare as warfare: how violent non-state groups use social services to attack the state. Stud Conflict Terrorism. 2008;31(4):350-370.
5. Marin M, Solomon H. Islamic State: understanding the nature of the beast and its funding. Contemp Rev Middle East. 2017;4(1):18-49.
6. Bressan D. November 1, 1755: the earthquake of Lisbon: wrath of god or natural disaster? Scientific American, History of Geology. https://blogs.scientificamerican.com/history-of-geology/november-1-1755-the-earthquake-of-lisbon-wraith-of-god-or-natural-disaster. Published November 2011. Accessed October 7, 2019.
7. Trading Economics. Morocco unemployment rate. Second quarter statistics. August 2019. https://tradingeconomics.com/morocco/unemployment-rate. Accessed October 7, 2019.
8. Knoema World Data Atlas 2015. Morocco adult literacy rates. https://knoema.com/atlas/Morocco/topics/Education/Literacy/Adult-literacy-rate. Accessed October 4, 2019.
9. The Legatum Prosperity Index 2018. Morocco. https://www.prosperity.com/globe/morocco. Accessed October 7, 2019.
10. University of Washington, Institute for Health Metrics and Evaluation. Morocco. http://www.healthdata.org/morocco. Published 2018. Accessed October 7, 2019.
11. Oxford Business Group. Access to health care broadens in Morocco. https://oxfordbusinessgroup.com/overview/forward-steps-access-care-has-broadened-and-infrastructure-improved-challenges-remain. Accessed September 12. 2019.
12. Wright NMJ, Hankins FM. Preventing radicalization and terrorism: Is there a GP response? Br J Gen Pract. 2016;66(647):288-289.
13. Buhi K, Everitt K, Jones E. Might depression psychosocial adversity, and limited social assets explain vulnerability to and resistance against violent radicalization? PlosOne. 2014;9(9):e105918.
14. DeAngelis T. Understanding terrorism. apa.org/monitor/2009/11/terrorism. Published November 2009. Accessed October 14, 2019.
15. Victoroff J. The mind of the terrorist: a review and critique of psychological approaches. J Conflict Resolut. 2005;49(1):3-42.
16. Lafree G, Ackerman G. The empirical study of terrorism: social and legal research. Ann Rev Law Soc Sci. 2009;5:347-374.
17. World Bank. Morocco—improving primary health in rural areas program-for-results project (English). http://documents.worldbank.org/curated/en/716821468274482723/Morocco-Improving-Primary-Health-in-Rural-Areas-Program-for-Results-Project. Published 2015. Accessed September 16, 2019.
18. Royaume du Maroc, Ministère de la Santé. Livre blanc: pour une nouvelle gouvernance du secteur de la santé. Paper presented at: 2nd National Health Conference; July 1-3, 2013; Marrakesh, Morocco.
19. Buhi K, Hicks MH, Lashley M, Jones E. A public health approach to understanding and preventing violent radicalization. BMC Med. 2012;10:16.
20. Mallonee S, Sahriat S, Stennies G, Waxweiler R, Hogan D, Jordan F. Physical injuries and fatalities resulting from the Oklahoma City bombing. JAMA. 1996;276(5):382-387.
21. Ushizawa H, Foxwell AR, Bice S, et al. Needs for disaster medicine: lessons from the field of the Great East Japan Earthquake. Western Pac Surveil Response J. 2013;4(1):51-55.
The relationship between the Kingdom of Morocco and the US began just after the US declared its own independence. It is one of the oldest of US partnerships with a foreign country, and since the end of the First Barbary War in 1805 it has remained one of the most stable. The Utah National Guard (UTNG) has an active state partnership program (SPP) with Morocco, which helps maintain that stability and fosters the relationship. The SPP provides the Kingdom of Morocco assistance in the areas of disaster medicine, prehospital medicine, and rural access to health care.
The objective of this review is to highlight the role the SPP plays in ensuring Morocco’s continued stability, enhancing its role as a leader among African nations, aiding its medically vulnerable rural populations to prevent recruitment by terrorist organizations, and maintaining its long-term relationship with the US.
Background
The Kingdom of Morocco resides in a geologically and politically unstable part of the world, yet it has been a stable constitutional monarchy. Like California, Morocco has a long coastline of more than 1,000 miles. It sits along an active earthquake fault line with a disaster response program that is only in its infancy. The Kingdom has a high youth unemployment rate and lacks adequate public education opportunities, which exacerbate feelings of government indifference. Morocco’s medical system is highly centralized, and large parts of the rural population lack access to basic medical care—potentially alienating the population. The Moroccan current disaster plan ORSEC (plan d’ Organization des Secours) was established in 1966 and updated in 2005 but does not provide a comprehensive, unified disaster response. The ORSEC plan is of French derivation and is not a list of actions but a general plan of organization and supply. 1
When governments fail to provide basic services—health care being just one—those services may be filled by groups seeking to influence the government and population by threatening acts of violence to achieve political, religious, and ideologic gain; for example, the Taliban in Afghanistan, the Muslim brotherhood in Egypt and in the West Bank, and the Islamic State in Iraq and Syria (ISIS) in Syria.2-5 These groups gain a foothold and legitimacy by providing mosques, youth groups, clinics, hospitals, and schools. 2-5
Identified Needs
Morocco is at risk of experiencing an earthquake and possible subsequent tsunami. In 1755, Morocco was impacted by the Great Lisbon earthquake and tsunami. Witnesses reported 15-meter waves with 24-meter crests.6 Building codes and architecture laws have changed little since the 1960 Agadir earthquake, which killed 12,000 people. The disaster response program—although improved since the 1960s—is still in the early stages of development, and another earthquake and possible subsequent tsunami would result in a disaster that could overwhelm the medical community of Morocco.
Perceived Government Indifference
The Moroccan constitutional monarchy is more stable than are the governments of its North African neighbors. King Mohammed VI presides over the government, and regular elections are held for members of Parliament, which names a prime minister. However, in August 2019, overall unemployment was at 8.5%, and youth unemployment was 22.3%.7 A United Nations report in August 2019 stated that literacy rates for Morocco were 71.7%. These data were from a 2015 census, the last year data were collected.8 These deficits in employment and education can foster anger toward the Moroccan government for not adequately providing these services and possibly introduce radicalization as a result of the population’s perceived government indifference and lack of economic mobility.
Access to Medical Care
Morocco has a 2-tiered medical system for providing services: urban and rural. In 2018 the Legatum Prosperity Index ranked Morocco 103 of 149 countries in health care. The prosperity index measures health variables, which include but were not limited to basic physical and mental health, health infrastructure, and preventive care.9 Outside the metropolitan areas, emergency medical care is nonexistent, primary care is sporadic, and there is little modern technology available.
Despite humanitarian efforts over many years, there is little to no medical care in the rural “medical desert.” A 2017 study from the University of Washington Institute for Health Metrics and Evaluation compared the global burden of disease in similar countries. The study found that Morocco was significantly higher than the mean in the prevalence of ischemic heart disease and Alzheimer disease, lower than the mean in the areas of neonatal disorders, lower respiratory infections, and tuberculosis, and statistically indistinct from the mean in stroke, congenital defects, road injuries, diabetes mellitus, and hypertensive heart disease compared with the disease prevalence of other countries of similar size and economic measures.10 The study also found a particularly acute disparity in access to health care in rural areas. In 2016, the Oxford Business Group reported staff shortages and disproportionate distribution of resources in the Moroccan health care system.11
Additionally, the lack of trained health care personnel has added to an already overstressed health care system. A chief stressor in a health care system is an insufficient replacement rate. Health employees working for the Moroccan Ministry of Health retire at a rate of 1,500 per year.10,11 These shortages may serve to further the feelings of frustration and government indifference. This frustration is momentarily decreased by humanitarian efforts that have taken place in the African continent in the past decades, but this band-aid approach to assisting the population that is medically underserved has done little to alleviate the long-term problem of access to care. And feelings of government abandonment can sow the seeds of discontent in the rural population, creating fertile ground for recruitment by terrorist organizations.2,3
Lack of Health Care and Radicalism
It has been postulated that there is a link between radicalization and lack of medical care. Depression and perceived government indifference are considered contributors to radicalization.12-16 In 2005, Victoroff suggested that there are certain psychological traits characteristic of “typical" terrorists: these include high affective valence regarding an ideologic issue, a personal stake (perceived oppression, persecution or humiliation, need for identity, glory, or vengeance), low cognitive ability, low tolerance for ambiguity, and a capacity to suppress instinctive and learned moral constraints against harming innocents.15 In 2009, Lafree and Ackerman suggested that terrorism feeds on the ability of groups to portray governments and their agents as illegitimate.16 It is possible that part of the illegitimacy campaign of radicalization and terrorist recruitment may be identification of the lack of health care by the government thus magnifying feelings of government abandonment in a vulnerable population.
In 2011, the new Moroccan constitution identified access to basic health care as a right of the Moroccan people.17 Additionally, in 2013, a government white paper was produced outlining the need to increase access to health care, particularly in rural areas, including a focus on infant and maternal mortality, diabetes mellitus (DM), heart disease, and respiratory problems.17,18
Proposed Solutions, A Beginning
A health outreach program with a regional health professional training center in a relatively stable country within the African Union (AU) would be a step toward delivering health care to Morocco and interested AU members. Interested nations have been and will continue to be invited to train at the Moroccan center and return to their countries and start training programs. This idea was echoed by the World Bank in a 2015 loan proposal to Morocco, which suggested that addressing disparities in access to health care is a social justice issue, with other benefits such as increased productivity, employment, lower out-of-pocket expenditures, and promotion of good governance.17
In 2012, Buhi reported that a positive regard for authorities and healthier influences seemed to be a protective factor against radicalization. He also suggested a public health approach to understanding and preventing violent radicalization.19 The solutions are complex, especially in rural areas and in vulnerable nations common to Africa.
Medical training efforts by the US Department of Defense (DoD), Medical Readiness Training Institute (DMRT), and international health specialists working with the military and civilian entities in neighboring African countries have improved response to regional disasters. However, to address the broader issues, a more permanent, cooperative possible solution may begin with the establishment in Morocco of a regional education center for disaster preparedness and for health care providers (HCPs). This would serve as a training program for disaster first responders. Graduates of the program would receive additional training to become HCPs similar to physician assistant (PA) and nurse practitioner (NP) programs in the US. Morocco is uniquely positioned to accomplish this due to its location, political stability, and ties with other African nations.
The goal of the Moroccan regional education center (within the King Mohammed V Hospital) is to bring together global health experts and increase the intellectual infrastructure of not only Morocco, but also offer this training program to interested countries within the AU. Advancement of the regional education center will require legislative changes to expand prescriptive privileges and scope of practice within each country. The medical element of the SPP as presently constituted without the regional education center will continue its humanitarian goals, but the proposed creation of the regional education center will educate participants to serve the rural communities within each participating country. Eventually the entire educational program will be the responsibility of the Moroccan military and the AU participants. This will require reprioritizing resources from the provision of humanitarian health care services to an HCP education approach.
Disaster Response
Deficits in disaster response capabilities have been identified by members of the Moroccan military with the assistance of the UTNG. The most glaring deficit identified was the disparity in training between military and civilian first responders. Thus, a training program was initiated by the Moroccan military and the UTNG that combined internationally recognized, durable, robust emergency training programs. These programs consisted of, but were not limited to, parts or entire programs of the following: basic disaster life support, advanced disaster life support, disaster casualty care, and advanced trauma life support. The goal of this training was to improve communication, reduce mortality, and create strike teams, which can quickly provide health care independent of a hospital during a disaster.
Patients can overwhelm hospitals in a disaster when need exceeds resources. In 1996, Mallonee reported that at least 67% of the patients who sought care at a hospital during the Oklahoma City bombing disaster did not need advanced medical treatment.20 Such patients could be seen at an identified casualty collection point by a strike team and treated and released rather than traveling to the hospital and using staff and resources that could be used more judiciously for the more seriously injured.21 These teams consist of trained first responders with an experienced HCP (physician, PA, NP) and a nurse and are trained to operate for up to 72 hours in a predetermined location and serve as a “filter” for the hospital. Their role is to treat and release the less severely injured and refer only the more severely injured to the hospital after basic stabilization, thus preserving precious resources necessary for the more seriously injured.
This disaster response training program was offered to the Moroccan military, ministry of health and ministry of tourism, and quickly turned into an Africa-wide interest. A regional training center was proposed. This was assisted with the cooperation of Weber State University in Ogden Utah, Utah Valley University in Orem, and private interests in a public/private/military state partnership. Program supplies and didactic instruction were and will be provided by the UTNG and supplemented through the DoD Africa command. Instruction will be a cooperative effort agreed on between the UTNG and the Moroccan military medical specialists within their specific area of expertise.
Underserved Communities
Finally, from this pool of interested strike team members, a health care provider school will be formed to educate, certify, and service the needs of the underserved communities in Morocco and interested AU countries. This program will be similar to the PA and NP programs in the US and will be geared to those graduates from the previous programs with intense classroom instruction for one year followed by a year of one-on-one preceptorship with an experienced physician. The goal of the program is to prepare individuals with patient care experience to fulfill a bigger role in health care in an underserved (usually austere, rural) area that currently has minimal health care presence. This fills a need identified by the World Bank in 2015 that the Moroccan government needs to respond to the demand for improved access to and quality of health care services—particularly to the rural poor.17
The Moroccan military has a presence in many medically underserved areas. The logical fit for the HCP program will be drawn from a pool of active-duty military individuals who express an interest and qualify through attendance in all phases of the training.
Conclusion
This program of disaster medical education, strike teams, and HCPs is currently training more than 200 students a year throughout Morocco. The proposed direction of this cooperative program to produce HCPs in rural areas will increase access to health care for the Moroccan people who are now underserved. Morocco, as a health care training hub in Africa, will increase access to health care for interested African countries. The goal politically will be to reduce feelings of government indifference in vulnerable populations and reduce recruitment into radical ideologies.
The relationship between the Kingdom of Morocco and the US began just after the US declared its own independence. It is one of the oldest of US partnerships with a foreign country, and since the end of the First Barbary War in 1805 it has remained one of the most stable. The Utah National Guard (UTNG) has an active state partnership program (SPP) with Morocco, which helps maintain that stability and fosters the relationship. The SPP provides the Kingdom of Morocco assistance in the areas of disaster medicine, prehospital medicine, and rural access to health care.
The objective of this review is to highlight the role the SPP plays in ensuring Morocco’s continued stability, enhancing its role as a leader among African nations, aiding its medically vulnerable rural populations to prevent recruitment by terrorist organizations, and maintaining its long-term relationship with the US.
Background
The Kingdom of Morocco resides in a geologically and politically unstable part of the world, yet it has been a stable constitutional monarchy. Like California, Morocco has a long coastline of more than 1,000 miles. It sits along an active earthquake fault line with a disaster response program that is only in its infancy. The Kingdom has a high youth unemployment rate and lacks adequate public education opportunities, which exacerbate feelings of government indifference. Morocco’s medical system is highly centralized, and large parts of the rural population lack access to basic medical care—potentially alienating the population. The Moroccan current disaster plan ORSEC (plan d’ Organization des Secours) was established in 1966 and updated in 2005 but does not provide a comprehensive, unified disaster response. The ORSEC plan is of French derivation and is not a list of actions but a general plan of organization and supply. 1
When governments fail to provide basic services—health care being just one—those services may be filled by groups seeking to influence the government and population by threatening acts of violence to achieve political, religious, and ideologic gain; for example, the Taliban in Afghanistan, the Muslim brotherhood in Egypt and in the West Bank, and the Islamic State in Iraq and Syria (ISIS) in Syria.2-5 These groups gain a foothold and legitimacy by providing mosques, youth groups, clinics, hospitals, and schools. 2-5
Identified Needs
Morocco is at risk of experiencing an earthquake and possible subsequent tsunami. In 1755, Morocco was impacted by the Great Lisbon earthquake and tsunami. Witnesses reported 15-meter waves with 24-meter crests.6 Building codes and architecture laws have changed little since the 1960 Agadir earthquake, which killed 12,000 people. The disaster response program—although improved since the 1960s—is still in the early stages of development, and another earthquake and possible subsequent tsunami would result in a disaster that could overwhelm the medical community of Morocco.
Perceived Government Indifference
The Moroccan constitutional monarchy is more stable than are the governments of its North African neighbors. King Mohammed VI presides over the government, and regular elections are held for members of Parliament, which names a prime minister. However, in August 2019, overall unemployment was at 8.5%, and youth unemployment was 22.3%.7 A United Nations report in August 2019 stated that literacy rates for Morocco were 71.7%. These data were from a 2015 census, the last year data were collected.8 These deficits in employment and education can foster anger toward the Moroccan government for not adequately providing these services and possibly introduce radicalization as a result of the population’s perceived government indifference and lack of economic mobility.
Access to Medical Care
Morocco has a 2-tiered medical system for providing services: urban and rural. In 2018 the Legatum Prosperity Index ranked Morocco 103 of 149 countries in health care. The prosperity index measures health variables, which include but were not limited to basic physical and mental health, health infrastructure, and preventive care.9 Outside the metropolitan areas, emergency medical care is nonexistent, primary care is sporadic, and there is little modern technology available.
Despite humanitarian efforts over many years, there is little to no medical care in the rural “medical desert.” A 2017 study from the University of Washington Institute for Health Metrics and Evaluation compared the global burden of disease in similar countries. The study found that Morocco was significantly higher than the mean in the prevalence of ischemic heart disease and Alzheimer disease, lower than the mean in the areas of neonatal disorders, lower respiratory infections, and tuberculosis, and statistically indistinct from the mean in stroke, congenital defects, road injuries, diabetes mellitus, and hypertensive heart disease compared with the disease prevalence of other countries of similar size and economic measures.10 The study also found a particularly acute disparity in access to health care in rural areas. In 2016, the Oxford Business Group reported staff shortages and disproportionate distribution of resources in the Moroccan health care system.11
Additionally, the lack of trained health care personnel has added to an already overstressed health care system. A chief stressor in a health care system is an insufficient replacement rate. Health employees working for the Moroccan Ministry of Health retire at a rate of 1,500 per year.10,11 These shortages may serve to further the feelings of frustration and government indifference. This frustration is momentarily decreased by humanitarian efforts that have taken place in the African continent in the past decades, but this band-aid approach to assisting the population that is medically underserved has done little to alleviate the long-term problem of access to care. And feelings of government abandonment can sow the seeds of discontent in the rural population, creating fertile ground for recruitment by terrorist organizations.2,3
Lack of Health Care and Radicalism
It has been postulated that there is a link between radicalization and lack of medical care. Depression and perceived government indifference are considered contributors to radicalization.12-16 In 2005, Victoroff suggested that there are certain psychological traits characteristic of “typical" terrorists: these include high affective valence regarding an ideologic issue, a personal stake (perceived oppression, persecution or humiliation, need for identity, glory, or vengeance), low cognitive ability, low tolerance for ambiguity, and a capacity to suppress instinctive and learned moral constraints against harming innocents.15 In 2009, Lafree and Ackerman suggested that terrorism feeds on the ability of groups to portray governments and their agents as illegitimate.16 It is possible that part of the illegitimacy campaign of radicalization and terrorist recruitment may be identification of the lack of health care by the government thus magnifying feelings of government abandonment in a vulnerable population.
In 2011, the new Moroccan constitution identified access to basic health care as a right of the Moroccan people.17 Additionally, in 2013, a government white paper was produced outlining the need to increase access to health care, particularly in rural areas, including a focus on infant and maternal mortality, diabetes mellitus (DM), heart disease, and respiratory problems.17,18
Proposed Solutions, A Beginning
A health outreach program with a regional health professional training center in a relatively stable country within the African Union (AU) would be a step toward delivering health care to Morocco and interested AU members. Interested nations have been and will continue to be invited to train at the Moroccan center and return to their countries and start training programs. This idea was echoed by the World Bank in a 2015 loan proposal to Morocco, which suggested that addressing disparities in access to health care is a social justice issue, with other benefits such as increased productivity, employment, lower out-of-pocket expenditures, and promotion of good governance.17
In 2012, Buhi reported that a positive regard for authorities and healthier influences seemed to be a protective factor against radicalization. He also suggested a public health approach to understanding and preventing violent radicalization.19 The solutions are complex, especially in rural areas and in vulnerable nations common to Africa.
Medical training efforts by the US Department of Defense (DoD), Medical Readiness Training Institute (DMRT), and international health specialists working with the military and civilian entities in neighboring African countries have improved response to regional disasters. However, to address the broader issues, a more permanent, cooperative possible solution may begin with the establishment in Morocco of a regional education center for disaster preparedness and for health care providers (HCPs). This would serve as a training program for disaster first responders. Graduates of the program would receive additional training to become HCPs similar to physician assistant (PA) and nurse practitioner (NP) programs in the US. Morocco is uniquely positioned to accomplish this due to its location, political stability, and ties with other African nations.
The goal of the Moroccan regional education center (within the King Mohammed V Hospital) is to bring together global health experts and increase the intellectual infrastructure of not only Morocco, but also offer this training program to interested countries within the AU. Advancement of the regional education center will require legislative changes to expand prescriptive privileges and scope of practice within each country. The medical element of the SPP as presently constituted without the regional education center will continue its humanitarian goals, but the proposed creation of the regional education center will educate participants to serve the rural communities within each participating country. Eventually the entire educational program will be the responsibility of the Moroccan military and the AU participants. This will require reprioritizing resources from the provision of humanitarian health care services to an HCP education approach.
Disaster Response
Deficits in disaster response capabilities have been identified by members of the Moroccan military with the assistance of the UTNG. The most glaring deficit identified was the disparity in training between military and civilian first responders. Thus, a training program was initiated by the Moroccan military and the UTNG that combined internationally recognized, durable, robust emergency training programs. These programs consisted of, but were not limited to, parts or entire programs of the following: basic disaster life support, advanced disaster life support, disaster casualty care, and advanced trauma life support. The goal of this training was to improve communication, reduce mortality, and create strike teams, which can quickly provide health care independent of a hospital during a disaster.
Patients can overwhelm hospitals in a disaster when need exceeds resources. In 1996, Mallonee reported that at least 67% of the patients who sought care at a hospital during the Oklahoma City bombing disaster did not need advanced medical treatment.20 Such patients could be seen at an identified casualty collection point by a strike team and treated and released rather than traveling to the hospital and using staff and resources that could be used more judiciously for the more seriously injured.21 These teams consist of trained first responders with an experienced HCP (physician, PA, NP) and a nurse and are trained to operate for up to 72 hours in a predetermined location and serve as a “filter” for the hospital. Their role is to treat and release the less severely injured and refer only the more severely injured to the hospital after basic stabilization, thus preserving precious resources necessary for the more seriously injured.
This disaster response training program was offered to the Moroccan military, ministry of health and ministry of tourism, and quickly turned into an Africa-wide interest. A regional training center was proposed. This was assisted with the cooperation of Weber State University in Ogden Utah, Utah Valley University in Orem, and private interests in a public/private/military state partnership. Program supplies and didactic instruction were and will be provided by the UTNG and supplemented through the DoD Africa command. Instruction will be a cooperative effort agreed on between the UTNG and the Moroccan military medical specialists within their specific area of expertise.
Underserved Communities
Finally, from this pool of interested strike team members, a health care provider school will be formed to educate, certify, and service the needs of the underserved communities in Morocco and interested AU countries. This program will be similar to the PA and NP programs in the US and will be geared to those graduates from the previous programs with intense classroom instruction for one year followed by a year of one-on-one preceptorship with an experienced physician. The goal of the program is to prepare individuals with patient care experience to fulfill a bigger role in health care in an underserved (usually austere, rural) area that currently has minimal health care presence. This fills a need identified by the World Bank in 2015 that the Moroccan government needs to respond to the demand for improved access to and quality of health care services—particularly to the rural poor.17
The Moroccan military has a presence in many medically underserved areas. The logical fit for the HCP program will be drawn from a pool of active-duty military individuals who express an interest and qualify through attendance in all phases of the training.
Conclusion
This program of disaster medical education, strike teams, and HCPs is currently training more than 200 students a year throughout Morocco. The proposed direction of this cooperative program to produce HCPs in rural areas will increase access to health care for the Moroccan people who are now underserved. Morocco, as a health care training hub in Africa, will increase access to health care for interested African countries. The goal politically will be to reduce feelings of government indifference in vulnerable populations and reduce recruitment into radical ideologies.
1. Nahon M, Michaloux M. L’organisation de la réponse de la sécurité civile: le dispositif ORSEC Organisation of civilian emergency services: The ORSEC plan. https://www.sciencedirect.com/science/article/pii/S2211423816300499#! Published July 2016. Accessed October 7, 2019.
2. Berman E. Hamas, Taliban and the Jewish underground: an economist's view of radical religious militias. NBER Working Paper No. w10004. https://ssrn.com/abstract=450885. Published September 2003. Accessed October 7, 2019.
3. Jordan J. Attacking the leader. Missing the mark; why terrorist groups survive decapitation strikes. Int Secur. 2014;38(4):7-38.
4. Grynkewich A. Welfare as warfare: how violent non-state groups use social services to attack the state. Stud Conflict Terrorism. 2008;31(4):350-370.
5. Marin M, Solomon H. Islamic State: understanding the nature of the beast and its funding. Contemp Rev Middle East. 2017;4(1):18-49.
6. Bressan D. November 1, 1755: the earthquake of Lisbon: wrath of god or natural disaster? Scientific American, History of Geology. https://blogs.scientificamerican.com/history-of-geology/november-1-1755-the-earthquake-of-lisbon-wraith-of-god-or-natural-disaster. Published November 2011. Accessed October 7, 2019.
7. Trading Economics. Morocco unemployment rate. Second quarter statistics. August 2019. https://tradingeconomics.com/morocco/unemployment-rate. Accessed October 7, 2019.
8. Knoema World Data Atlas 2015. Morocco adult literacy rates. https://knoema.com/atlas/Morocco/topics/Education/Literacy/Adult-literacy-rate. Accessed October 4, 2019.
9. The Legatum Prosperity Index 2018. Morocco. https://www.prosperity.com/globe/morocco. Accessed October 7, 2019.
10. University of Washington, Institute for Health Metrics and Evaluation. Morocco. http://www.healthdata.org/morocco. Published 2018. Accessed October 7, 2019.
11. Oxford Business Group. Access to health care broadens in Morocco. https://oxfordbusinessgroup.com/overview/forward-steps-access-care-has-broadened-and-infrastructure-improved-challenges-remain. Accessed September 12. 2019.
12. Wright NMJ, Hankins FM. Preventing radicalization and terrorism: Is there a GP response? Br J Gen Pract. 2016;66(647):288-289.
13. Buhi K, Everitt K, Jones E. Might depression psychosocial adversity, and limited social assets explain vulnerability to and resistance against violent radicalization? PlosOne. 2014;9(9):e105918.
14. DeAngelis T. Understanding terrorism. apa.org/monitor/2009/11/terrorism. Published November 2009. Accessed October 14, 2019.
15. Victoroff J. The mind of the terrorist: a review and critique of psychological approaches. J Conflict Resolut. 2005;49(1):3-42.
16. Lafree G, Ackerman G. The empirical study of terrorism: social and legal research. Ann Rev Law Soc Sci. 2009;5:347-374.
17. World Bank. Morocco—improving primary health in rural areas program-for-results project (English). http://documents.worldbank.org/curated/en/716821468274482723/Morocco-Improving-Primary-Health-in-Rural-Areas-Program-for-Results-Project. Published 2015. Accessed September 16, 2019.
18. Royaume du Maroc, Ministère de la Santé. Livre blanc: pour une nouvelle gouvernance du secteur de la santé. Paper presented at: 2nd National Health Conference; July 1-3, 2013; Marrakesh, Morocco.
19. Buhi K, Hicks MH, Lashley M, Jones E. A public health approach to understanding and preventing violent radicalization. BMC Med. 2012;10:16.
20. Mallonee S, Sahriat S, Stennies G, Waxweiler R, Hogan D, Jordan F. Physical injuries and fatalities resulting from the Oklahoma City bombing. JAMA. 1996;276(5):382-387.
21. Ushizawa H, Foxwell AR, Bice S, et al. Needs for disaster medicine: lessons from the field of the Great East Japan Earthquake. Western Pac Surveil Response J. 2013;4(1):51-55.
1. Nahon M, Michaloux M. L’organisation de la réponse de la sécurité civile: le dispositif ORSEC Organisation of civilian emergency services: The ORSEC plan. https://www.sciencedirect.com/science/article/pii/S2211423816300499#! Published July 2016. Accessed October 7, 2019.
2. Berman E. Hamas, Taliban and the Jewish underground: an economist's view of radical religious militias. NBER Working Paper No. w10004. https://ssrn.com/abstract=450885. Published September 2003. Accessed October 7, 2019.
3. Jordan J. Attacking the leader. Missing the mark; why terrorist groups survive decapitation strikes. Int Secur. 2014;38(4):7-38.
4. Grynkewich A. Welfare as warfare: how violent non-state groups use social services to attack the state. Stud Conflict Terrorism. 2008;31(4):350-370.
5. Marin M, Solomon H. Islamic State: understanding the nature of the beast and its funding. Contemp Rev Middle East. 2017;4(1):18-49.
6. Bressan D. November 1, 1755: the earthquake of Lisbon: wrath of god or natural disaster? Scientific American, History of Geology. https://blogs.scientificamerican.com/history-of-geology/november-1-1755-the-earthquake-of-lisbon-wraith-of-god-or-natural-disaster. Published November 2011. Accessed October 7, 2019.
7. Trading Economics. Morocco unemployment rate. Second quarter statistics. August 2019. https://tradingeconomics.com/morocco/unemployment-rate. Accessed October 7, 2019.
8. Knoema World Data Atlas 2015. Morocco adult literacy rates. https://knoema.com/atlas/Morocco/topics/Education/Literacy/Adult-literacy-rate. Accessed October 4, 2019.
9. The Legatum Prosperity Index 2018. Morocco. https://www.prosperity.com/globe/morocco. Accessed October 7, 2019.
10. University of Washington, Institute for Health Metrics and Evaluation. Morocco. http://www.healthdata.org/morocco. Published 2018. Accessed October 7, 2019.
11. Oxford Business Group. Access to health care broadens in Morocco. https://oxfordbusinessgroup.com/overview/forward-steps-access-care-has-broadened-and-infrastructure-improved-challenges-remain. Accessed September 12. 2019.
12. Wright NMJ, Hankins FM. Preventing radicalization and terrorism: Is there a GP response? Br J Gen Pract. 2016;66(647):288-289.
13. Buhi K, Everitt K, Jones E. Might depression psychosocial adversity, and limited social assets explain vulnerability to and resistance against violent radicalization? PlosOne. 2014;9(9):e105918.
14. DeAngelis T. Understanding terrorism. apa.org/monitor/2009/11/terrorism. Published November 2009. Accessed October 14, 2019.
15. Victoroff J. The mind of the terrorist: a review and critique of psychological approaches. J Conflict Resolut. 2005;49(1):3-42.
16. Lafree G, Ackerman G. The empirical study of terrorism: social and legal research. Ann Rev Law Soc Sci. 2009;5:347-374.
17. World Bank. Morocco—improving primary health in rural areas program-for-results project (English). http://documents.worldbank.org/curated/en/716821468274482723/Morocco-Improving-Primary-Health-in-Rural-Areas-Program-for-Results-Project. Published 2015. Accessed September 16, 2019.
18. Royaume du Maroc, Ministère de la Santé. Livre blanc: pour une nouvelle gouvernance du secteur de la santé. Paper presented at: 2nd National Health Conference; July 1-3, 2013; Marrakesh, Morocco.
19. Buhi K, Hicks MH, Lashley M, Jones E. A public health approach to understanding and preventing violent radicalization. BMC Med. 2012;10:16.
20. Mallonee S, Sahriat S, Stennies G, Waxweiler R, Hogan D, Jordan F. Physical injuries and fatalities resulting from the Oklahoma City bombing. JAMA. 1996;276(5):382-387.
21. Ushizawa H, Foxwell AR, Bice S, et al. Needs for disaster medicine: lessons from the field of the Great East Japan Earthquake. Western Pac Surveil Response J. 2013;4(1):51-55.
Inhaled nitric oxide improves activity in pulmonary fibrosis patients at risk of PH
NEW ORLEANS – In patients with interstitial lung diseases at risk of pulmonary hypertension, inhaled nitric oxide produced meaningful improvements in activity that have been maintained over the long term, an investigator reported here.
Inhaled nitric oxide, which improved moderate to vigorous physical activity by 34% versus placebo in an 8-week controlled trial, has demonstrated long-term maintenance of activity parameters in open-label extension data, presented at the annual meeting of the American College of Chest Physicians.
The treatment was safe and well tolerated in this cohort of subjects at risk of pulmonary hypertension associated with pulmonary fibrosis (PH-PF), said Steven D. Nathan, MD, director of the advanced lung disease and lung transplant program at Inova Fairfax (Va.) Hospital.
The findings to date suggest inhaled nitric oxide (iNO) is a potentially effective treatment option for patients at risk for pulmonary hypertension, which is associated with poor outcomes in various forms of interstitial lung disease, Dr. Nathan said in his presentation, adding that a second cohort of PH-PF patients has been fully recruited and continue to be followed.
“Hopefully, once we show that iNO is positive and validate what we’ve seen with cohort one, then we’ll be moving on to cohort three, which will be a pivotal phase 3 clinical study with actigraphy activity–monitoring being the primary endpoint, and that has been agreed upon by the Food and Drug Administration,” he said.
The actigraph device used in the study, worn on the wrist of the nondominant arm, continuously measures patient movement in acceleration units and allows for categorization of intensity, from sedentary to vigorous, Dr. Nathan explained in this presentation.
“To me, actigraphy activity–monitoring is kind of a step beyond the 6-minute walk test,” he said. “We get a sense of how [patients] might function, based on the 6-minute walk test, but what actigraphy gives us is actually how they do function once they leave the clinic. So I think this is emerging as a very viable and valuable endpoint in clinical trials.”
Dr. Nathan reported on 23 patients with a variety of pulmonary fibrotic interstitial lung diseases randomized to receive iNO 30 mcg/kg based on their ideal body weight (IBW) per hour, and 18 who were randomized to placebo, for 8 weeks of blinded treatment. After that, patients from both arms transitioned to open-label treatment, stepping up to 45 mcg/kg IBW/hr for at least 8 weeks, and then to 75 mcg/kg IBW/hr.
After the 8 weeks of blinded treatment, activity as measured by actigraphy was maintained in the patients receiving iNO, and decreased in the placebo arm (P = .05), according to Dr. Nathan, who added that this difference was largely driven by changes in levels of moderate to vigorous physical activity, which improved in the treatment arm, while declining substantially in the placebo arm.
Clinically significant improvements in moderate to vigorous physical activity were seen in 23.1% of patients in the treatment arm and 0% of the placebo arm, while clinically significant declines in that measure were seen in 38.5% of the treatment group versus 71.4% of the placebo group.
Data from the open-label extension phase, which included a total of 18 patients, show that activity was “well maintained” over a total of 20 weeks, with patients formerly in the placebo arm demonstrating levels of activity comparable to what was achieved in the patients randomized to treatment: “We felt like this supports the clinical efficacy of the nitric oxide effect, that the placebo arm started to behave like the treatment arm,” Dr. Nathan said.
Some adverse events were reported in the study, but none were felt to be attributable to the iNO, according to Dr. Nathan.
Dr. Nathan provided disclosures related to Roche-Genentech, Boehringer Ingelheim, Promedior, Bellerophon, and United Therapeutics.
SOURCE: Nathan SD et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.308.
NEW ORLEANS – In patients with interstitial lung diseases at risk of pulmonary hypertension, inhaled nitric oxide produced meaningful improvements in activity that have been maintained over the long term, an investigator reported here.
Inhaled nitric oxide, which improved moderate to vigorous physical activity by 34% versus placebo in an 8-week controlled trial, has demonstrated long-term maintenance of activity parameters in open-label extension data, presented at the annual meeting of the American College of Chest Physicians.
The treatment was safe and well tolerated in this cohort of subjects at risk of pulmonary hypertension associated with pulmonary fibrosis (PH-PF), said Steven D. Nathan, MD, director of the advanced lung disease and lung transplant program at Inova Fairfax (Va.) Hospital.
The findings to date suggest inhaled nitric oxide (iNO) is a potentially effective treatment option for patients at risk for pulmonary hypertension, which is associated with poor outcomes in various forms of interstitial lung disease, Dr. Nathan said in his presentation, adding that a second cohort of PH-PF patients has been fully recruited and continue to be followed.
“Hopefully, once we show that iNO is positive and validate what we’ve seen with cohort one, then we’ll be moving on to cohort three, which will be a pivotal phase 3 clinical study with actigraphy activity–monitoring being the primary endpoint, and that has been agreed upon by the Food and Drug Administration,” he said.
The actigraph device used in the study, worn on the wrist of the nondominant arm, continuously measures patient movement in acceleration units and allows for categorization of intensity, from sedentary to vigorous, Dr. Nathan explained in this presentation.
“To me, actigraphy activity–monitoring is kind of a step beyond the 6-minute walk test,” he said. “We get a sense of how [patients] might function, based on the 6-minute walk test, but what actigraphy gives us is actually how they do function once they leave the clinic. So I think this is emerging as a very viable and valuable endpoint in clinical trials.”
Dr. Nathan reported on 23 patients with a variety of pulmonary fibrotic interstitial lung diseases randomized to receive iNO 30 mcg/kg based on their ideal body weight (IBW) per hour, and 18 who were randomized to placebo, for 8 weeks of blinded treatment. After that, patients from both arms transitioned to open-label treatment, stepping up to 45 mcg/kg IBW/hr for at least 8 weeks, and then to 75 mcg/kg IBW/hr.
After the 8 weeks of blinded treatment, activity as measured by actigraphy was maintained in the patients receiving iNO, and decreased in the placebo arm (P = .05), according to Dr. Nathan, who added that this difference was largely driven by changes in levels of moderate to vigorous physical activity, which improved in the treatment arm, while declining substantially in the placebo arm.
Clinically significant improvements in moderate to vigorous physical activity were seen in 23.1% of patients in the treatment arm and 0% of the placebo arm, while clinically significant declines in that measure were seen in 38.5% of the treatment group versus 71.4% of the placebo group.
Data from the open-label extension phase, which included a total of 18 patients, show that activity was “well maintained” over a total of 20 weeks, with patients formerly in the placebo arm demonstrating levels of activity comparable to what was achieved in the patients randomized to treatment: “We felt like this supports the clinical efficacy of the nitric oxide effect, that the placebo arm started to behave like the treatment arm,” Dr. Nathan said.
Some adverse events were reported in the study, but none were felt to be attributable to the iNO, according to Dr. Nathan.
Dr. Nathan provided disclosures related to Roche-Genentech, Boehringer Ingelheim, Promedior, Bellerophon, and United Therapeutics.
SOURCE: Nathan SD et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.308.
NEW ORLEANS – In patients with interstitial lung diseases at risk of pulmonary hypertension, inhaled nitric oxide produced meaningful improvements in activity that have been maintained over the long term, an investigator reported here.
Inhaled nitric oxide, which improved moderate to vigorous physical activity by 34% versus placebo in an 8-week controlled trial, has demonstrated long-term maintenance of activity parameters in open-label extension data, presented at the annual meeting of the American College of Chest Physicians.
The treatment was safe and well tolerated in this cohort of subjects at risk of pulmonary hypertension associated with pulmonary fibrosis (PH-PF), said Steven D. Nathan, MD, director of the advanced lung disease and lung transplant program at Inova Fairfax (Va.) Hospital.
The findings to date suggest inhaled nitric oxide (iNO) is a potentially effective treatment option for patients at risk for pulmonary hypertension, which is associated with poor outcomes in various forms of interstitial lung disease, Dr. Nathan said in his presentation, adding that a second cohort of PH-PF patients has been fully recruited and continue to be followed.
“Hopefully, once we show that iNO is positive and validate what we’ve seen with cohort one, then we’ll be moving on to cohort three, which will be a pivotal phase 3 clinical study with actigraphy activity–monitoring being the primary endpoint, and that has been agreed upon by the Food and Drug Administration,” he said.
The actigraph device used in the study, worn on the wrist of the nondominant arm, continuously measures patient movement in acceleration units and allows for categorization of intensity, from sedentary to vigorous, Dr. Nathan explained in this presentation.
“To me, actigraphy activity–monitoring is kind of a step beyond the 6-minute walk test,” he said. “We get a sense of how [patients] might function, based on the 6-minute walk test, but what actigraphy gives us is actually how they do function once they leave the clinic. So I think this is emerging as a very viable and valuable endpoint in clinical trials.”
Dr. Nathan reported on 23 patients with a variety of pulmonary fibrotic interstitial lung diseases randomized to receive iNO 30 mcg/kg based on their ideal body weight (IBW) per hour, and 18 who were randomized to placebo, for 8 weeks of blinded treatment. After that, patients from both arms transitioned to open-label treatment, stepping up to 45 mcg/kg IBW/hr for at least 8 weeks, and then to 75 mcg/kg IBW/hr.
After the 8 weeks of blinded treatment, activity as measured by actigraphy was maintained in the patients receiving iNO, and decreased in the placebo arm (P = .05), according to Dr. Nathan, who added that this difference was largely driven by changes in levels of moderate to vigorous physical activity, which improved in the treatment arm, while declining substantially in the placebo arm.
Clinically significant improvements in moderate to vigorous physical activity were seen in 23.1% of patients in the treatment arm and 0% of the placebo arm, while clinically significant declines in that measure were seen in 38.5% of the treatment group versus 71.4% of the placebo group.
Data from the open-label extension phase, which included a total of 18 patients, show that activity was “well maintained” over a total of 20 weeks, with patients formerly in the placebo arm demonstrating levels of activity comparable to what was achieved in the patients randomized to treatment: “We felt like this supports the clinical efficacy of the nitric oxide effect, that the placebo arm started to behave like the treatment arm,” Dr. Nathan said.
Some adverse events were reported in the study, but none were felt to be attributable to the iNO, according to Dr. Nathan.
Dr. Nathan provided disclosures related to Roche-Genentech, Boehringer Ingelheim, Promedior, Bellerophon, and United Therapeutics.
SOURCE: Nathan SD et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.308.
REPORTING FROM CHEST 2019
Does BSO status affect health outcomes for women taking estrogen for menopause?
Do health effects of menopausal estrogen therapy differ between women with bilateral oophorectomy versus those with conserved ovaries? To answer this question a group of investigators performed a subanalysis of the Women’s Health Initiative (WHI) Estrogen-Alone Trial,1 which included 40 clinical centers across the United States. They examined estrogen therapy outcomes by bilateral salpingo-oophorectomy (BSO) status, with additional stratification by 10-year age groups in 9,939 women aged 50 to 79 years with prior hysterectomy and known oophorectomy status. In the WHI trial, women were randomly assigned to conjugated equine estrogens (CEE) 0.625 mg/d or placebo for a median of 7.2 years. Investigators assessed the incidence of coronary heart disease and invasive breast cancer (the trial’s 2 primary end points), all-cause mortality, and a “global index”—these end points plus stroke, pulmonary embolism, colorectal cancer, and hip fracture—during the intervention phase and 18-year cumulative follow-up.
OBG Management caught up with lead author JoAnn E. Manson, MD, DrPH, NCMP, to discuss the study’s results.
OBG Management : How many women undergo BSO with their hysterectomy?
Dr. JoAnn E. Manson, MD, DrPH, NCMP: Of the 425,000 women who undergo hysterectomy in the United States for benign reasons each year,2,3 about 40% of them undergo BSO—so between 150,000 and 200,000 women per year undergo BSO with their hysterectomy.4,5
OBG Management : Although BSO is performed with hysterectomy to minimize patients’ future ovarian cancer risk, does BSO have health risks of its own, and how has estrogen been shown to affect these risks?
Dr. Manson: First, yes, BSO has been associated with health risks, especially when it is performed at a young age, such as before age 45. It has been linked to an increased risk of heart disease, osteoporosis, cognitive decline, and all-cause mortality. According to observational studies, estrogen therapy appears to offset many of these risks, particularly those related to heart disease and osteoporosis (the evidence is less clear on cognitive deficits).5
OBG Management : What did you find in your trial when you randomly assigned women in the age groups of 50 to 79 who underwent hysterectomy with and without BSO to estrogen therapy or placebo?
Dr. Manson: The WHI is the first study to be conducted in a randomized trial setting to analyze the health risks and benefits of estrogen therapy according to whether or not women had their ovaries removed. What we found was that the woman’s age had a strong influence on the effects of estrogen therapy among women who had BSO but only a negligible effect among women who had conserved ovaries. Overall, across the full age range, the effects of estrogen therapy did not differ substantially between women who had a BSO and those who had their ovaries conserved.
However, there were major differences by age group among the women who had BSO. A significant 32% reduction in all-cause mortality emerged during the 18-year follow-up period among the younger women (below age 60) who had BSO when they received estrogen therapy as compared with placebo. By contrast, the women who had conserved ovaries did not have this significant reduction in all-cause mortality, or in most of the other outcomes on estrogen compared with placebo. Overall, the effects of estrogen therapy tended to be relatively neutral in the women with conserved ovaries.
Now, the reduction in all-cause mortality with estrogen therapy was particularly pronounced among women who had BSO before age 45. They had a 40% statistically significant reduction in all-cause mortality with estrogen therapy compared with placebo. Also, among the women with BSO, there was a strong association between the timing of estrogen initiation and the magnitude of reduction in mortality. Women who started the estrogen therapy within 10 years of having the BSO had a 34% significant reduction in all-cause mortality, and those who started estrogen more than 20 years after having their ovaries removed had no reduction in mortality.
Continue to:
OBG Management : Do your data give support to the timing hypothesis?
Dr. Manson: Yes, our findings do support a timing hypothesis that was particularly pronounced for women who underwent BSO. It was the women who had early surgical menopause (before age 45) and those who started the estrogen therapy within 10 years of having their ovaries removed who had the greatest reduction in all-cause mortality and the most favorable benefit-risk profile from hormone therapy. So, the results do lend support to the timing hypothesis.
By contrast, women who had BSO at hysterectomy and began hormone therapy at age 70 or older had net adverse effects from hormone therapy. They posted a 40% increase in the global index—which is a summary measure of adverse effects on cardiovascular disease, cancer, and other major health outcomes. So, the women with BSO who were randomized in the trial at age 70 and older, had unfavorable results from estrogen therapy and an increase in the global index, in contrast to the women who were below age 60 or within 10 years of menopause.
OBG Management : Given your study findings, in which women would you recommend estrogen therapy? And are there groups of women in which you would advise avoiding estrogen therapy?
Dr. Manson: Current guidelines6,7 recommend estrogen therapy for women who have early menopause, particularly an early surgical menopause and BSO prior to the average age at natural menopause. Unless the woman has contraindications to estrogen therapy, the recommendations are to treat with estrogen until the average age of menopause—until about age 50 to 51.
Our study findings provide reassurance that, if a woman continues to have indications for estrogen (vasomotor symptoms, or other indications for estrogen therapy), there is relative safety of continuing estrogen-alone therapy through her 50s, until age 60. For example, a woman who, after the average age of menopause continues to have vasomotor symptoms, or if she has bone health problems, our study would suggest that estrogen therapy would continue to have a favorable benefit-risk profile until at least the age of 60. Decisions would have to be individualized, especially after age 60, with shared decision-making particularly important for those decisions. (Some women, depending on their risk profile, may continue to be candidates for estrogen therapy past age 60.)
So, this study provides reassurance regarding use of estrogen therapy for women in their 50s if they have had BSO. Actually, the women who had conserved ovaries also had relative safety with estrogen therapy until age 60. They just didn’t show the significant benefits for all-cause mortality. Overall, their pattern of health-related benefits and risks was neutral. Thus, if vasomotor symptom management, quality of life benefits, or bone health effects are sought, taking hormone therapy is a quite reasonable choice for these women.
By contrast, women who have had a BSO and are age 70 or older should really avoid initiating estrogen therapy because it would follow a prolonged period of estrogen deficiency, or very low estrogen levels, and these women appeared to have a net adverse effect from initiating hormone therapy (with increases in the global index found).
Continue to:
OBG Management : Did taking estrogen therapy prior to trial enrollment make a difference when it came to study outcomes?
Dr. Manson: We found minimal if any effect in our analyses. In fact, even the women who did not have prior (pre-randomization) use of estrogen therapy tended to do well on estrogen-alone therapy if they were younger than age 60. This was particularly true for the women who had BSO. Even if they had not used estrogen previously, and they were many years past the BSO, they still did well on estrogen therapy if they were below age 60.
1. Manson JE, Aragaki AK, Bassuk SS. Menopausal estrogen-alone therapy and health outcomes in women with and without bilateral oophorectomy: a randomized trial. Ann Intern Med. 2019 September 10. doi:10.7326/M19-0274.
2. Einarsson J. Are hysterectomy volumes in the US really falling? Contemporary OB/GYN. 1 September 2017. www.contemporaryobgyn.net/gynecology/are-hysterectomy-volumes-us-really-falling. November 4, 2019.
3. Temkin SM, Minasian L, Noone AM. The end of the hysterectomy epidemic and endometrial cancer incidence: what are the unintended consequences of declining hysterectomy rates? Front Oncol. 2016;6:89.
4. Doll KM, Dusetzina SB, Robinson W. Trends in inpatient and outpatient hysterectomy and oophorectomy rates among commercially insured women in the United States, 2000-2014. JAMA Surg. 2016;151:876-877.
5. Adelman MR, Sharp HT. Ovarian conservation vs removal at the time of benign hysterectomy. Am J Obstet Gynecol. 2018;218:269-279.
6. ACOG Practice Bulletin No. 141: management of menopausal symptoms [published corrections appear in: Obstet Gynecol. 2016;127(1):166. and Obstet Gynecol. 2018;131(3):604]. Obstet Gynecol. 2014;123:202-216.
7. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24:728-753.
Do health effects of menopausal estrogen therapy differ between women with bilateral oophorectomy versus those with conserved ovaries? To answer this question a group of investigators performed a subanalysis of the Women’s Health Initiative (WHI) Estrogen-Alone Trial,1 which included 40 clinical centers across the United States. They examined estrogen therapy outcomes by bilateral salpingo-oophorectomy (BSO) status, with additional stratification by 10-year age groups in 9,939 women aged 50 to 79 years with prior hysterectomy and known oophorectomy status. In the WHI trial, women were randomly assigned to conjugated equine estrogens (CEE) 0.625 mg/d or placebo for a median of 7.2 years. Investigators assessed the incidence of coronary heart disease and invasive breast cancer (the trial’s 2 primary end points), all-cause mortality, and a “global index”—these end points plus stroke, pulmonary embolism, colorectal cancer, and hip fracture—during the intervention phase and 18-year cumulative follow-up.
OBG Management caught up with lead author JoAnn E. Manson, MD, DrPH, NCMP, to discuss the study’s results.
OBG Management : How many women undergo BSO with their hysterectomy?
Dr. JoAnn E. Manson, MD, DrPH, NCMP: Of the 425,000 women who undergo hysterectomy in the United States for benign reasons each year,2,3 about 40% of them undergo BSO—so between 150,000 and 200,000 women per year undergo BSO with their hysterectomy.4,5
OBG Management : Although BSO is performed with hysterectomy to minimize patients’ future ovarian cancer risk, does BSO have health risks of its own, and how has estrogen been shown to affect these risks?
Dr. Manson: First, yes, BSO has been associated with health risks, especially when it is performed at a young age, such as before age 45. It has been linked to an increased risk of heart disease, osteoporosis, cognitive decline, and all-cause mortality. According to observational studies, estrogen therapy appears to offset many of these risks, particularly those related to heart disease and osteoporosis (the evidence is less clear on cognitive deficits).5
OBG Management : What did you find in your trial when you randomly assigned women in the age groups of 50 to 79 who underwent hysterectomy with and without BSO to estrogen therapy or placebo?
Dr. Manson: The WHI is the first study to be conducted in a randomized trial setting to analyze the health risks and benefits of estrogen therapy according to whether or not women had their ovaries removed. What we found was that the woman’s age had a strong influence on the effects of estrogen therapy among women who had BSO but only a negligible effect among women who had conserved ovaries. Overall, across the full age range, the effects of estrogen therapy did not differ substantially between women who had a BSO and those who had their ovaries conserved.
However, there were major differences by age group among the women who had BSO. A significant 32% reduction in all-cause mortality emerged during the 18-year follow-up period among the younger women (below age 60) who had BSO when they received estrogen therapy as compared with placebo. By contrast, the women who had conserved ovaries did not have this significant reduction in all-cause mortality, or in most of the other outcomes on estrogen compared with placebo. Overall, the effects of estrogen therapy tended to be relatively neutral in the women with conserved ovaries.
Now, the reduction in all-cause mortality with estrogen therapy was particularly pronounced among women who had BSO before age 45. They had a 40% statistically significant reduction in all-cause mortality with estrogen therapy compared with placebo. Also, among the women with BSO, there was a strong association between the timing of estrogen initiation and the magnitude of reduction in mortality. Women who started the estrogen therapy within 10 years of having the BSO had a 34% significant reduction in all-cause mortality, and those who started estrogen more than 20 years after having their ovaries removed had no reduction in mortality.
Continue to:
OBG Management : Do your data give support to the timing hypothesis?
Dr. Manson: Yes, our findings do support a timing hypothesis that was particularly pronounced for women who underwent BSO. It was the women who had early surgical menopause (before age 45) and those who started the estrogen therapy within 10 years of having their ovaries removed who had the greatest reduction in all-cause mortality and the most favorable benefit-risk profile from hormone therapy. So, the results do lend support to the timing hypothesis.
By contrast, women who had BSO at hysterectomy and began hormone therapy at age 70 or older had net adverse effects from hormone therapy. They posted a 40% increase in the global index—which is a summary measure of adverse effects on cardiovascular disease, cancer, and other major health outcomes. So, the women with BSO who were randomized in the trial at age 70 and older, had unfavorable results from estrogen therapy and an increase in the global index, in contrast to the women who were below age 60 or within 10 years of menopause.
OBG Management : Given your study findings, in which women would you recommend estrogen therapy? And are there groups of women in which you would advise avoiding estrogen therapy?
Dr. Manson: Current guidelines6,7 recommend estrogen therapy for women who have early menopause, particularly an early surgical menopause and BSO prior to the average age at natural menopause. Unless the woman has contraindications to estrogen therapy, the recommendations are to treat with estrogen until the average age of menopause—until about age 50 to 51.
Our study findings provide reassurance that, if a woman continues to have indications for estrogen (vasomotor symptoms, or other indications for estrogen therapy), there is relative safety of continuing estrogen-alone therapy through her 50s, until age 60. For example, a woman who, after the average age of menopause continues to have vasomotor symptoms, or if she has bone health problems, our study would suggest that estrogen therapy would continue to have a favorable benefit-risk profile until at least the age of 60. Decisions would have to be individualized, especially after age 60, with shared decision-making particularly important for those decisions. (Some women, depending on their risk profile, may continue to be candidates for estrogen therapy past age 60.)
So, this study provides reassurance regarding use of estrogen therapy for women in their 50s if they have had BSO. Actually, the women who had conserved ovaries also had relative safety with estrogen therapy until age 60. They just didn’t show the significant benefits for all-cause mortality. Overall, their pattern of health-related benefits and risks was neutral. Thus, if vasomotor symptom management, quality of life benefits, or bone health effects are sought, taking hormone therapy is a quite reasonable choice for these women.
By contrast, women who have had a BSO and are age 70 or older should really avoid initiating estrogen therapy because it would follow a prolonged period of estrogen deficiency, or very low estrogen levels, and these women appeared to have a net adverse effect from initiating hormone therapy (with increases in the global index found).
Continue to:
OBG Management : Did taking estrogen therapy prior to trial enrollment make a difference when it came to study outcomes?
Dr. Manson: We found minimal if any effect in our analyses. In fact, even the women who did not have prior (pre-randomization) use of estrogen therapy tended to do well on estrogen-alone therapy if they were younger than age 60. This was particularly true for the women who had BSO. Even if they had not used estrogen previously, and they were many years past the BSO, they still did well on estrogen therapy if they were below age 60.
Do health effects of menopausal estrogen therapy differ between women with bilateral oophorectomy versus those with conserved ovaries? To answer this question a group of investigators performed a subanalysis of the Women’s Health Initiative (WHI) Estrogen-Alone Trial,1 which included 40 clinical centers across the United States. They examined estrogen therapy outcomes by bilateral salpingo-oophorectomy (BSO) status, with additional stratification by 10-year age groups in 9,939 women aged 50 to 79 years with prior hysterectomy and known oophorectomy status. In the WHI trial, women were randomly assigned to conjugated equine estrogens (CEE) 0.625 mg/d or placebo for a median of 7.2 years. Investigators assessed the incidence of coronary heart disease and invasive breast cancer (the trial’s 2 primary end points), all-cause mortality, and a “global index”—these end points plus stroke, pulmonary embolism, colorectal cancer, and hip fracture—during the intervention phase and 18-year cumulative follow-up.
OBG Management caught up with lead author JoAnn E. Manson, MD, DrPH, NCMP, to discuss the study’s results.
OBG Management : How many women undergo BSO with their hysterectomy?
Dr. JoAnn E. Manson, MD, DrPH, NCMP: Of the 425,000 women who undergo hysterectomy in the United States for benign reasons each year,2,3 about 40% of them undergo BSO—so between 150,000 and 200,000 women per year undergo BSO with their hysterectomy.4,5
OBG Management : Although BSO is performed with hysterectomy to minimize patients’ future ovarian cancer risk, does BSO have health risks of its own, and how has estrogen been shown to affect these risks?
Dr. Manson: First, yes, BSO has been associated with health risks, especially when it is performed at a young age, such as before age 45. It has been linked to an increased risk of heart disease, osteoporosis, cognitive decline, and all-cause mortality. According to observational studies, estrogen therapy appears to offset many of these risks, particularly those related to heart disease and osteoporosis (the evidence is less clear on cognitive deficits).5
OBG Management : What did you find in your trial when you randomly assigned women in the age groups of 50 to 79 who underwent hysterectomy with and without BSO to estrogen therapy or placebo?
Dr. Manson: The WHI is the first study to be conducted in a randomized trial setting to analyze the health risks and benefits of estrogen therapy according to whether or not women had their ovaries removed. What we found was that the woman’s age had a strong influence on the effects of estrogen therapy among women who had BSO but only a negligible effect among women who had conserved ovaries. Overall, across the full age range, the effects of estrogen therapy did not differ substantially between women who had a BSO and those who had their ovaries conserved.
However, there were major differences by age group among the women who had BSO. A significant 32% reduction in all-cause mortality emerged during the 18-year follow-up period among the younger women (below age 60) who had BSO when they received estrogen therapy as compared with placebo. By contrast, the women who had conserved ovaries did not have this significant reduction in all-cause mortality, or in most of the other outcomes on estrogen compared with placebo. Overall, the effects of estrogen therapy tended to be relatively neutral in the women with conserved ovaries.
Now, the reduction in all-cause mortality with estrogen therapy was particularly pronounced among women who had BSO before age 45. They had a 40% statistically significant reduction in all-cause mortality with estrogen therapy compared with placebo. Also, among the women with BSO, there was a strong association between the timing of estrogen initiation and the magnitude of reduction in mortality. Women who started the estrogen therapy within 10 years of having the BSO had a 34% significant reduction in all-cause mortality, and those who started estrogen more than 20 years after having their ovaries removed had no reduction in mortality.
Continue to:
OBG Management : Do your data give support to the timing hypothesis?
Dr. Manson: Yes, our findings do support a timing hypothesis that was particularly pronounced for women who underwent BSO. It was the women who had early surgical menopause (before age 45) and those who started the estrogen therapy within 10 years of having their ovaries removed who had the greatest reduction in all-cause mortality and the most favorable benefit-risk profile from hormone therapy. So, the results do lend support to the timing hypothesis.
By contrast, women who had BSO at hysterectomy and began hormone therapy at age 70 or older had net adverse effects from hormone therapy. They posted a 40% increase in the global index—which is a summary measure of adverse effects on cardiovascular disease, cancer, and other major health outcomes. So, the women with BSO who were randomized in the trial at age 70 and older, had unfavorable results from estrogen therapy and an increase in the global index, in contrast to the women who were below age 60 or within 10 years of menopause.
OBG Management : Given your study findings, in which women would you recommend estrogen therapy? And are there groups of women in which you would advise avoiding estrogen therapy?
Dr. Manson: Current guidelines6,7 recommend estrogen therapy for women who have early menopause, particularly an early surgical menopause and BSO prior to the average age at natural menopause. Unless the woman has contraindications to estrogen therapy, the recommendations are to treat with estrogen until the average age of menopause—until about age 50 to 51.
Our study findings provide reassurance that, if a woman continues to have indications for estrogen (vasomotor symptoms, or other indications for estrogen therapy), there is relative safety of continuing estrogen-alone therapy through her 50s, until age 60. For example, a woman who, after the average age of menopause continues to have vasomotor symptoms, or if she has bone health problems, our study would suggest that estrogen therapy would continue to have a favorable benefit-risk profile until at least the age of 60. Decisions would have to be individualized, especially after age 60, with shared decision-making particularly important for those decisions. (Some women, depending on their risk profile, may continue to be candidates for estrogen therapy past age 60.)
So, this study provides reassurance regarding use of estrogen therapy for women in their 50s if they have had BSO. Actually, the women who had conserved ovaries also had relative safety with estrogen therapy until age 60. They just didn’t show the significant benefits for all-cause mortality. Overall, their pattern of health-related benefits and risks was neutral. Thus, if vasomotor symptom management, quality of life benefits, or bone health effects are sought, taking hormone therapy is a quite reasonable choice for these women.
By contrast, women who have had a BSO and are age 70 or older should really avoid initiating estrogen therapy because it would follow a prolonged period of estrogen deficiency, or very low estrogen levels, and these women appeared to have a net adverse effect from initiating hormone therapy (with increases in the global index found).
Continue to:
OBG Management : Did taking estrogen therapy prior to trial enrollment make a difference when it came to study outcomes?
Dr. Manson: We found minimal if any effect in our analyses. In fact, even the women who did not have prior (pre-randomization) use of estrogen therapy tended to do well on estrogen-alone therapy if they were younger than age 60. This was particularly true for the women who had BSO. Even if they had not used estrogen previously, and they were many years past the BSO, they still did well on estrogen therapy if they were below age 60.
1. Manson JE, Aragaki AK, Bassuk SS. Menopausal estrogen-alone therapy and health outcomes in women with and without bilateral oophorectomy: a randomized trial. Ann Intern Med. 2019 September 10. doi:10.7326/M19-0274.
2. Einarsson J. Are hysterectomy volumes in the US really falling? Contemporary OB/GYN. 1 September 2017. www.contemporaryobgyn.net/gynecology/are-hysterectomy-volumes-us-really-falling. November 4, 2019.
3. Temkin SM, Minasian L, Noone AM. The end of the hysterectomy epidemic and endometrial cancer incidence: what are the unintended consequences of declining hysterectomy rates? Front Oncol. 2016;6:89.
4. Doll KM, Dusetzina SB, Robinson W. Trends in inpatient and outpatient hysterectomy and oophorectomy rates among commercially insured women in the United States, 2000-2014. JAMA Surg. 2016;151:876-877.
5. Adelman MR, Sharp HT. Ovarian conservation vs removal at the time of benign hysterectomy. Am J Obstet Gynecol. 2018;218:269-279.
6. ACOG Practice Bulletin No. 141: management of menopausal symptoms [published corrections appear in: Obstet Gynecol. 2016;127(1):166. and Obstet Gynecol. 2018;131(3):604]. Obstet Gynecol. 2014;123:202-216.
7. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24:728-753.
1. Manson JE, Aragaki AK, Bassuk SS. Menopausal estrogen-alone therapy and health outcomes in women with and without bilateral oophorectomy: a randomized trial. Ann Intern Med. 2019 September 10. doi:10.7326/M19-0274.
2. Einarsson J. Are hysterectomy volumes in the US really falling? Contemporary OB/GYN. 1 September 2017. www.contemporaryobgyn.net/gynecology/are-hysterectomy-volumes-us-really-falling. November 4, 2019.
3. Temkin SM, Minasian L, Noone AM. The end of the hysterectomy epidemic and endometrial cancer incidence: what are the unintended consequences of declining hysterectomy rates? Front Oncol. 2016;6:89.
4. Doll KM, Dusetzina SB, Robinson W. Trends in inpatient and outpatient hysterectomy and oophorectomy rates among commercially insured women in the United States, 2000-2014. JAMA Surg. 2016;151:876-877.
5. Adelman MR, Sharp HT. Ovarian conservation vs removal at the time of benign hysterectomy. Am J Obstet Gynecol. 2018;218:269-279.
6. ACOG Practice Bulletin No. 141: management of menopausal symptoms [published corrections appear in: Obstet Gynecol. 2016;127(1):166. and Obstet Gynecol. 2018;131(3):604]. Obstet Gynecol. 2014;123:202-216.
7. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24:728-753.
Court blocks immigration health insurance rule
A district judge has temporarily blocked an order by President Trump that would make having health insurance or the ability to pay for medical care a requirement for immigrants seeking U.S. visas.
There are serious questions about whether President Trump’s immigration rule was arbitrary and capricious and thus, a violation of the Administrative Procedure Act, Judge Michael H. Simon of the U.S. District Court of the District of Oregon wrote in a Nov. 2, 2019, decision.
Further, the plaintiffs had demonstrated they were likely to suffer irreparable harm in the absence of temporary relief, that the balance of hardships tipped sharply toward the plaintiffs, and that temporary relief was in the public interest, Judge Simon wrote in his 18-page order. The new requirement, announced in a proclamation on Oct. 4., was scheduled to take effect on Nov. 3.
White House press secretary Stephanie Grisham said the administration strongly disagreed with the district court’s decision to impose the nationwide injunction against the policy without even affording the government an opportunity to provide a written defense.
“It is wrong and unfair for a single district court judge to thwart the policies that the President determined would best protect the United States health care system – and for the United States taxpayers to suffer the grave consequences of the immense strain inflicted on the health care system from subsidizing uncompensated care for those seeking admission,” Ms. Grisham said in a statement. “The administration looks forward to the opportunity to make its defense in court, and it will continue to vigorously defend the President’s policies to protect the interests of the American people.”
Jesse Bless, director of federal litigation for the American Immigration Lawyers Association, which represented the plaintiffs in the case, said he applauded the court’s ruling for protecting countless families.
“Thousands across the country can breathe a sigh of relief today because the court recognized the urgent and irreparable harm that would have been inflicted in the absence of a [temporary retraining order],” Mr. Bless said in a statement. “This proclamation would permanently separate families and damage employers; it is a clear violation of the constitution. The president simply does not have the authority to rewrite the law by proclamation.”
The Oct. 4 proclamation calls on visa applicants to demonstrate to immigration authorities that they can obtain coverage by an approved health insurer within 30 days of entering the United States or show evidence they possess the financial resources to pay for foreseeable medical costs. Approved coverage would include, but not be limited to, an employer-sponsored plan, an unsubsidized health plan offered in the individual market, a family member’s plan, or a visitor health insurance with at least 364 days of coverage. President Trump said that the restriction would protect Americans from bearing the burden of uncompensated health care costs generated by immigrants.
The nonpartisan Migration Policy Institute estimates the new requirement may restrict up to 375,000 prospective legal immigrants from moving to the United States annually.
A district judge has temporarily blocked an order by President Trump that would make having health insurance or the ability to pay for medical care a requirement for immigrants seeking U.S. visas.
There are serious questions about whether President Trump’s immigration rule was arbitrary and capricious and thus, a violation of the Administrative Procedure Act, Judge Michael H. Simon of the U.S. District Court of the District of Oregon wrote in a Nov. 2, 2019, decision.
Further, the plaintiffs had demonstrated they were likely to suffer irreparable harm in the absence of temporary relief, that the balance of hardships tipped sharply toward the plaintiffs, and that temporary relief was in the public interest, Judge Simon wrote in his 18-page order. The new requirement, announced in a proclamation on Oct. 4., was scheduled to take effect on Nov. 3.
White House press secretary Stephanie Grisham said the administration strongly disagreed with the district court’s decision to impose the nationwide injunction against the policy without even affording the government an opportunity to provide a written defense.
“It is wrong and unfair for a single district court judge to thwart the policies that the President determined would best protect the United States health care system – and for the United States taxpayers to suffer the grave consequences of the immense strain inflicted on the health care system from subsidizing uncompensated care for those seeking admission,” Ms. Grisham said in a statement. “The administration looks forward to the opportunity to make its defense in court, and it will continue to vigorously defend the President’s policies to protect the interests of the American people.”
Jesse Bless, director of federal litigation for the American Immigration Lawyers Association, which represented the plaintiffs in the case, said he applauded the court’s ruling for protecting countless families.
“Thousands across the country can breathe a sigh of relief today because the court recognized the urgent and irreparable harm that would have been inflicted in the absence of a [temporary retraining order],” Mr. Bless said in a statement. “This proclamation would permanently separate families and damage employers; it is a clear violation of the constitution. The president simply does not have the authority to rewrite the law by proclamation.”
The Oct. 4 proclamation calls on visa applicants to demonstrate to immigration authorities that they can obtain coverage by an approved health insurer within 30 days of entering the United States or show evidence they possess the financial resources to pay for foreseeable medical costs. Approved coverage would include, but not be limited to, an employer-sponsored plan, an unsubsidized health plan offered in the individual market, a family member’s plan, or a visitor health insurance with at least 364 days of coverage. President Trump said that the restriction would protect Americans from bearing the burden of uncompensated health care costs generated by immigrants.
The nonpartisan Migration Policy Institute estimates the new requirement may restrict up to 375,000 prospective legal immigrants from moving to the United States annually.
A district judge has temporarily blocked an order by President Trump that would make having health insurance or the ability to pay for medical care a requirement for immigrants seeking U.S. visas.
There are serious questions about whether President Trump’s immigration rule was arbitrary and capricious and thus, a violation of the Administrative Procedure Act, Judge Michael H. Simon of the U.S. District Court of the District of Oregon wrote in a Nov. 2, 2019, decision.
Further, the plaintiffs had demonstrated they were likely to suffer irreparable harm in the absence of temporary relief, that the balance of hardships tipped sharply toward the plaintiffs, and that temporary relief was in the public interest, Judge Simon wrote in his 18-page order. The new requirement, announced in a proclamation on Oct. 4., was scheduled to take effect on Nov. 3.
White House press secretary Stephanie Grisham said the administration strongly disagreed with the district court’s decision to impose the nationwide injunction against the policy without even affording the government an opportunity to provide a written defense.
“It is wrong and unfair for a single district court judge to thwart the policies that the President determined would best protect the United States health care system – and for the United States taxpayers to suffer the grave consequences of the immense strain inflicted on the health care system from subsidizing uncompensated care for those seeking admission,” Ms. Grisham said in a statement. “The administration looks forward to the opportunity to make its defense in court, and it will continue to vigorously defend the President’s policies to protect the interests of the American people.”
Jesse Bless, director of federal litigation for the American Immigration Lawyers Association, which represented the plaintiffs in the case, said he applauded the court’s ruling for protecting countless families.
“Thousands across the country can breathe a sigh of relief today because the court recognized the urgent and irreparable harm that would have been inflicted in the absence of a [temporary retraining order],” Mr. Bless said in a statement. “This proclamation would permanently separate families and damage employers; it is a clear violation of the constitution. The president simply does not have the authority to rewrite the law by proclamation.”
The Oct. 4 proclamation calls on visa applicants to demonstrate to immigration authorities that they can obtain coverage by an approved health insurer within 30 days of entering the United States or show evidence they possess the financial resources to pay for foreseeable medical costs. Approved coverage would include, but not be limited to, an employer-sponsored plan, an unsubsidized health plan offered in the individual market, a family member’s plan, or a visitor health insurance with at least 364 days of coverage. President Trump said that the restriction would protect Americans from bearing the burden of uncompensated health care costs generated by immigrants.
The nonpartisan Migration Policy Institute estimates the new requirement may restrict up to 375,000 prospective legal immigrants from moving to the United States annually.
Systemic Epstein-Barr Virus–Positive T-cell Lymphoma of Childhood
Case Report
A 7-year-old Chinese boy presented with multiple painful oral and tongue ulcers of 2 weeks’ duration as well as acute onset of moderate to high fever (highest temperature, 39.3°C) for 5 days. The fever was reported to have run a relapsing course, accompanied by rigors but without convulsions or cognitive changes. At times, the patient had nasal congestion, nasal discharge, and cough. He also had a transient eruption on the back and hands as well as an indurated red nodule on the left forearm.
Before the patient was hospitalized, antibiotic therapy was administered by other physicians, but the condition of fever and oral ulcers did not improve. After the patient was hospitalized, new tender nodules emerged on the scalp, buttocks, and lower extremities. New ulcers also appeared on the palate.
History
Two months earlier, the patient had presented with a painful perioral skin ulcer that resolved after being treated as contagious eczema. Another dermatologist previously had considered a diagnosis of hand-foot-and-mouth disease.
The patient was born by normal spontaneous vaginal delivery, without abnormality. He was breastfed; feeding, growth, and the developmental history showed no abnormality. He was the family’s eldest child, with a healthy brother and sister. There was no history of familial illness. He received bacillus Calmette-Guérin and poliomyelitis vaccines after birth; the rest of the vaccine history was unclear. There was no history of immunologic abnormality.
Physical Examination
A 1.5×1.5-cm, warm, red nodule with a central black crust was noted on the left forearm (Figure 1A). Several similar lesions were noted on the buttocks, scalp, and lower extremities. Multiple ulcers, as large as 1 cm, were present on the tongue, palate, and left angle of the mouth (Figure 1B). The pharynx was congested, and the tonsils were mildly enlarged. Multiple enlarged, movable, nontender lymph nodes could be palpated in the cervical basins, axillae, and groin. No purpura or ecchymosis was detected.
Laboratory Results
Laboratory testing revealed a normal total white blood cell count (4.26×109/L [reference range, 4.0–12.0×109/L]), with normal neutrophils (1.36×109/L [reference range, 1.32–7.90×109/L]), lymphocytes (2.77×109/L [reference range, 1.20–6.00×109/L]), and monocytes (0.13×109/L [reference range, 0.08–0.80×109/L]); a mildly decreased hemoglobin level (115 g/L [reference range, 120–160 g/L]); a normal platelet count (102×109/L [reference range, 100–380×109/L]); an elevated lactate dehydrogenase level (614 U/L [reference range, 110–330 U/L]); an elevated α-hydroxybutyrate dehydrogenase level (483 U/L [reference range, 120–270 U/L]); elevated prothrombin time (15.3 s [reference range, 9–14 s]); elevated activated partial thromboplastin time (59.8 s [reference range, 20.6–39.6 s]); and an elevated D-dimer level (1.51 mg/L [reference range, <0.73 mg/L]). In addition, autoantibody testing revealed a positive antinuclear antibody titer of 1:320 and a strong positive anti–Ro-52 level.
The peripheral blood lymphocyte classification demonstrated a prominent elevated percentage of T lymphocytes, with predominantly CD8+ cells (CD3, 94.87%; CD8, 71.57%; CD4, 24.98%; CD4:CD8 ratio, 0.35) and a diminished percentage of B lymphocytes and natural killer (NK) cells. Epstein-Barr virus (EBV) antibody testing was positive for anti–viral capsid antigen (VCA) IgG and negative for anti-VCA IgM.
Smears of the ulcer on the tongue demonstrated gram-positive cocci, gram-negative bacilli, and diplococci. Culture of sputum showed methicillin-resistant Staphylococcus aureus. Inspection for acid-fast bacilli in sputum yielded negative results 3 times. A purified protein derivative skin test for Mycobacterium tuberculosis infection was negative.
Imaging and Other Studies
Computed tomography of the chest and abdomen demonstrated 2 nodular opacities on the lower right lung; spotted opacities on the upper right lung; floccular opacities on the rest area of the lung; mild pleural effusion; enlargement of lymph nodes on the mediastinum, the bilateral hilum of the lung, and mesentery; and hepatosplenomegaly. Electrocardiography showed sinus tachycardia. Nasal cavity endoscopy showed sinusitis. Fundus examination showed vasculopathy of the left retina. A colonoscopy showed normal mucosa.
Histopathology
Biopsy of the nodule on the left arm showed dense, superficial to deep perivascular, periadnexal, perineural, and panniculitislike lymphoid infiltrates, as well as a sparse interstitial infiltrate with irregular and pleomorphic medium to large nuclei. Lymphoid cells showed mild epidermotropism, with tagging to the basal layer. Some vessel walls were infiltrated by similar cells (Figure 2). Infiltrative atypical lymphoid cells expressed CD3 and CD7 and were mostly CD8+, with a few CD4+ cells and most cells negative for CD5, CD20, CD30, CD56, and anaplastic lymphoma kinase. Cytotoxic markers granzyme B and T-cell intracellular antigen protein 1 were scattered positive. Immunostaining for Ki-67 protein highlighted an increased proliferative rate of 80% in malignant cells. In situ hybridization for EBV-encoded RNA (EBER) demonstrated EBV-positive atypical lymphoid cells (Figure 3). Analysis for T-cell receptor (TCR) γ gene rearrangement revealed a monoclonal pattern. Bone marrow aspirate showed proliferation of the 3 cell lines. The percentage of T lymphocytes was increased (20% of all nucleated cells). No hemophagocytic activity was found.
Diagnosis
A diagnosis of systemic EBV-positive T-cell lymphoma was made. Before the final diagnosis was made, the patient was treated by rheumatologists with antibiotics, antiviral drugs, nonsteroidal anti-inflammatory drugs, and other symptomatic treatments. Following antibiotic therapy, a sputum culture reverted to normal flora, the coagulation index (ie, prothrombin time, activated partial thromboplastin time) returned to normal, and the D-dimer level decreased to 1.19 mg/L.
The patient’s parents refused to accept chemotherapy for him. Instead, they chose herbal therapy only; 5 months later, they reported that all of his symptoms had resolved; however, the disease suddenly relapsed after another 7 months, with multiple skin nodules and fever. The patient died, even with chemotherapy in another hospital.
Comment
Prevalence and Presentation
Epstein-Barr virus is a ubiquitous γ-herpesvirus with tropism for B cells, affecting more than 90% of the adult population worldwide. In addition to infecting B cells, EBV is capable of infecting T and NK cells, leading to various EBV-related lymphoproliferative disorders (LPDs). The frequency and clinical presentation of infection varies based on the type of EBV-infected cells and the state of host immunity.1-3
Primary infection usually is asymptomatic and occurs early in life; when symptomatic, the disease usually presents as infectious mononucleosis (IM), characterized by polyclonal expansion of infected B cells and subsequent cytotoxic T-cell response. A diagnosis of EBV infection can be made by testing for specific IgM and IgG antibodies against VCA, early antigens, and EBV nuclear antigen proteins.3,4
Associated LPDs
Although most symptoms associated with IM resolve within weeks or months, persistent or recurrent IM-like symptoms or even lasting disease occasionally occur, particularly in children and young adults. This complication is known as chronic active EBV infection (CAEBV), frequently associated with EBV-infected T-cell or NK-cell proliferation, especially in East Asian populations.3,5
Epstein-Barr virus–positive T-cell and NK-cell LPDs of childhood include CAEBV infection of T-cell and NK-cell types and systemic EBV-positive T-cell lymphoma of childhood. The former includes hydroa vacciniforme–like LPD and severe mosquito bite allergy.3
Systemic EBV-Positive T-cell Lymphoma of Childhood
This entity occurs not only in children but also in adolescents and young adults. A fulminant illness characterized by clonal proliferation of EBV-infected cytotoxic T cells, it can develop shortly after primary EBV infection or is linked to CAEBV infection. The disorder is rare and has a racial predilection for Asian (ie, Japanese, Chinese, Korean) populations and indigenous populations of Mexico and Central and South America.6-8
Complications
Systemic EBV-positive T-cell lymphoma of childhood is often complicated by hemophagocytic syndrome, coagulopathy, sepsis, and multiorgan failure. Other signs and symptoms include high fever, rash, jaundice, diarrhea, pancytopenia, and hepatosplenomegaly. The liver, spleen, lymph nodes, and bone marrow are commonly involved, and the disease can involve skin, the heart, and the lungs.9,10
Diagnosis
When systemic EBV-positive T-cell lymphoma occurs shortly after IM, serology shows low or absent anti-VCA IgM and positive anti-VCA IgG. Infiltrating T cells usually are small and lack cytologic atypia; however, cases with pleomorphic, medium to large lymphoid cells, irregular nuclei, and frequent mitoses have been described. Hemophagocytosis can be seen in the liver, spleen, and bone marrow.3,11
The most typical phenotype of systemic EBV-positive T-cell lymphoma is CD2+CD3+CD8+CD20−CD56−, with expression of the cytotoxic granules known as T-cell intracellular antigen 1 and granzyme B. Rare cases of CD4+ and mixed CD4+/CD8+ phenotypes have been described, usually in the setting of CAEBV infection.3,12 Neoplastic cells have monoclonally rearranged TCR-γ genes and consistent EBER positivity with in situ hybridization.13 A final diagnosis is based on a comprehensive analysis of clinical, morphological, immunohistochemical, and molecular biological aspects.
Clinical Course and Prognosis
Most patients with systemic EBV-positive T-cell lymphoma have an aggressive clinical course with high mortality. In a few cases, patients were reported to respond to a regimen of etoposide and dexamethasone, followed by allogeneic hematopoietic stem cell transplantation.3
In recognition of the aggressive clinical behavior and desire to clearly distinguish systemic EBV-positive T-cell lymphoma from CAEBV infection, the older term systemic EBV-positive T-cell LPD of childhood, which had been introduced in 2008 to the World Health Organization classification, was changed to systemic EBV-positive T-cell lymphoma of childhood in the revised 2016 World Health Organization classification.6,12 However, Kim et al14 reported a case with excellent response to corticosteroid administration, suggesting that systemic EBV-positive T-cell lymphoma of childhood may be more heterogeneous in terms of prognosis.
Our patient presented with acute IM-like symptoms, including high fever, tonsillar enlargement, lymphadenopathy, and hepatosplenomegaly, as well as uncommon oral ulcers and skin lesions, including indurated nodules. Histopathologic changes in the skin nodule, proliferation in bone marrow, immunohistochemical phenotype, and positivity of EBER and TCR-γ monoclonal rearrangement were all consistent with systemic EBV-positive T-cell lymphoma of childhood. The patient was positive for VCA IgG and negative for VCA IgM, compatible with systemic EBV-positive T-cell lymphoma of childhood occurring shortly after IM. Neither pancytopenia, hemophagocytic syndrome, nor multiorgan failure occurred during the course.
Differential Diagnosis
It is important to distinguish IM from systemic EBV-positive T-cell lymphoma of childhood and CAEBV infection. Detection of anti–VCA IgM in the early stage, its disappearance during the clinical course, and appearance of anti-EBV–determined nuclear antigen is useful to distinguish IM from the neoplasms, as systemic EBV-positive T-cell lymphoma of childhood is negative for anti-EBV–determined nuclear antigen. Carefully following the clinical course also is important.3,15
Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis can occur in association with systemic EBV-positive T-cell lymphoma of childhood and might represent a continuum of disease rather than distinct entities.14 The most useful marker for differentiating EBV-associated hemophagocytic lymphohistiocytosis and systemic EBV-positive T-cell lymphoma of childhood is an abnormal karyotype rather than molecular clonality.16
Outcome
Mortality risk in EBV-associated T-cell and NK-cell LPD is not primarily dependent on whether the lesion has progressed to lymphoma but instead is related to associated complications.17
Conclusion
Although systemic EBV-positive T-cell lymphoma of childhood is a rare disorder and has race predilection, dermatologists should be aware due to the aggressive clinical source and poor prognosis. Histopathology and in situ hybridization for EBER and TCR gene rearrangements are critical for final diagnosis. Although rare cases can show temporary resolution, the final outcome of this disease is not optimistic.
- Ameli F, Ghafourian F, Masir N. Systematic Epstein-Barr virus-positive T-cell lymphoproliferative disease presenting as a persistent fever and cough: a case report. J Med Case Rep. 2014;8:288.
- Kim HJ, Ko YH, Kim JE, et al. Epstein-Barr virus-associated lympho-proliferative disorders: review and update on 2016 WHO classification. J Pathol Transl Med. 2017;51:352-358.
- Dojcinov SD, Fend F, Quintanilla-Martinez L. EBV-positive lymphoproliferations of B- T- and NK-cell derivation in non-immunocompromised hosts [published online March 7, 2018]. Pathogens. doi:10.3390/pathogens7010028.
- Luzuriaga K, Sullivan JL. Infectious mononucleosis. N Engl J Med. 2010;362:1993-2000.
- Cohen JI, Kimura H, Nakamura S, et al. Epstein-Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: a status report and summary of an international meeting, 8-9 September 2008. Ann Oncol. 2009;20:1472-1482.
- Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375-2390.
- Kim WY, Montes-Mojarro IA, Fend F, et al. Epstein-Barr virus-associated T and NK-cell lymphoproliferative diseases. Front Pediatr. 2019;7:71.
- Hong M, Ko YH, Yoo KH, et al. EBV-positive T/NK-cell lymphoproliferative disease of childhood. Korean J Pathol. 2013;47:137-147.
- Quintanilla-Martinez L, Kumar S, Fend F, et al. Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome. Blood. 2000;96:443-451.
- Chen G, Chen L, Qin X, et al. Systemic Epstein-Barr virus positive T-cell lymphoproliferative disease of childhood with hemophagocytic syndrome. Int J Clin Exp Pathol. 2014;7:7110-7113.
- Grywalska E, Rolinski J. Epstein-Barr virus-associated lymphomas. Semin Oncol. 2015;42:291-303.
- Huang W, Lv N, Ying J, et al. Clinicopathological characteristics of four cases of EBV positive T-cell lymphoproliferative disorders of childhood in China. Int J Clin Exp Pathol. 2014;7:4991-4999.
- Tabanelli V, Agostinelli C, Sabattini E, et al. Systemic Epstein-Barr-virus-positive T cell lymphoproliferative childhood disease in a 22-year-old Caucasian man: a case report and review of the literature. J Med Case Rep. 2011;5:218.
- Kim DH, Kim M, Kim Y, et al. Systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood with good response to steroid therapy. J Pediatr Hematol Oncol. 2017;39:e497-e500.
- Arai A, Yamaguchi T, Komatsu H, et al. Infectious mononucleosis accompanied by clonal proliferation of EBV-infected cells and infection of CD8-positive cells. Int J Hematol. 2014;99:671-675.
- Smith MC, Cohen DN, Greig B, et al. The ambiguous boundary between EBV-related hemophagocytic lymphohistiocytosis and systemic EBV-driven T cell lymphoproliferative disorder. Int J Clin Exp Pathol. 2014;7:5738-5749.
- Paik JH, Choe JY, Kim H, et al. Clinicopathological categorization of Epstein-Barr virus-positive T/NK-cell lymphoproliferative disease: an analysis of 42 cases with an emphasis on prognostic implications. Leuk Lymphoma. 2017;58:53-63.
Case Report
A 7-year-old Chinese boy presented with multiple painful oral and tongue ulcers of 2 weeks’ duration as well as acute onset of moderate to high fever (highest temperature, 39.3°C) for 5 days. The fever was reported to have run a relapsing course, accompanied by rigors but without convulsions or cognitive changes. At times, the patient had nasal congestion, nasal discharge, and cough. He also had a transient eruption on the back and hands as well as an indurated red nodule on the left forearm.
Before the patient was hospitalized, antibiotic therapy was administered by other physicians, but the condition of fever and oral ulcers did not improve. After the patient was hospitalized, new tender nodules emerged on the scalp, buttocks, and lower extremities. New ulcers also appeared on the palate.
History
Two months earlier, the patient had presented with a painful perioral skin ulcer that resolved after being treated as contagious eczema. Another dermatologist previously had considered a diagnosis of hand-foot-and-mouth disease.
The patient was born by normal spontaneous vaginal delivery, without abnormality. He was breastfed; feeding, growth, and the developmental history showed no abnormality. He was the family’s eldest child, with a healthy brother and sister. There was no history of familial illness. He received bacillus Calmette-Guérin and poliomyelitis vaccines after birth; the rest of the vaccine history was unclear. There was no history of immunologic abnormality.
Physical Examination
A 1.5×1.5-cm, warm, red nodule with a central black crust was noted on the left forearm (Figure 1A). Several similar lesions were noted on the buttocks, scalp, and lower extremities. Multiple ulcers, as large as 1 cm, were present on the tongue, palate, and left angle of the mouth (Figure 1B). The pharynx was congested, and the tonsils were mildly enlarged. Multiple enlarged, movable, nontender lymph nodes could be palpated in the cervical basins, axillae, and groin. No purpura or ecchymosis was detected.
Laboratory Results
Laboratory testing revealed a normal total white blood cell count (4.26×109/L [reference range, 4.0–12.0×109/L]), with normal neutrophils (1.36×109/L [reference range, 1.32–7.90×109/L]), lymphocytes (2.77×109/L [reference range, 1.20–6.00×109/L]), and monocytes (0.13×109/L [reference range, 0.08–0.80×109/L]); a mildly decreased hemoglobin level (115 g/L [reference range, 120–160 g/L]); a normal platelet count (102×109/L [reference range, 100–380×109/L]); an elevated lactate dehydrogenase level (614 U/L [reference range, 110–330 U/L]); an elevated α-hydroxybutyrate dehydrogenase level (483 U/L [reference range, 120–270 U/L]); elevated prothrombin time (15.3 s [reference range, 9–14 s]); elevated activated partial thromboplastin time (59.8 s [reference range, 20.6–39.6 s]); and an elevated D-dimer level (1.51 mg/L [reference range, <0.73 mg/L]). In addition, autoantibody testing revealed a positive antinuclear antibody titer of 1:320 and a strong positive anti–Ro-52 level.
The peripheral blood lymphocyte classification demonstrated a prominent elevated percentage of T lymphocytes, with predominantly CD8+ cells (CD3, 94.87%; CD8, 71.57%; CD4, 24.98%; CD4:CD8 ratio, 0.35) and a diminished percentage of B lymphocytes and natural killer (NK) cells. Epstein-Barr virus (EBV) antibody testing was positive for anti–viral capsid antigen (VCA) IgG and negative for anti-VCA IgM.
Smears of the ulcer on the tongue demonstrated gram-positive cocci, gram-negative bacilli, and diplococci. Culture of sputum showed methicillin-resistant Staphylococcus aureus. Inspection for acid-fast bacilli in sputum yielded negative results 3 times. A purified protein derivative skin test for Mycobacterium tuberculosis infection was negative.
Imaging and Other Studies
Computed tomography of the chest and abdomen demonstrated 2 nodular opacities on the lower right lung; spotted opacities on the upper right lung; floccular opacities on the rest area of the lung; mild pleural effusion; enlargement of lymph nodes on the mediastinum, the bilateral hilum of the lung, and mesentery; and hepatosplenomegaly. Electrocardiography showed sinus tachycardia. Nasal cavity endoscopy showed sinusitis. Fundus examination showed vasculopathy of the left retina. A colonoscopy showed normal mucosa.
Histopathology
Biopsy of the nodule on the left arm showed dense, superficial to deep perivascular, periadnexal, perineural, and panniculitislike lymphoid infiltrates, as well as a sparse interstitial infiltrate with irregular and pleomorphic medium to large nuclei. Lymphoid cells showed mild epidermotropism, with tagging to the basal layer. Some vessel walls were infiltrated by similar cells (Figure 2). Infiltrative atypical lymphoid cells expressed CD3 and CD7 and were mostly CD8+, with a few CD4+ cells and most cells negative for CD5, CD20, CD30, CD56, and anaplastic lymphoma kinase. Cytotoxic markers granzyme B and T-cell intracellular antigen protein 1 were scattered positive. Immunostaining for Ki-67 protein highlighted an increased proliferative rate of 80% in malignant cells. In situ hybridization for EBV-encoded RNA (EBER) demonstrated EBV-positive atypical lymphoid cells (Figure 3). Analysis for T-cell receptor (TCR) γ gene rearrangement revealed a monoclonal pattern. Bone marrow aspirate showed proliferation of the 3 cell lines. The percentage of T lymphocytes was increased (20% of all nucleated cells). No hemophagocytic activity was found.
Diagnosis
A diagnosis of systemic EBV-positive T-cell lymphoma was made. Before the final diagnosis was made, the patient was treated by rheumatologists with antibiotics, antiviral drugs, nonsteroidal anti-inflammatory drugs, and other symptomatic treatments. Following antibiotic therapy, a sputum culture reverted to normal flora, the coagulation index (ie, prothrombin time, activated partial thromboplastin time) returned to normal, and the D-dimer level decreased to 1.19 mg/L.
The patient’s parents refused to accept chemotherapy for him. Instead, they chose herbal therapy only; 5 months later, they reported that all of his symptoms had resolved; however, the disease suddenly relapsed after another 7 months, with multiple skin nodules and fever. The patient died, even with chemotherapy in another hospital.
Comment
Prevalence and Presentation
Epstein-Barr virus is a ubiquitous γ-herpesvirus with tropism for B cells, affecting more than 90% of the adult population worldwide. In addition to infecting B cells, EBV is capable of infecting T and NK cells, leading to various EBV-related lymphoproliferative disorders (LPDs). The frequency and clinical presentation of infection varies based on the type of EBV-infected cells and the state of host immunity.1-3
Primary infection usually is asymptomatic and occurs early in life; when symptomatic, the disease usually presents as infectious mononucleosis (IM), characterized by polyclonal expansion of infected B cells and subsequent cytotoxic T-cell response. A diagnosis of EBV infection can be made by testing for specific IgM and IgG antibodies against VCA, early antigens, and EBV nuclear antigen proteins.3,4
Associated LPDs
Although most symptoms associated with IM resolve within weeks or months, persistent or recurrent IM-like symptoms or even lasting disease occasionally occur, particularly in children and young adults. This complication is known as chronic active EBV infection (CAEBV), frequently associated with EBV-infected T-cell or NK-cell proliferation, especially in East Asian populations.3,5
Epstein-Barr virus–positive T-cell and NK-cell LPDs of childhood include CAEBV infection of T-cell and NK-cell types and systemic EBV-positive T-cell lymphoma of childhood. The former includes hydroa vacciniforme–like LPD and severe mosquito bite allergy.3
Systemic EBV-Positive T-cell Lymphoma of Childhood
This entity occurs not only in children but also in adolescents and young adults. A fulminant illness characterized by clonal proliferation of EBV-infected cytotoxic T cells, it can develop shortly after primary EBV infection or is linked to CAEBV infection. The disorder is rare and has a racial predilection for Asian (ie, Japanese, Chinese, Korean) populations and indigenous populations of Mexico and Central and South America.6-8
Complications
Systemic EBV-positive T-cell lymphoma of childhood is often complicated by hemophagocytic syndrome, coagulopathy, sepsis, and multiorgan failure. Other signs and symptoms include high fever, rash, jaundice, diarrhea, pancytopenia, and hepatosplenomegaly. The liver, spleen, lymph nodes, and bone marrow are commonly involved, and the disease can involve skin, the heart, and the lungs.9,10
Diagnosis
When systemic EBV-positive T-cell lymphoma occurs shortly after IM, serology shows low or absent anti-VCA IgM and positive anti-VCA IgG. Infiltrating T cells usually are small and lack cytologic atypia; however, cases with pleomorphic, medium to large lymphoid cells, irregular nuclei, and frequent mitoses have been described. Hemophagocytosis can be seen in the liver, spleen, and bone marrow.3,11
The most typical phenotype of systemic EBV-positive T-cell lymphoma is CD2+CD3+CD8+CD20−CD56−, with expression of the cytotoxic granules known as T-cell intracellular antigen 1 and granzyme B. Rare cases of CD4+ and mixed CD4+/CD8+ phenotypes have been described, usually in the setting of CAEBV infection.3,12 Neoplastic cells have monoclonally rearranged TCR-γ genes and consistent EBER positivity with in situ hybridization.13 A final diagnosis is based on a comprehensive analysis of clinical, morphological, immunohistochemical, and molecular biological aspects.
Clinical Course and Prognosis
Most patients with systemic EBV-positive T-cell lymphoma have an aggressive clinical course with high mortality. In a few cases, patients were reported to respond to a regimen of etoposide and dexamethasone, followed by allogeneic hematopoietic stem cell transplantation.3
In recognition of the aggressive clinical behavior and desire to clearly distinguish systemic EBV-positive T-cell lymphoma from CAEBV infection, the older term systemic EBV-positive T-cell LPD of childhood, which had been introduced in 2008 to the World Health Organization classification, was changed to systemic EBV-positive T-cell lymphoma of childhood in the revised 2016 World Health Organization classification.6,12 However, Kim et al14 reported a case with excellent response to corticosteroid administration, suggesting that systemic EBV-positive T-cell lymphoma of childhood may be more heterogeneous in terms of prognosis.
Our patient presented with acute IM-like symptoms, including high fever, tonsillar enlargement, lymphadenopathy, and hepatosplenomegaly, as well as uncommon oral ulcers and skin lesions, including indurated nodules. Histopathologic changes in the skin nodule, proliferation in bone marrow, immunohistochemical phenotype, and positivity of EBER and TCR-γ monoclonal rearrangement were all consistent with systemic EBV-positive T-cell lymphoma of childhood. The patient was positive for VCA IgG and negative for VCA IgM, compatible with systemic EBV-positive T-cell lymphoma of childhood occurring shortly after IM. Neither pancytopenia, hemophagocytic syndrome, nor multiorgan failure occurred during the course.
Differential Diagnosis
It is important to distinguish IM from systemic EBV-positive T-cell lymphoma of childhood and CAEBV infection. Detection of anti–VCA IgM in the early stage, its disappearance during the clinical course, and appearance of anti-EBV–determined nuclear antigen is useful to distinguish IM from the neoplasms, as systemic EBV-positive T-cell lymphoma of childhood is negative for anti-EBV–determined nuclear antigen. Carefully following the clinical course also is important.3,15
Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis can occur in association with systemic EBV-positive T-cell lymphoma of childhood and might represent a continuum of disease rather than distinct entities.14 The most useful marker for differentiating EBV-associated hemophagocytic lymphohistiocytosis and systemic EBV-positive T-cell lymphoma of childhood is an abnormal karyotype rather than molecular clonality.16
Outcome
Mortality risk in EBV-associated T-cell and NK-cell LPD is not primarily dependent on whether the lesion has progressed to lymphoma but instead is related to associated complications.17
Conclusion
Although systemic EBV-positive T-cell lymphoma of childhood is a rare disorder and has race predilection, dermatologists should be aware due to the aggressive clinical source and poor prognosis. Histopathology and in situ hybridization for EBER and TCR gene rearrangements are critical for final diagnosis. Although rare cases can show temporary resolution, the final outcome of this disease is not optimistic.
Case Report
A 7-year-old Chinese boy presented with multiple painful oral and tongue ulcers of 2 weeks’ duration as well as acute onset of moderate to high fever (highest temperature, 39.3°C) for 5 days. The fever was reported to have run a relapsing course, accompanied by rigors but without convulsions or cognitive changes. At times, the patient had nasal congestion, nasal discharge, and cough. He also had a transient eruption on the back and hands as well as an indurated red nodule on the left forearm.
Before the patient was hospitalized, antibiotic therapy was administered by other physicians, but the condition of fever and oral ulcers did not improve. After the patient was hospitalized, new tender nodules emerged on the scalp, buttocks, and lower extremities. New ulcers also appeared on the palate.
History
Two months earlier, the patient had presented with a painful perioral skin ulcer that resolved after being treated as contagious eczema. Another dermatologist previously had considered a diagnosis of hand-foot-and-mouth disease.
The patient was born by normal spontaneous vaginal delivery, without abnormality. He was breastfed; feeding, growth, and the developmental history showed no abnormality. He was the family’s eldest child, with a healthy brother and sister. There was no history of familial illness. He received bacillus Calmette-Guérin and poliomyelitis vaccines after birth; the rest of the vaccine history was unclear. There was no history of immunologic abnormality.
Physical Examination
A 1.5×1.5-cm, warm, red nodule with a central black crust was noted on the left forearm (Figure 1A). Several similar lesions were noted on the buttocks, scalp, and lower extremities. Multiple ulcers, as large as 1 cm, were present on the tongue, palate, and left angle of the mouth (Figure 1B). The pharynx was congested, and the tonsils were mildly enlarged. Multiple enlarged, movable, nontender lymph nodes could be palpated in the cervical basins, axillae, and groin. No purpura or ecchymosis was detected.
Laboratory Results
Laboratory testing revealed a normal total white blood cell count (4.26×109/L [reference range, 4.0–12.0×109/L]), with normal neutrophils (1.36×109/L [reference range, 1.32–7.90×109/L]), lymphocytes (2.77×109/L [reference range, 1.20–6.00×109/L]), and monocytes (0.13×109/L [reference range, 0.08–0.80×109/L]); a mildly decreased hemoglobin level (115 g/L [reference range, 120–160 g/L]); a normal platelet count (102×109/L [reference range, 100–380×109/L]); an elevated lactate dehydrogenase level (614 U/L [reference range, 110–330 U/L]); an elevated α-hydroxybutyrate dehydrogenase level (483 U/L [reference range, 120–270 U/L]); elevated prothrombin time (15.3 s [reference range, 9–14 s]); elevated activated partial thromboplastin time (59.8 s [reference range, 20.6–39.6 s]); and an elevated D-dimer level (1.51 mg/L [reference range, <0.73 mg/L]). In addition, autoantibody testing revealed a positive antinuclear antibody titer of 1:320 and a strong positive anti–Ro-52 level.
The peripheral blood lymphocyte classification demonstrated a prominent elevated percentage of T lymphocytes, with predominantly CD8+ cells (CD3, 94.87%; CD8, 71.57%; CD4, 24.98%; CD4:CD8 ratio, 0.35) and a diminished percentage of B lymphocytes and natural killer (NK) cells. Epstein-Barr virus (EBV) antibody testing was positive for anti–viral capsid antigen (VCA) IgG and negative for anti-VCA IgM.
Smears of the ulcer on the tongue demonstrated gram-positive cocci, gram-negative bacilli, and diplococci. Culture of sputum showed methicillin-resistant Staphylococcus aureus. Inspection for acid-fast bacilli in sputum yielded negative results 3 times. A purified protein derivative skin test for Mycobacterium tuberculosis infection was negative.
Imaging and Other Studies
Computed tomography of the chest and abdomen demonstrated 2 nodular opacities on the lower right lung; spotted opacities on the upper right lung; floccular opacities on the rest area of the lung; mild pleural effusion; enlargement of lymph nodes on the mediastinum, the bilateral hilum of the lung, and mesentery; and hepatosplenomegaly. Electrocardiography showed sinus tachycardia. Nasal cavity endoscopy showed sinusitis. Fundus examination showed vasculopathy of the left retina. A colonoscopy showed normal mucosa.
Histopathology
Biopsy of the nodule on the left arm showed dense, superficial to deep perivascular, periadnexal, perineural, and panniculitislike lymphoid infiltrates, as well as a sparse interstitial infiltrate with irregular and pleomorphic medium to large nuclei. Lymphoid cells showed mild epidermotropism, with tagging to the basal layer. Some vessel walls were infiltrated by similar cells (Figure 2). Infiltrative atypical lymphoid cells expressed CD3 and CD7 and were mostly CD8+, with a few CD4+ cells and most cells negative for CD5, CD20, CD30, CD56, and anaplastic lymphoma kinase. Cytotoxic markers granzyme B and T-cell intracellular antigen protein 1 were scattered positive. Immunostaining for Ki-67 protein highlighted an increased proliferative rate of 80% in malignant cells. In situ hybridization for EBV-encoded RNA (EBER) demonstrated EBV-positive atypical lymphoid cells (Figure 3). Analysis for T-cell receptor (TCR) γ gene rearrangement revealed a monoclonal pattern. Bone marrow aspirate showed proliferation of the 3 cell lines. The percentage of T lymphocytes was increased (20% of all nucleated cells). No hemophagocytic activity was found.
Diagnosis
A diagnosis of systemic EBV-positive T-cell lymphoma was made. Before the final diagnosis was made, the patient was treated by rheumatologists with antibiotics, antiviral drugs, nonsteroidal anti-inflammatory drugs, and other symptomatic treatments. Following antibiotic therapy, a sputum culture reverted to normal flora, the coagulation index (ie, prothrombin time, activated partial thromboplastin time) returned to normal, and the D-dimer level decreased to 1.19 mg/L.
The patient’s parents refused to accept chemotherapy for him. Instead, they chose herbal therapy only; 5 months later, they reported that all of his symptoms had resolved; however, the disease suddenly relapsed after another 7 months, with multiple skin nodules and fever. The patient died, even with chemotherapy in another hospital.
Comment
Prevalence and Presentation
Epstein-Barr virus is a ubiquitous γ-herpesvirus with tropism for B cells, affecting more than 90% of the adult population worldwide. In addition to infecting B cells, EBV is capable of infecting T and NK cells, leading to various EBV-related lymphoproliferative disorders (LPDs). The frequency and clinical presentation of infection varies based on the type of EBV-infected cells and the state of host immunity.1-3
Primary infection usually is asymptomatic and occurs early in life; when symptomatic, the disease usually presents as infectious mononucleosis (IM), characterized by polyclonal expansion of infected B cells and subsequent cytotoxic T-cell response. A diagnosis of EBV infection can be made by testing for specific IgM and IgG antibodies against VCA, early antigens, and EBV nuclear antigen proteins.3,4
Associated LPDs
Although most symptoms associated with IM resolve within weeks or months, persistent or recurrent IM-like symptoms or even lasting disease occasionally occur, particularly in children and young adults. This complication is known as chronic active EBV infection (CAEBV), frequently associated with EBV-infected T-cell or NK-cell proliferation, especially in East Asian populations.3,5
Epstein-Barr virus–positive T-cell and NK-cell LPDs of childhood include CAEBV infection of T-cell and NK-cell types and systemic EBV-positive T-cell lymphoma of childhood. The former includes hydroa vacciniforme–like LPD and severe mosquito bite allergy.3
Systemic EBV-Positive T-cell Lymphoma of Childhood
This entity occurs not only in children but also in adolescents and young adults. A fulminant illness characterized by clonal proliferation of EBV-infected cytotoxic T cells, it can develop shortly after primary EBV infection or is linked to CAEBV infection. The disorder is rare and has a racial predilection for Asian (ie, Japanese, Chinese, Korean) populations and indigenous populations of Mexico and Central and South America.6-8
Complications
Systemic EBV-positive T-cell lymphoma of childhood is often complicated by hemophagocytic syndrome, coagulopathy, sepsis, and multiorgan failure. Other signs and symptoms include high fever, rash, jaundice, diarrhea, pancytopenia, and hepatosplenomegaly. The liver, spleen, lymph nodes, and bone marrow are commonly involved, and the disease can involve skin, the heart, and the lungs.9,10
Diagnosis
When systemic EBV-positive T-cell lymphoma occurs shortly after IM, serology shows low or absent anti-VCA IgM and positive anti-VCA IgG. Infiltrating T cells usually are small and lack cytologic atypia; however, cases with pleomorphic, medium to large lymphoid cells, irregular nuclei, and frequent mitoses have been described. Hemophagocytosis can be seen in the liver, spleen, and bone marrow.3,11
The most typical phenotype of systemic EBV-positive T-cell lymphoma is CD2+CD3+CD8+CD20−CD56−, with expression of the cytotoxic granules known as T-cell intracellular antigen 1 and granzyme B. Rare cases of CD4+ and mixed CD4+/CD8+ phenotypes have been described, usually in the setting of CAEBV infection.3,12 Neoplastic cells have monoclonally rearranged TCR-γ genes and consistent EBER positivity with in situ hybridization.13 A final diagnosis is based on a comprehensive analysis of clinical, morphological, immunohistochemical, and molecular biological aspects.
Clinical Course and Prognosis
Most patients with systemic EBV-positive T-cell lymphoma have an aggressive clinical course with high mortality. In a few cases, patients were reported to respond to a regimen of etoposide and dexamethasone, followed by allogeneic hematopoietic stem cell transplantation.3
In recognition of the aggressive clinical behavior and desire to clearly distinguish systemic EBV-positive T-cell lymphoma from CAEBV infection, the older term systemic EBV-positive T-cell LPD of childhood, which had been introduced in 2008 to the World Health Organization classification, was changed to systemic EBV-positive T-cell lymphoma of childhood in the revised 2016 World Health Organization classification.6,12 However, Kim et al14 reported a case with excellent response to corticosteroid administration, suggesting that systemic EBV-positive T-cell lymphoma of childhood may be more heterogeneous in terms of prognosis.
Our patient presented with acute IM-like symptoms, including high fever, tonsillar enlargement, lymphadenopathy, and hepatosplenomegaly, as well as uncommon oral ulcers and skin lesions, including indurated nodules. Histopathologic changes in the skin nodule, proliferation in bone marrow, immunohistochemical phenotype, and positivity of EBER and TCR-γ monoclonal rearrangement were all consistent with systemic EBV-positive T-cell lymphoma of childhood. The patient was positive for VCA IgG and negative for VCA IgM, compatible with systemic EBV-positive T-cell lymphoma of childhood occurring shortly after IM. Neither pancytopenia, hemophagocytic syndrome, nor multiorgan failure occurred during the course.
Differential Diagnosis
It is important to distinguish IM from systemic EBV-positive T-cell lymphoma of childhood and CAEBV infection. Detection of anti–VCA IgM in the early stage, its disappearance during the clinical course, and appearance of anti-EBV–determined nuclear antigen is useful to distinguish IM from the neoplasms, as systemic EBV-positive T-cell lymphoma of childhood is negative for anti-EBV–determined nuclear antigen. Carefully following the clinical course also is important.3,15
Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis can occur in association with systemic EBV-positive T-cell lymphoma of childhood and might represent a continuum of disease rather than distinct entities.14 The most useful marker for differentiating EBV-associated hemophagocytic lymphohistiocytosis and systemic EBV-positive T-cell lymphoma of childhood is an abnormal karyotype rather than molecular clonality.16
Outcome
Mortality risk in EBV-associated T-cell and NK-cell LPD is not primarily dependent on whether the lesion has progressed to lymphoma but instead is related to associated complications.17
Conclusion
Although systemic EBV-positive T-cell lymphoma of childhood is a rare disorder and has race predilection, dermatologists should be aware due to the aggressive clinical source and poor prognosis. Histopathology and in situ hybridization for EBER and TCR gene rearrangements are critical for final diagnosis. Although rare cases can show temporary resolution, the final outcome of this disease is not optimistic.
- Ameli F, Ghafourian F, Masir N. Systematic Epstein-Barr virus-positive T-cell lymphoproliferative disease presenting as a persistent fever and cough: a case report. J Med Case Rep. 2014;8:288.
- Kim HJ, Ko YH, Kim JE, et al. Epstein-Barr virus-associated lympho-proliferative disorders: review and update on 2016 WHO classification. J Pathol Transl Med. 2017;51:352-358.
- Dojcinov SD, Fend F, Quintanilla-Martinez L. EBV-positive lymphoproliferations of B- T- and NK-cell derivation in non-immunocompromised hosts [published online March 7, 2018]. Pathogens. doi:10.3390/pathogens7010028.
- Luzuriaga K, Sullivan JL. Infectious mononucleosis. N Engl J Med. 2010;362:1993-2000.
- Cohen JI, Kimura H, Nakamura S, et al. Epstein-Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: a status report and summary of an international meeting, 8-9 September 2008. Ann Oncol. 2009;20:1472-1482.
- Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375-2390.
- Kim WY, Montes-Mojarro IA, Fend F, et al. Epstein-Barr virus-associated T and NK-cell lymphoproliferative diseases. Front Pediatr. 2019;7:71.
- Hong M, Ko YH, Yoo KH, et al. EBV-positive T/NK-cell lymphoproliferative disease of childhood. Korean J Pathol. 2013;47:137-147.
- Quintanilla-Martinez L, Kumar S, Fend F, et al. Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome. Blood. 2000;96:443-451.
- Chen G, Chen L, Qin X, et al. Systemic Epstein-Barr virus positive T-cell lymphoproliferative disease of childhood with hemophagocytic syndrome. Int J Clin Exp Pathol. 2014;7:7110-7113.
- Grywalska E, Rolinski J. Epstein-Barr virus-associated lymphomas. Semin Oncol. 2015;42:291-303.
- Huang W, Lv N, Ying J, et al. Clinicopathological characteristics of four cases of EBV positive T-cell lymphoproliferative disorders of childhood in China. Int J Clin Exp Pathol. 2014;7:4991-4999.
- Tabanelli V, Agostinelli C, Sabattini E, et al. Systemic Epstein-Barr-virus-positive T cell lymphoproliferative childhood disease in a 22-year-old Caucasian man: a case report and review of the literature. J Med Case Rep. 2011;5:218.
- Kim DH, Kim M, Kim Y, et al. Systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood with good response to steroid therapy. J Pediatr Hematol Oncol. 2017;39:e497-e500.
- Arai A, Yamaguchi T, Komatsu H, et al. Infectious mononucleosis accompanied by clonal proliferation of EBV-infected cells and infection of CD8-positive cells. Int J Hematol. 2014;99:671-675.
- Smith MC, Cohen DN, Greig B, et al. The ambiguous boundary between EBV-related hemophagocytic lymphohistiocytosis and systemic EBV-driven T cell lymphoproliferative disorder. Int J Clin Exp Pathol. 2014;7:5738-5749.
- Paik JH, Choe JY, Kim H, et al. Clinicopathological categorization of Epstein-Barr virus-positive T/NK-cell lymphoproliferative disease: an analysis of 42 cases with an emphasis on prognostic implications. Leuk Lymphoma. 2017;58:53-63.
- Ameli F, Ghafourian F, Masir N. Systematic Epstein-Barr virus-positive T-cell lymphoproliferative disease presenting as a persistent fever and cough: a case report. J Med Case Rep. 2014;8:288.
- Kim HJ, Ko YH, Kim JE, et al. Epstein-Barr virus-associated lympho-proliferative disorders: review and update on 2016 WHO classification. J Pathol Transl Med. 2017;51:352-358.
- Dojcinov SD, Fend F, Quintanilla-Martinez L. EBV-positive lymphoproliferations of B- T- and NK-cell derivation in non-immunocompromised hosts [published online March 7, 2018]. Pathogens. doi:10.3390/pathogens7010028.
- Luzuriaga K, Sullivan JL. Infectious mononucleosis. N Engl J Med. 2010;362:1993-2000.
- Cohen JI, Kimura H, Nakamura S, et al. Epstein-Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: a status report and summary of an international meeting, 8-9 September 2008. Ann Oncol. 2009;20:1472-1482.
- Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375-2390.
- Kim WY, Montes-Mojarro IA, Fend F, et al. Epstein-Barr virus-associated T and NK-cell lymphoproliferative diseases. Front Pediatr. 2019;7:71.
- Hong M, Ko YH, Yoo KH, et al. EBV-positive T/NK-cell lymphoproliferative disease of childhood. Korean J Pathol. 2013;47:137-147.
- Quintanilla-Martinez L, Kumar S, Fend F, et al. Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome. Blood. 2000;96:443-451.
- Chen G, Chen L, Qin X, et al. Systemic Epstein-Barr virus positive T-cell lymphoproliferative disease of childhood with hemophagocytic syndrome. Int J Clin Exp Pathol. 2014;7:7110-7113.
- Grywalska E, Rolinski J. Epstein-Barr virus-associated lymphomas. Semin Oncol. 2015;42:291-303.
- Huang W, Lv N, Ying J, et al. Clinicopathological characteristics of four cases of EBV positive T-cell lymphoproliferative disorders of childhood in China. Int J Clin Exp Pathol. 2014;7:4991-4999.
- Tabanelli V, Agostinelli C, Sabattini E, et al. Systemic Epstein-Barr-virus-positive T cell lymphoproliferative childhood disease in a 22-year-old Caucasian man: a case report and review of the literature. J Med Case Rep. 2011;5:218.
- Kim DH, Kim M, Kim Y, et al. Systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood with good response to steroid therapy. J Pediatr Hematol Oncol. 2017;39:e497-e500.
- Arai A, Yamaguchi T, Komatsu H, et al. Infectious mononucleosis accompanied by clonal proliferation of EBV-infected cells and infection of CD8-positive cells. Int J Hematol. 2014;99:671-675.
- Smith MC, Cohen DN, Greig B, et al. The ambiguous boundary between EBV-related hemophagocytic lymphohistiocytosis and systemic EBV-driven T cell lymphoproliferative disorder. Int J Clin Exp Pathol. 2014;7:5738-5749.
- Paik JH, Choe JY, Kim H, et al. Clinicopathological categorization of Epstein-Barr virus-positive T/NK-cell lymphoproliferative disease: an analysis of 42 cases with an emphasis on prognostic implications. Leuk Lymphoma. 2017;58:53-63.
Practice Points
- Systemic Epstein-Barr virus (EBV)–positive T-cell lymphoma of childhood is a fulminant illness with a predilection for Asians and indigenous populations from Mexico and Central and South America. In most patients, the disease has an aggressive clinical course with high mortality.
- The disease often is complicated by hemophagocytic syndrome, coagulopathy, sepsis, and multiorgan failure. When these severe complications are absent, the prognosis might be better.
- In situ hybridization for EBV-encoded RNA and for T-cell receptor gene rearrangements is an important tool to establish the diagnosis as well as for treatment options and predicting the prognosis.
Seborrhea Herpeticum: Cutaneous Herpes Simplex Virus Infection Within Infantile Seborrheic Dermatitis
Classically, eczema herpeticum is associated with atopic dermatitis (AD), but it also has been previously reported in the setting of pemphigus vulgaris, Darier disease, ichthyosis vulgaris, burns, psoriasis, and irritant contact dermatitis.1,2 Descriptions of cutaneous herpes simplex virus (HSV) in the setting of seborrheic dermatitis are lacking.
Case Report
A 2-month-old infant boy who was otherwise healthy presented to the emergency department with a new rash on the scalp. Initially there were a few clusters of small fluid-filled lesions that evolved over several days into diffuse clusters covering the scalp and extending onto the forehead and upper chest (Figure). The patient’s medical history was notable for infantile seborrheic dermatitis and a family history of AD. His grandmother, who was his primary caretaker, had a recent history of herpes labialis.
Physical examination revealed numerous discrete, erythematous, and punched-out erosions diffusely on the scalp. There were fewer similar erosions on the forehead and upper chest. There were no oral or periocular lesions. There were no areas of lichenification or eczematous plaques on the remainder of the trunk or extremities. Laboratory testing was positive for HSV type 1 polymerase chain reaction and positive for HSV type 1 viral culture. Liver enzymes were elevated with alanine aminotransferase at 107 U/L (reference range, 7–52 U/L) and aspartate aminotransferase at 94 U/L (reference range, 13–39 U/L).
The patient was admitted to the hospital and was treated by the dermatology and infectious disease services. Intravenous acyclovir 60 mg/kg daily was administered for 3 days until all lesions had crusted over. On the day of discharge, the patient was transitioned to oral valacyclovir 20 mg/kg daily for 7 days with resolution. One month later he developed a recurrence that was within his existing seborrheic dermatitis. After a repeat 7-day course of oral valacyclovir 20 mg/kg daily, he was placed on prophylaxis therapy of oral acyclovir 10 mg/kg daily. Gentle skin care precautions also were recommended.
Comment
Eczema herpeticum refers to disseminated cutaneous infection with HSV types 1 or 2 in the setting of underlying dermatosis.2 Although it is classically associated with AD, it has been reported in a number of other chronic skin disorders and can lead to serious complications, including hepatitis, keratoconjunctivitis, and meningitis. In those with AD who develop HSV, presentation may occur in active dermatitis locations because of skin barrier disruption, which may lead to increased susceptibility to viral infection.3
Herpes simplex virus in a background of seborrheic dermatitis has not been well described. Although the pathogenesis of seborrheic dermatitis has not been fully reported, several gene mutations and protein deficiencies have been identified in patients and animal models that are associated with immune response or epidermal differentiation.4 Therefore, it is possible that, as with AD, a disruption in the skin barrier increases susceptibility to viral infection.
It also has been suggested that infantile seborrheic dermatitis and AD represent the same spectrum of disease.5 Given our patient’s family history of AD, it is possible his presentation represents early underlying AD. Providers should be aware that cutaneous HSV can be confined to a seborrheic distribution and may represent underlying epidermal dysfunction secondary to seborrheic dermatitis.
- Wheeler CE, Abele DC. Eczema herpeticum, primary and recurrent. Arch Dermatol. 1966;93:162-173.
- Santmyire-Rosenberger BR, Nigra TP. Psoriasis herpeticum: three cases of Kaposi’s varicelliform eruption in psoriasis. J Am Acad Dermatol. 2005;53:52-56.
- Wollenberg A, Wetzel S, Burgdorf WH, et al. Viral infections in atopic dermatitis: pathogenic aspects and clinical management. J Allergy Clin Immunol. 2003;112:667-674.
- Karakadze M, Hirt P, Wikramanayake T. The genetic basis of seborrhoeic dermatitis: a review. J Eur Acad Dermatol Venereol. 2017;32:529-536.
- Alexopoulos A, Kakourou T, Orfanou I, et al. Retrospective analysis of the relationship between infantile seborrheic dermatitis and atopic dermatitis. Pediatr Dermatol. 2013;31:125-130.
Classically, eczema herpeticum is associated with atopic dermatitis (AD), but it also has been previously reported in the setting of pemphigus vulgaris, Darier disease, ichthyosis vulgaris, burns, psoriasis, and irritant contact dermatitis.1,2 Descriptions of cutaneous herpes simplex virus (HSV) in the setting of seborrheic dermatitis are lacking.
Case Report
A 2-month-old infant boy who was otherwise healthy presented to the emergency department with a new rash on the scalp. Initially there were a few clusters of small fluid-filled lesions that evolved over several days into diffuse clusters covering the scalp and extending onto the forehead and upper chest (Figure). The patient’s medical history was notable for infantile seborrheic dermatitis and a family history of AD. His grandmother, who was his primary caretaker, had a recent history of herpes labialis.
Physical examination revealed numerous discrete, erythematous, and punched-out erosions diffusely on the scalp. There were fewer similar erosions on the forehead and upper chest. There were no oral or periocular lesions. There were no areas of lichenification or eczematous plaques on the remainder of the trunk or extremities. Laboratory testing was positive for HSV type 1 polymerase chain reaction and positive for HSV type 1 viral culture. Liver enzymes were elevated with alanine aminotransferase at 107 U/L (reference range, 7–52 U/L) and aspartate aminotransferase at 94 U/L (reference range, 13–39 U/L).
The patient was admitted to the hospital and was treated by the dermatology and infectious disease services. Intravenous acyclovir 60 mg/kg daily was administered for 3 days until all lesions had crusted over. On the day of discharge, the patient was transitioned to oral valacyclovir 20 mg/kg daily for 7 days with resolution. One month later he developed a recurrence that was within his existing seborrheic dermatitis. After a repeat 7-day course of oral valacyclovir 20 mg/kg daily, he was placed on prophylaxis therapy of oral acyclovir 10 mg/kg daily. Gentle skin care precautions also were recommended.
Comment
Eczema herpeticum refers to disseminated cutaneous infection with HSV types 1 or 2 in the setting of underlying dermatosis.2 Although it is classically associated with AD, it has been reported in a number of other chronic skin disorders and can lead to serious complications, including hepatitis, keratoconjunctivitis, and meningitis. In those with AD who develop HSV, presentation may occur in active dermatitis locations because of skin barrier disruption, which may lead to increased susceptibility to viral infection.3
Herpes simplex virus in a background of seborrheic dermatitis has not been well described. Although the pathogenesis of seborrheic dermatitis has not been fully reported, several gene mutations and protein deficiencies have been identified in patients and animal models that are associated with immune response or epidermal differentiation.4 Therefore, it is possible that, as with AD, a disruption in the skin barrier increases susceptibility to viral infection.
It also has been suggested that infantile seborrheic dermatitis and AD represent the same spectrum of disease.5 Given our patient’s family history of AD, it is possible his presentation represents early underlying AD. Providers should be aware that cutaneous HSV can be confined to a seborrheic distribution and may represent underlying epidermal dysfunction secondary to seborrheic dermatitis.
Classically, eczema herpeticum is associated with atopic dermatitis (AD), but it also has been previously reported in the setting of pemphigus vulgaris, Darier disease, ichthyosis vulgaris, burns, psoriasis, and irritant contact dermatitis.1,2 Descriptions of cutaneous herpes simplex virus (HSV) in the setting of seborrheic dermatitis are lacking.
Case Report
A 2-month-old infant boy who was otherwise healthy presented to the emergency department with a new rash on the scalp. Initially there were a few clusters of small fluid-filled lesions that evolved over several days into diffuse clusters covering the scalp and extending onto the forehead and upper chest (Figure). The patient’s medical history was notable for infantile seborrheic dermatitis and a family history of AD. His grandmother, who was his primary caretaker, had a recent history of herpes labialis.
Physical examination revealed numerous discrete, erythematous, and punched-out erosions diffusely on the scalp. There were fewer similar erosions on the forehead and upper chest. There were no oral or periocular lesions. There were no areas of lichenification or eczematous plaques on the remainder of the trunk or extremities. Laboratory testing was positive for HSV type 1 polymerase chain reaction and positive for HSV type 1 viral culture. Liver enzymes were elevated with alanine aminotransferase at 107 U/L (reference range, 7–52 U/L) and aspartate aminotransferase at 94 U/L (reference range, 13–39 U/L).
The patient was admitted to the hospital and was treated by the dermatology and infectious disease services. Intravenous acyclovir 60 mg/kg daily was administered for 3 days until all lesions had crusted over. On the day of discharge, the patient was transitioned to oral valacyclovir 20 mg/kg daily for 7 days with resolution. One month later he developed a recurrence that was within his existing seborrheic dermatitis. After a repeat 7-day course of oral valacyclovir 20 mg/kg daily, he was placed on prophylaxis therapy of oral acyclovir 10 mg/kg daily. Gentle skin care precautions also were recommended.
Comment
Eczema herpeticum refers to disseminated cutaneous infection with HSV types 1 or 2 in the setting of underlying dermatosis.2 Although it is classically associated with AD, it has been reported in a number of other chronic skin disorders and can lead to serious complications, including hepatitis, keratoconjunctivitis, and meningitis. In those with AD who develop HSV, presentation may occur in active dermatitis locations because of skin barrier disruption, which may lead to increased susceptibility to viral infection.3
Herpes simplex virus in a background of seborrheic dermatitis has not been well described. Although the pathogenesis of seborrheic dermatitis has not been fully reported, several gene mutations and protein deficiencies have been identified in patients and animal models that are associated with immune response or epidermal differentiation.4 Therefore, it is possible that, as with AD, a disruption in the skin barrier increases susceptibility to viral infection.
It also has been suggested that infantile seborrheic dermatitis and AD represent the same spectrum of disease.5 Given our patient’s family history of AD, it is possible his presentation represents early underlying AD. Providers should be aware that cutaneous HSV can be confined to a seborrheic distribution and may represent underlying epidermal dysfunction secondary to seborrheic dermatitis.
- Wheeler CE, Abele DC. Eczema herpeticum, primary and recurrent. Arch Dermatol. 1966;93:162-173.
- Santmyire-Rosenberger BR, Nigra TP. Psoriasis herpeticum: three cases of Kaposi’s varicelliform eruption in psoriasis. J Am Acad Dermatol. 2005;53:52-56.
- Wollenberg A, Wetzel S, Burgdorf WH, et al. Viral infections in atopic dermatitis: pathogenic aspects and clinical management. J Allergy Clin Immunol. 2003;112:667-674.
- Karakadze M, Hirt P, Wikramanayake T. The genetic basis of seborrhoeic dermatitis: a review. J Eur Acad Dermatol Venereol. 2017;32:529-536.
- Alexopoulos A, Kakourou T, Orfanou I, et al. Retrospective analysis of the relationship between infantile seborrheic dermatitis and atopic dermatitis. Pediatr Dermatol. 2013;31:125-130.
- Wheeler CE, Abele DC. Eczema herpeticum, primary and recurrent. Arch Dermatol. 1966;93:162-173.
- Santmyire-Rosenberger BR, Nigra TP. Psoriasis herpeticum: three cases of Kaposi’s varicelliform eruption in psoriasis. J Am Acad Dermatol. 2005;53:52-56.
- Wollenberg A, Wetzel S, Burgdorf WH, et al. Viral infections in atopic dermatitis: pathogenic aspects and clinical management. J Allergy Clin Immunol. 2003;112:667-674.
- Karakadze M, Hirt P, Wikramanayake T. The genetic basis of seborrhoeic dermatitis: a review. J Eur Acad Dermatol Venereol. 2017;32:529-536.
- Alexopoulos A, Kakourou T, Orfanou I, et al. Retrospective analysis of the relationship between infantile seborrheic dermatitis and atopic dermatitis. Pediatr Dermatol. 2013;31:125-130.
Practice Points
- Cutaneous herpes simplex virus may present in a seborrheic distribution within infantile seborrheic dermatitis, suggesting underlying dysfunction secondary to seborrheic dermatitis.
- Treatment of seborrhea herpeticum involves antiviral therapy to treat the secondary viral infection and gentle skin care precautions for the primary condition.
