Suicide is a staggering, tragic, and growing cause of death in the United States. One out of every 62 Americans will die from suicide, based on the national lifetime prevalence rate.¹ More than 42,000 Americans died from suicide in 2014, making suicide the second leading cause of death in individuals age 15 to 34, the fourth leading cause among those age 35 to 54, and the tenth leading cause of death in the country overall.² The incidence of suicide in the general population of the United States increased by 24% between 1999 and 2014.³ This tragedy obviously is not solving itself.

The proposal

U.S. Centers for Disease Control and Prevention (CDC) publishes statistics about the number of suicides, as well as demographic information, collected from coroners and medical examiners across the country. However, these sources do not provide a biological sample that could be used to gather data concerning DNA, RNA, and other potential blood markers, including those reflecting inflammatory and epigenetic processes. However, such biological samples are commonly collected by the U.S. medicolegal death investigation system. In 2003, this system investigated 450,000 unnatural and/or unexplained deaths (ie, approximately 20% of the 2.4 million deaths in the United States that year).⁴

Each unnatural or unexplained death is examined, often extensively, by a coroner or medical examiner. This examination system costs more than $600 million annually. Yet the data that are collected are handled on a case-by-case and often county-by-county basis, rather than in aggregate. The essence of the proposal presented here is to take the information and biological samples collected in this process and put them into a National Suicide Database (NSD), which then can serve as a resource for scientists to increase our understanding of the genetic, epigenetic, and other factors underlying death due to suicide. This increased understanding will result in the development more effective tools to detect to those at risk for suicide (ie, risk factor tests), to monitor treatment, and to develop new treatments based on a better understanding of the underlying pathophysiology and pathogenesis of suicide. These tools will reduce:

• the number of lives lost to suicide
• the pain and suffering of loved ones
• lost productivity to society, especially when one considers that suicide disproportionately affects individuals during the most productive period of their lives (ie, age 15 to 54).

The NSD will be organized as a government–private partnership, with the government represented by the National Institutes of Health (NIH) and/or the CDC. The goal will be to take the information that is currently being collected by the nation’s medicolegal death investigation system, including the biological samples, systematize it, enter it into a common database, and make it available to qualified researchers across the country. The administrative arm of the system will be responsible for ensuring systematic data collection, storage in a searchable and integrated database housed within the NIH and/or the CDC, and vetting researchers who will have access to the data, including those with expertise in genomics, molecular biology, suicide, epidemiology, and data-mining. (Currently, the CDC’s National Violent Death Reporting System, which is a state-based surveillance system, pools data on violent deaths from multiple sources into a usable, anonymous database. These sources include state and local medical examiners, coroners, law enforcement, crime labs, and vital statistics records, but they do not include any biological material even though it is collected [personal correspondence with the CDC, July 2016].)

Because information on suicides currently are handled primarily on a county-by-county basis, data concerning these deaths are not facilitating a better understanding of the causes and strategies for preventing suicide. Correcting this situation is the goal of this proposal, as modeled by the National Cancer Institute’s War on Cancer, which has transformed the treatment and the outcomes of cancer. If this proposal is enacted, the same type of transformation will occur and result in a reduction in the suicide rate and better outcomes for the psychiatric illnesses that underlie most instances of suicide.

The proposed NSD will address a major and common problem for researchers in this area—small sample sizes. When considered from the perspective of the size of samples feasible for most independent research teams to collect and study, suicide on an annual basis is rare—however, that is not the case when the incidence of suicide in the nation as a whole is considered. In contrast to the data concerning suicides that individual research teams can collect, the proposed genomic database will grow by approximately 40,000 individuals every year, until a meaningful reduction in deaths due to suicide is achieved.

From a research perspective, suicide, although tragic, is one of the few binary outcomes in psychiatry—that is, life or death. Although there may be >1 genetic and/or epigenetic contributor to suicide, within a relatively short period of time, the proposed database will amass—and continue to amass on an ongoing basis—data from a large population of suicide victims. Researchers then can compare the findings from this database with the normative human genome, looking for variants that are over-represented in the population of those who have died by suicide.

Environmental factors undoubtedly also contribute to the risk of suicide, given that the incidence of suicide increases with age, particularly among white males, and with the addition of psychiatric and medical comorbidities. Inflammatory processes also have been implicated in the pathophysiology of a number of psychiatric disorders, including major depression, which is the primary psychiatric risk factor for suicide. Therefore, consideration should be given to collecting whole blood samples if the time between death and autopsy is within an appropriate limit to obtain interpretable data concerning RNA (ie, gene expression) and even biomarkers of inflammatory and other processes at the time of the suicide. This approach has been used by Niculescu et al^5,6 for whole blood gene expression. The rationale for using samples of whole blood is that this strategy could be more easily adapted to clinical practice in contrast to using samples from the target organ (ie, brain) or cerebrospinal fluid.

Roadblocks to progress. In the absence of this proposed NSD, progress in this area has been stymied despite concerted governmental efforts (Box^7-10). One reason for the lack of progress has been that governmental efforts have focused on a public health model rather than also including a basic science model aimed at exploring the biological mechanisms underlying the risk of death from suicide. In the current decentralized system, individual researchers and even teams of researchers cannot easily collect data from a sufficiently large population of suicide victims to make inroads in gaining the needed understanding.

Because of the relatively small samples that individual research teams can collect in a reasonable period of time (ie, in terms of grant cycles), many investigators have studied suicide attempts as a surrogate for suicide itself, undoubtedly because suicide attempts are more numerous than suicides themselves, making it easier to collect data. However, there is evidence that these 2 populations—suicide attempters vs those who die by suicide—only partially overlap.

First, the frequency of suicide attempts is 10 to 20 times higher than actual suicides. Second, suicide attempters are 3 times more likely to be female whereas those who die by suicide are 4 times more likely to be male. Third, most individuals who die by suicide do so on their first or second attempt, whereas individuals who have made ≥4 attempts have an increased risk of future attempts rather than for completed suicide compared with the general population. Fourth, certain psychiatric illnesses are more often associated with death by suicide (particularly major depressive disorder, bipolar disorder, and schizophrenia in the first 5 years of an illness) whereas multiple suicide attempts are more often associated with other psychiatric diagnoses such as antisocial and borderline personality disorders.

Finally, in a study in men with a psychiatric disorder, Niculescu et al⁵ started with 412 candidate genes and found that 208 were associated with suicidal ideation but not suicide itself, whereas 76 genes were associated with both suicidal ideation and completion. Taken together, this evidence suggests that findings concerning suicide attempters, especially those who have made multiple (ie, >3) attempts, might not be extrapolatable to the population of actual suicides.

Is there evidence that this proposal could work?

Yes, research supports the potential utility of the proposed NSD, and this section highlights some of the major findings from these studies, although this review is not intended to be exhaustive.

First, considerable evidence exists for a biological basis for the risk of death due to suicide. The concordance rates for suicide are 10 times higher in monozygotic (“identical”) vs dizygotic (“fraternal”) twins (24.1% vs 2.8%) and 2 to 5 times higher in relatives of those who die by suicide than in the general population. Heritability estimates of fatal suicides and nonfatal suicide attempts in biological relatives of adoptees who die from suicide range from 17% to 45%.¹¹

Second, studies using information from small samples that was arduously collected by individual research groups have yielded important positive data. Most recently, in 2015, a multidisciplinary group led by Niculescu et al⁵ at Indiana University and other institutions described a test that could predict suicidality in men. This test was developed on the basis of a within-participant discovery approach to identify genes that change in expression between states of no suicidal ideation and high suicidal ideation, which was combined with clinical information assessed by 2 scales, the Convergent Functional Information for Suicidality and the Simplified Affective State Scale. Gene expression was measured in whole blood collected postmortem unless the method of suicide involved a medication overdose that could affect gene expression. These researchers identified 76 genes that likely were involved in suicidal ideation and suicide.

This report had a number of limitations.⁵ All of the individuals in these studies were being treated for psychiatric illness, were being closely followed by the investigators, and all were male. In addition, as noted above, suicides by overdose were eliminated from the analysis.

In a subsequent study published in 2016, the Niculescu group⁶ extended their work to women and identified 50 genes contributing to suicide risk in women. Underscoring the need for larger samples, only 3 of the top contributing genes were seen in both men and women, suggesting that there are likely significant sex differences in the biology of suicide completion. This important work needs to be replicated and extended.

In addition to these remarkable advances made in genetic understanding of the risk of suicide, recent research also has demonstrated a role for epigenetic and inflammatory processes as contributors to suicide risk.^12-15

There are likely many contributors, including genetic, epigenetic, and environmental factors such as inflammatory processes, that increase the risk of suicide. The goal of this article is not to provide an exhaustive or integrative review of research in this area but rather to argue for the establishment of a national initiative to study all of these factors and to begin that process by establishing the NSD.

What will be the foreseeable outcome of this initiative?

The establishment of the NSD is expected to lead to better identification of those who are genetically at increased risk of suicide as well as biological factors (eg, inflammatory or other processes) and environmental factors (eg, drug abuse), which can turn that genetic risk into reality. Using research results made possible by the implementation of this proposal, objective testing can be developed to monitor risk more effectively than is currently possible using clinical assessment alone.

Furthermore, this work also can provide targets for developing new treatments. For example, there is convergence between the work of Niculescu et al,^5,6 who identified genetic biomarkers for mechanistic target of rapamycin (mTOR) signaling as a risk factor in individuals who died by suicide and the work of Li et al and other researchers,^16-18 whose findings have implicated mTOR-dependent synapse formation as a mechanism underlying the rapid (ie, within hours to a couple of days) antidepressant effects of N-methyl-d-aspartate antagonists, such as ketamine, CP-101,606, and esketamine. In fact, the authors of a study presented earlier this year reported that esketamine—an active enantiomer of ketamine—rapidly reduced suicidal ideation as well as other depressive symptoms in individuals admitted to the hospital for suicidal ideation.¹⁹ (mTOR is a serine/threonine protein kinase that regulates a number of biological processes in addition to synaptogenesis, including cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and autophagy.^20,21)

In aggregate, establishment of this proposed database will facilitate identification of biological (and therefore pharmaceutical) mechanisms beyond those involving biogenic amines, which have been the exclusive biological targets for antidepressants for the past 50 years.²² The likely consequences of the findings generated from research made possible by the proposed NSD will open completely new vistas for helping people at risk for suicide and psychiatric illnesses.

What foreseeable obstacles will need to be addressed?

Of course, obstacles and problems will arise but these will not exceed those encountered by the War on Cancer and they can similarly be overcome with sufficient public support and cooperation. Potential obstacles include:

• need for incremental funding
• obtaining the cooperation of the offices of each county medical examiner or coroner in a process that includes uniform systematic data collection
• determining the situations (eg, time after death and means of death) that will allow for meaningful collection of data such as RNA and inflammatory biomarkers
• establishing how data and particularly biological samples will be transported and stored
• issues related to privacy of health information particularly for relatives of suicide victims
• ensuring the reliability, validity, and comparability of the data received from different medical examiners and coroners.

With regard to the last issue, because stigma is associated with death by suicide, some true suicides could be missed, which would compromise sensitivity but simultaneously increase specificity. Other obstacles or problems may arise; however, I am certain that all such issues are surmountable and that the resulting NSD will be much better than what we have now and will propel our understanding of the biological underpinnings of the loss of life to suicide. (The author proposed a similar but even more ambitious plan 25 years ago,²³ but he believes that this is an idea whose time has come.)

Acknowledgments

The author thanks Wayne C. Drevets, MD, Alexander Niculescu, MD, PhD, John Oldman, MD, and John Savitz, PhD, David Sheehan, MD, and Matthew Macaluso, DO for their review and suggestions concerning this proposal/manuscript, and Kaylee Hervey, MPH, from the Sedgwick County Health Department, Wichita, Kansas, for her input. The author also thanks Ruth Ross, as always, for her excellent editing and general assistance.

Suicide is a staggering, tragic, and growing cause of death in the United States. One out of every 62 Americans will die from suicide, based on the national lifetime prevalence rate.¹ More than 42,000 Americans died from suicide in 2014, making suicide the second leading cause of death in individuals age 15 to 34, the fourth leading cause among those age 35 to 54, and the tenth leading cause of death in the country overall.² The incidence of suicide in the general population of the United States increased by 24% between 1999 and 2014.³ This tragedy obviously is not solving itself.

The proposal

U.S. Centers for Disease Control and Prevention (CDC) publishes statistics about the number of suicides, as well as demographic information, collected from coroners and medical examiners across the country. However, these sources do not provide a biological sample that could be used to gather data concerning DNA, RNA, and other potential blood markers, including those reflecting inflammatory and epigenetic processes. However, such biological samples are commonly collected by the U.S. medicolegal death investigation system. In 2003, this system investigated 450,000 unnatural and/or unexplained deaths (ie, approximately 20% of the 2.4 million deaths in the United States that year).⁴

Each unnatural or unexplained death is examined, often extensively, by a coroner or medical examiner. This examination system costs more than $600 million annually. Yet the data that are collected are handled on a case-by-case and often county-by-county basis, rather than in aggregate. The essence of the proposal presented here is to take the information and biological samples collected in this process and put them into a National Suicide Database (NSD), which then can serve as a resource for scientists to increase our understanding of the genetic, epigenetic, and other factors underlying death due to suicide. This increased understanding will result in the development more effective tools to detect to those at risk for suicide (ie, risk factor tests), to monitor treatment, and to develop new treatments based on a better understanding of the underlying pathophysiology and pathogenesis of suicide. These tools will reduce:

• the number of lives lost to suicide
• the pain and suffering of loved ones
• lost productivity to society, especially when one considers that suicide disproportionately affects individuals during the most productive period of their lives (ie, age 15 to 54).

The NSD will be organized as a government–private partnership, with the government represented by the National Institutes of Health (NIH) and/or the CDC. The goal will be to take the information that is currently being collected by the nation’s medicolegal death investigation system, including the biological samples, systematize it, enter it into a common database, and make it available to qualified researchers across the country. The administrative arm of the system will be responsible for ensuring systematic data collection, storage in a searchable and integrated database housed within the NIH and/or the CDC, and vetting researchers who will have access to the data, including those with expertise in genomics, molecular biology, suicide, epidemiology, and data-mining. (Currently, the CDC’s National Violent Death Reporting System, which is a state-based surveillance system, pools data on violent deaths from multiple sources into a usable, anonymous database. These sources include state and local medical examiners, coroners, law enforcement, crime labs, and vital statistics records, but they do not include any biological material even though it is collected [personal correspondence with the CDC, July 2016].)

Because information on suicides currently are handled primarily on a county-by-county basis, data concerning these deaths are not facilitating a better understanding of the causes and strategies for preventing suicide. Correcting this situation is the goal of this proposal, as modeled by the National Cancer Institute’s War on Cancer, which has transformed the treatment and the outcomes of cancer. If this proposal is enacted, the same type of transformation will occur and result in a reduction in the suicide rate and better outcomes for the psychiatric illnesses that underlie most instances of suicide.

The proposed NSD will address a major and common problem for researchers in this area—small sample sizes. When considered from the perspective of the size of samples feasible for most independent research teams to collect and study, suicide on an annual basis is rare—however, that is not the case when the incidence of suicide in the nation as a whole is considered. In contrast to the data concerning suicides that individual research teams can collect, the proposed genomic database will grow by approximately 40,000 individuals every year, until a meaningful reduction in deaths due to suicide is achieved.

From a research perspective, suicide, although tragic, is one of the few binary outcomes in psychiatry—that is, life or death. Although there may be >1 genetic and/or epigenetic contributor to suicide, within a relatively short period of time, the proposed database will amass—and continue to amass on an ongoing basis—data from a large population of suicide victims. Researchers then can compare the findings from this database with the normative human genome, looking for variants that are over-represented in the population of those who have died by suicide.

Environmental factors undoubtedly also contribute to the risk of suicide, given that the incidence of suicide increases with age, particularly among white males, and with the addition of psychiatric and medical comorbidities. Inflammatory processes also have been implicated in the pathophysiology of a number of psychiatric disorders, including major depression, which is the primary psychiatric risk factor for suicide. Therefore, consideration should be given to collecting whole blood samples if the time between death and autopsy is within an appropriate limit to obtain interpretable data concerning RNA (ie, gene expression) and even biomarkers of inflammatory and other processes at the time of the suicide. This approach has been used by Niculescu et al^5,6 for whole blood gene expression. The rationale for using samples of whole blood is that this strategy could be more easily adapted to clinical practice in contrast to using samples from the target organ (ie, brain) or cerebrospinal fluid.

Roadblocks to progress. In the absence of this proposed NSD, progress in this area has been stymied despite concerted governmental efforts (Box^7-10). One reason for the lack of progress has been that governmental efforts have focused on a public health model rather than also including a basic science model aimed at exploring the biological mechanisms underlying the risk of death from suicide. In the current decentralized system, individual researchers and even teams of researchers cannot easily collect data from a sufficiently large population of suicide victims to make inroads in gaining the needed understanding.

Because of the relatively small samples that individual research teams can collect in a reasonable period of time (ie, in terms of grant cycles), many investigators have studied suicide attempts as a surrogate for suicide itself, undoubtedly because suicide attempts are more numerous than suicides themselves, making it easier to collect data. However, there is evidence that these 2 populations—suicide attempters vs those who die by suicide—only partially overlap.

First, the frequency of suicide attempts is 10 to 20 times higher than actual suicides. Second, suicide attempters are 3 times more likely to be female whereas those who die by suicide are 4 times more likely to be male. Third, most individuals who die by suicide do so on their first or second attempt, whereas individuals who have made ≥4 attempts have an increased risk of future attempts rather than for completed suicide compared with the general population. Fourth, certain psychiatric illnesses are more often associated with death by suicide (particularly major depressive disorder, bipolar disorder, and schizophrenia in the first 5 years of an illness) whereas multiple suicide attempts are more often associated with other psychiatric diagnoses such as antisocial and borderline personality disorders.

Finally, in a study in men with a psychiatric disorder, Niculescu et al⁵ started with 412 candidate genes and found that 208 were associated with suicidal ideation but not suicide itself, whereas 76 genes were associated with both suicidal ideation and completion. Taken together, this evidence suggests that findings concerning suicide attempters, especially those who have made multiple (ie, >3) attempts, might not be extrapolatable to the population of actual suicides.

Is there evidence that this proposal could work?

Yes, research supports the potential utility of the proposed NSD, and this section highlights some of the major findings from these studies, although this review is not intended to be exhaustive.

First, considerable evidence exists for a biological basis for the risk of death due to suicide. The concordance rates for suicide are 10 times higher in monozygotic (“identical”) vs dizygotic (“fraternal”) twins (24.1% vs 2.8%) and 2 to 5 times higher in relatives of those who die by suicide than in the general population. Heritability estimates of fatal suicides and nonfatal suicide attempts in biological relatives of adoptees who die from suicide range from 17% to 45%.¹¹

Second, studies using information from small samples that was arduously collected by individual research groups have yielded important positive data. Most recently, in 2015, a multidisciplinary group led by Niculescu et al⁵ at Indiana University and other institutions described a test that could predict suicidality in men. This test was developed on the basis of a within-participant discovery approach to identify genes that change in expression between states of no suicidal ideation and high suicidal ideation, which was combined with clinical information assessed by 2 scales, the Convergent Functional Information for Suicidality and the Simplified Affective State Scale. Gene expression was measured in whole blood collected postmortem unless the method of suicide involved a medication overdose that could affect gene expression. These researchers identified 76 genes that likely were involved in suicidal ideation and suicide.

This report had a number of limitations.⁵ All of the individuals in these studies were being treated for psychiatric illness, were being closely followed by the investigators, and all were male. In addition, as noted above, suicides by overdose were eliminated from the analysis.

In a subsequent study published in 2016, the Niculescu group⁶ extended their work to women and identified 50 genes contributing to suicide risk in women. Underscoring the need for larger samples, only 3 of the top contributing genes were seen in both men and women, suggesting that there are likely significant sex differences in the biology of suicide completion. This important work needs to be replicated and extended.

In addition to these remarkable advances made in genetic understanding of the risk of suicide, recent research also has demonstrated a role for epigenetic and inflammatory processes as contributors to suicide risk.^12-15

There are likely many contributors, including genetic, epigenetic, and environmental factors such as inflammatory processes, that increase the risk of suicide. The goal of this article is not to provide an exhaustive or integrative review of research in this area but rather to argue for the establishment of a national initiative to study all of these factors and to begin that process by establishing the NSD.

What will be the foreseeable outcome of this initiative?

The establishment of the NSD is expected to lead to better identification of those who are genetically at increased risk of suicide as well as biological factors (eg, inflammatory or other processes) and environmental factors (eg, drug abuse), which can turn that genetic risk into reality. Using research results made possible by the implementation of this proposal, objective testing can be developed to monitor risk more effectively than is currently possible using clinical assessment alone.

Furthermore, this work also can provide targets for developing new treatments. For example, there is convergence between the work of Niculescu et al,^5,6 who identified genetic biomarkers for mechanistic target of rapamycin (mTOR) signaling as a risk factor in individuals who died by suicide and the work of Li et al and other researchers,^16-18 whose findings have implicated mTOR-dependent synapse formation as a mechanism underlying the rapid (ie, within hours to a couple of days) antidepressant effects of N-methyl-d-aspartate antagonists, such as ketamine, CP-101,606, and esketamine. In fact, the authors of a study presented earlier this year reported that esketamine—an active enantiomer of ketamine—rapidly reduced suicidal ideation as well as other depressive symptoms in individuals admitted to the hospital for suicidal ideation.¹⁹ (mTOR is a serine/threonine protein kinase that regulates a number of biological processes in addition to synaptogenesis, including cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and autophagy.^20,21)

In aggregate, establishment of this proposed database will facilitate identification of biological (and therefore pharmaceutical) mechanisms beyond those involving biogenic amines, which have been the exclusive biological targets for antidepressants for the past 50 years.²² The likely consequences of the findings generated from research made possible by the proposed NSD will open completely new vistas for helping people at risk for suicide and psychiatric illnesses.

What foreseeable obstacles will need to be addressed?

Of course, obstacles and problems will arise but these will not exceed those encountered by the War on Cancer and they can similarly be overcome with sufficient public support and cooperation. Potential obstacles include:

• need for incremental funding
• obtaining the cooperation of the offices of each county medical examiner or coroner in a process that includes uniform systematic data collection
• determining the situations (eg, time after death and means of death) that will allow for meaningful collection of data such as RNA and inflammatory biomarkers
• establishing how data and particularly biological samples will be transported and stored
• issues related to privacy of health information particularly for relatives of suicide victims
• ensuring the reliability, validity, and comparability of the data received from different medical examiners and coroners.

With regard to the last issue, because stigma is associated with death by suicide, some true suicides could be missed, which would compromise sensitivity but simultaneously increase specificity. Other obstacles or problems may arise; however, I am certain that all such issues are surmountable and that the resulting NSD will be much better than what we have now and will propel our understanding of the biological underpinnings of the loss of life to suicide. (The author proposed a similar but even more ambitious plan 25 years ago,²³ but he believes that this is an idea whose time has come.)

Acknowledgments

The author thanks Wayne C. Drevets, MD, Alexander Niculescu, MD, PhD, John Oldman, MD, and John Savitz, PhD, David Sheehan, MD, and Matthew Macaluso, DO for their review and suggestions concerning this proposal/manuscript, and Kaylee Hervey, MPH, from the Sedgwick County Health Department, Wichita, Kansas, for her input. The author also thanks Ruth Ross, as always, for her excellent editing and general assistance.

Suicide is a staggering, tragic, and growing cause of death in the United States. One out of every 62 Americans will die from suicide, based on the national lifetime prevalence rate.¹ More than 42,000 Americans died from suicide in 2014, making suicide the second leading cause of death in individuals age 15 to 34, the fourth leading cause among those age 35 to 54, and the tenth leading cause of death in the country overall.² The incidence of suicide in the general population of the United States increased by 24% between 1999 and 2014.³ This tragedy obviously is not solving itself.

The proposal

U.S. Centers for Disease Control and Prevention (CDC) publishes statistics about the number of suicides, as well as demographic information, collected from coroners and medical examiners across the country. However, these sources do not provide a biological sample that could be used to gather data concerning DNA, RNA, and other potential blood markers, including those reflecting inflammatory and epigenetic processes. However, such biological samples are commonly collected by the U.S. medicolegal death investigation system. In 2003, this system investigated 450,000 unnatural and/or unexplained deaths (ie, approximately 20% of the 2.4 million deaths in the United States that year).⁴

Each unnatural or unexplained death is examined, often extensively, by a coroner or medical examiner. This examination system costs more than $600 million annually. Yet the data that are collected are handled on a case-by-case and often county-by-county basis, rather than in aggregate. The essence of the proposal presented here is to take the information and biological samples collected in this process and put them into a National Suicide Database (NSD), which then can serve as a resource for scientists to increase our understanding of the genetic, epigenetic, and other factors underlying death due to suicide. This increased understanding will result in the development more effective tools to detect to those at risk for suicide (ie, risk factor tests), to monitor treatment, and to develop new treatments based on a better understanding of the underlying pathophysiology and pathogenesis of suicide. These tools will reduce:

• the number of lives lost to suicide
• the pain and suffering of loved ones
• lost productivity to society, especially when one considers that suicide disproportionately affects individuals during the most productive period of their lives (ie, age 15 to 54).

The NSD will be organized as a government–private partnership, with the government represented by the National Institutes of Health (NIH) and/or the CDC. The goal will be to take the information that is currently being collected by the nation’s medicolegal death investigation system, including the biological samples, systematize it, enter it into a common database, and make it available to qualified researchers across the country. The administrative arm of the system will be responsible for ensuring systematic data collection, storage in a searchable and integrated database housed within the NIH and/or the CDC, and vetting researchers who will have access to the data, including those with expertise in genomics, molecular biology, suicide, epidemiology, and data-mining. (Currently, the CDC’s National Violent Death Reporting System, which is a state-based surveillance system, pools data on violent deaths from multiple sources into a usable, anonymous database. These sources include state and local medical examiners, coroners, law enforcement, crime labs, and vital statistics records, but they do not include any biological material even though it is collected [personal correspondence with the CDC, July 2016].)

Because information on suicides currently are handled primarily on a county-by-county basis, data concerning these deaths are not facilitating a better understanding of the causes and strategies for preventing suicide. Correcting this situation is the goal of this proposal, as modeled by the National Cancer Institute’s War on Cancer, which has transformed the treatment and the outcomes of cancer. If this proposal is enacted, the same type of transformation will occur and result in a reduction in the suicide rate and better outcomes for the psychiatric illnesses that underlie most instances of suicide.

The proposed NSD will address a major and common problem for researchers in this area—small sample sizes. When considered from the perspective of the size of samples feasible for most independent research teams to collect and study, suicide on an annual basis is rare—however, that is not the case when the incidence of suicide in the nation as a whole is considered. In contrast to the data concerning suicides that individual research teams can collect, the proposed genomic database will grow by approximately 40,000 individuals every year, until a meaningful reduction in deaths due to suicide is achieved.

From a research perspective, suicide, although tragic, is one of the few binary outcomes in psychiatry—that is, life or death. Although there may be >1 genetic and/or epigenetic contributor to suicide, within a relatively short period of time, the proposed database will amass—and continue to amass on an ongoing basis—data from a large population of suicide victims. Researchers then can compare the findings from this database with the normative human genome, looking for variants that are over-represented in the population of those who have died by suicide.

Environmental factors undoubtedly also contribute to the risk of suicide, given that the incidence of suicide increases with age, particularly among white males, and with the addition of psychiatric and medical comorbidities. Inflammatory processes also have been implicated in the pathophysiology of a number of psychiatric disorders, including major depression, which is the primary psychiatric risk factor for suicide. Therefore, consideration should be given to collecting whole blood samples if the time between death and autopsy is within an appropriate limit to obtain interpretable data concerning RNA (ie, gene expression) and even biomarkers of inflammatory and other processes at the time of the suicide. This approach has been used by Niculescu et al^5,6 for whole blood gene expression. The rationale for using samples of whole blood is that this strategy could be more easily adapted to clinical practice in contrast to using samples from the target organ (ie, brain) or cerebrospinal fluid.

Roadblocks to progress. In the absence of this proposed NSD, progress in this area has been stymied despite concerted governmental efforts (Box^7-10). One reason for the lack of progress has been that governmental efforts have focused on a public health model rather than also including a basic science model aimed at exploring the biological mechanisms underlying the risk of death from suicide. In the current decentralized system, individual researchers and even teams of researchers cannot easily collect data from a sufficiently large population of suicide victims to make inroads in gaining the needed understanding.

Because of the relatively small samples that individual research teams can collect in a reasonable period of time (ie, in terms of grant cycles), many investigators have studied suicide attempts as a surrogate for suicide itself, undoubtedly because suicide attempts are more numerous than suicides themselves, making it easier to collect data. However, there is evidence that these 2 populations—suicide attempters vs those who die by suicide—only partially overlap.

First, the frequency of suicide attempts is 10 to 20 times higher than actual suicides. Second, suicide attempters are 3 times more likely to be female whereas those who die by suicide are 4 times more likely to be male. Third, most individuals who die by suicide do so on their first or second attempt, whereas individuals who have made ≥4 attempts have an increased risk of future attempts rather than for completed suicide compared with the general population. Fourth, certain psychiatric illnesses are more often associated with death by suicide (particularly major depressive disorder, bipolar disorder, and schizophrenia in the first 5 years of an illness) whereas multiple suicide attempts are more often associated with other psychiatric diagnoses such as antisocial and borderline personality disorders.

Finally, in a study in men with a psychiatric disorder, Niculescu et al⁵ started with 412 candidate genes and found that 208 were associated with suicidal ideation but not suicide itself, whereas 76 genes were associated with both suicidal ideation and completion. Taken together, this evidence suggests that findings concerning suicide attempters, especially those who have made multiple (ie, >3) attempts, might not be extrapolatable to the population of actual suicides.

Is there evidence that this proposal could work?

Yes, research supports the potential utility of the proposed NSD, and this section highlights some of the major findings from these studies, although this review is not intended to be exhaustive.

First, considerable evidence exists for a biological basis for the risk of death due to suicide. The concordance rates for suicide are 10 times higher in monozygotic (“identical”) vs dizygotic (“fraternal”) twins (24.1% vs 2.8%) and 2 to 5 times higher in relatives of those who die by suicide than in the general population. Heritability estimates of fatal suicides and nonfatal suicide attempts in biological relatives of adoptees who die from suicide range from 17% to 45%.¹¹

Second, studies using information from small samples that was arduously collected by individual research groups have yielded important positive data. Most recently, in 2015, a multidisciplinary group led by Niculescu et al⁵ at Indiana University and other institutions described a test that could predict suicidality in men. This test was developed on the basis of a within-participant discovery approach to identify genes that change in expression between states of no suicidal ideation and high suicidal ideation, which was combined with clinical information assessed by 2 scales, the Convergent Functional Information for Suicidality and the Simplified Affective State Scale. Gene expression was measured in whole blood collected postmortem unless the method of suicide involved a medication overdose that could affect gene expression. These researchers identified 76 genes that likely were involved in suicidal ideation and suicide.

This report had a number of limitations.⁵ All of the individuals in these studies were being treated for psychiatric illness, were being closely followed by the investigators, and all were male. In addition, as noted above, suicides by overdose were eliminated from the analysis.

In a subsequent study published in 2016, the Niculescu group⁶ extended their work to women and identified 50 genes contributing to suicide risk in women. Underscoring the need for larger samples, only 3 of the top contributing genes were seen in both men and women, suggesting that there are likely significant sex differences in the biology of suicide completion. This important work needs to be replicated and extended.

In addition to these remarkable advances made in genetic understanding of the risk of suicide, recent research also has demonstrated a role for epigenetic and inflammatory processes as contributors to suicide risk.^12-15

There are likely many contributors, including genetic, epigenetic, and environmental factors such as inflammatory processes, that increase the risk of suicide. The goal of this article is not to provide an exhaustive or integrative review of research in this area but rather to argue for the establishment of a national initiative to study all of these factors and to begin that process by establishing the NSD.

What will be the foreseeable outcome of this initiative?

The establishment of the NSD is expected to lead to better identification of those who are genetically at increased risk of suicide as well as biological factors (eg, inflammatory or other processes) and environmental factors (eg, drug abuse), which can turn that genetic risk into reality. Using research results made possible by the implementation of this proposal, objective testing can be developed to monitor risk more effectively than is currently possible using clinical assessment alone.

Furthermore, this work also can provide targets for developing new treatments. For example, there is convergence between the work of Niculescu et al,^5,6 who identified genetic biomarkers for mechanistic target of rapamycin (mTOR) signaling as a risk factor in individuals who died by suicide and the work of Li et al and other researchers,^16-18 whose findings have implicated mTOR-dependent synapse formation as a mechanism underlying the rapid (ie, within hours to a couple of days) antidepressant effects of N-methyl-d-aspartate antagonists, such as ketamine, CP-101,606, and esketamine. In fact, the authors of a study presented earlier this year reported that esketamine—an active enantiomer of ketamine—rapidly reduced suicidal ideation as well as other depressive symptoms in individuals admitted to the hospital for suicidal ideation.¹⁹ (mTOR is a serine/threonine protein kinase that regulates a number of biological processes in addition to synaptogenesis, including cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and autophagy.^20,21)

In aggregate, establishment of this proposed database will facilitate identification of biological (and therefore pharmaceutical) mechanisms beyond those involving biogenic amines, which have been the exclusive biological targets for antidepressants for the past 50 years.²² The likely consequences of the findings generated from research made possible by the proposed NSD will open completely new vistas for helping people at risk for suicide and psychiatric illnesses.

What foreseeable obstacles will need to be addressed?

Of course, obstacles and problems will arise but these will not exceed those encountered by the War on Cancer and they can similarly be overcome with sufficient public support and cooperation. Potential obstacles include:

• need for incremental funding
• obtaining the cooperation of the offices of each county medical examiner or coroner in a process that includes uniform systematic data collection
• determining the situations (eg, time after death and means of death) that will allow for meaningful collection of data such as RNA and inflammatory biomarkers
• establishing how data and particularly biological samples will be transported and stored
• issues related to privacy of health information particularly for relatives of suicide victims
• ensuring the reliability, validity, and comparability of the data received from different medical examiners and coroners.

With regard to the last issue, because stigma is associated with death by suicide, some true suicides could be missed, which would compromise sensitivity but simultaneously increase specificity. Other obstacles or problems may arise; however, I am certain that all such issues are surmountable and that the resulting NSD will be much better than what we have now and will propel our understanding of the biological underpinnings of the loss of life to suicide. (The author proposed a similar but even more ambitious plan 25 years ago,²³ but he believes that this is an idea whose time has come.)

Acknowledgments

The author thanks Wayne C. Drevets, MD, Alexander Niculescu, MD, PhD, John Oldman, MD, and John Savitz, PhD, David Sheehan, MD, and Matthew Macaluso, DO for their review and suggestions concerning this proposal/manuscript, and Kaylee Hervey, MPH, from the Sedgwick County Health Department, Wichita, Kansas, for her input. The author also thanks Ruth Ross, as always, for her excellent editing and general assistance.

This implies early senescence, segmental aging, and, in young adult patients, premature onset of multi-system medical illnesses associated with aging, including cardiovascular disease, cancer, brain atrophy, and cognitive decline. This might be the real reason why persons with schizophrenia die 25 to 30 years too early, not only because of an unhealthy lifestyle and iatrogenic cardio-metabolic adverse effects.

One of the most consistent observations pointing to accelerated aging in schizophrenia is shortened telomeres.^2,3 Telomeres are the terminal part of chromosomes (similar to the plastic aglets of shoelaces), which are known to shorten with each cell division because of “end replication losses.” Telomeres are measured in lymphocytes, which researchers regard as “windows to the brain” because they reflect brain aging.⁴ One study of lymphocytes in patients with schizophrenia found that they appear to be approximately 25 years older than the lymphocytes of healthy individuals!⁴

Possible causes of accelerated aging

Inflammation. The leading hypothesis for accelerated aging in schizophrenia is based on the inflammatory theory of aging. Schizophrenia has been strongly linked to immune dysregulation and neuroinflammation.⁵ Other components of the accelerated aging hypothesis include oxidative and nitrosative stress, which is associated with high levels of free radicals, and, importantly, mitochondrial dysfunction that fails to generate antioxidants (glutathione peroxidase, superoxide dismutase, and catalase) that can neutralize free radicals and reverse oxidative stress, as numerous studies have shown.

Clinically, and at a relatively young age, persons with schizophrenia show many physical features consistent with aging,⁶ including the following system changes:

• CNS: dilated ventricles, reduced brain volume and gray matter volume; hypofrontality, neurocognitive deficits such as executive functioning, working memory, and attention; neurophysiologic (low amplitudes on evoked potentials)
• Musculoskeletal system: abnormalities in muscle fibers; altered nerve conduction velocity; reduced bone density
• Skin: aging skin
• Eyes: increased rate of cataracts (not caused by medications); degradation in motion discrimination
• Endocrine system: abnormal gonadal hormones; low estrogen; low androgen; thyroid dysfunction, elevated cortisol
• Metabolism: increased rates of obesity; glucose dysregulation even before antipsychotic treatment; increased insulin resistance; abnormal glucose tolerance; reduced insulin-like growth factor-1 levels
• Immune system: increased pro-inflammatory cytokines (interleukin [IL]-1B, IL-6, IL-3, IL-4, IL-10, IL-13, tumor necrosis factor-Symbol Stdα) and decrease in anti-inflammatory cytokines (IL-2, interferon [INF]-Symbol Stdα, INF-Symbol Stdγ) and vitamin D
• Cardiovascular: systolic hypertension, increased pulse pressure
• Oxidative stress and mitochondrial dysfunction: increase in reactive oxygen species in brain tissue and increased DNA and RNA oxidation markers
• Telomere dynamics: significantly higher rates of telomere loss.

The mitochondrial theory of aging.⁷ The origin of this theory dates back to the landmark work of Denham Harman more than 2 decades ago in which he proposed a connection between free radicals and aging, which is associated with cell mutations and cancer.⁸ He suggested that because mitochondrial DNA is not protected by histones as DNA in the nucleus is, it might be the main target for free radicals, making the mitochondria more susceptible to oxidative damage. Therefore, it is possible that the high oxidative stress of schizophrenia could contribute to mitochondrial dysfunction, which leads to further telomere erosion.⁹ Perhaps reducing oxidative stress in schizophrenia with a powerful antioxidant, such as the supplement N-acetylcysteine,¹⁰ could help repair the dysfunctional mitochondria found in patients with schizophrenia and might mitigate accelerated aging.

I would like to propose a bolder, even radical, “out-of-the-box” therapeutic strategy for accelerated aging: mitochondrial transplantation. In fact, “mitochondrial donation” and transplant has been performed on fetuses with genetically defective mitochondria, which has prevented rapid death after birth.¹¹

Similarities with progeria. The accumulating evidence for accelerated aging in schizophrenia has promoted some researchers to consider it a form of progeria¹² because of the accelerated aging features that patients with schizophrenia manifest. Patients with schizophrenia share some risk factors with patients with progeria, including high paternal age, prenatal stress, prenatal famine, low birth weight, and premature cognitive decline. Both progeria and schizophrenia are associated with increased apoptosis and cell senescence, which could reduce the risk of cancer but result in premature aging along with age-related medical disorders that lead to mortality in the elderly.

This is why collaborative care between psychiatrists and primary care providers is so vital for patients with schizophrenia from the onset of the illness during the teens and young adulthood, not after years of treatment and unhealthy lifestyle habits (smoking, sedentary living, high-fat and high-calorie diet), which add insult to injury, culminating in loss of 25 to 30 years of potential life. Preventative medical care starting when schizophrenia is first diagnosed is vital, in addition to comprehensive psychiatric care, because premature mortality is the worst outcome in medicine.

Henry A. Nasrallah, MD

Editor-in-Chief

This implies early senescence, segmental aging, and, in young adult patients, premature onset of multi-system medical illnesses associated with aging, including cardiovascular disease, cancer, brain atrophy, and cognitive decline. This might be the real reason why persons with schizophrenia die 25 to 30 years too early, not only because of an unhealthy lifestyle and iatrogenic cardio-metabolic adverse effects.

One of the most consistent observations pointing to accelerated aging in schizophrenia is shortened telomeres.^2,3 Telomeres are the terminal part of chromosomes (similar to the plastic aglets of shoelaces), which are known to shorten with each cell division because of “end replication losses.” Telomeres are measured in lymphocytes, which researchers regard as “windows to the brain” because they reflect brain aging.⁴ One study of lymphocytes in patients with schizophrenia found that they appear to be approximately 25 years older than the lymphocytes of healthy individuals!⁴

Possible causes of accelerated aging

Inflammation. The leading hypothesis for accelerated aging in schizophrenia is based on the inflammatory theory of aging. Schizophrenia has been strongly linked to immune dysregulation and neuroinflammation.⁵ Other components of the accelerated aging hypothesis include oxidative and nitrosative stress, which is associated with high levels of free radicals, and, importantly, mitochondrial dysfunction that fails to generate antioxidants (glutathione peroxidase, superoxide dismutase, and catalase) that can neutralize free radicals and reverse oxidative stress, as numerous studies have shown.

Clinically, and at a relatively young age, persons with schizophrenia show many physical features consistent with aging,⁶ including the following system changes:

• CNS: dilated ventricles, reduced brain volume and gray matter volume; hypofrontality, neurocognitive deficits such as executive functioning, working memory, and attention; neurophysiologic (low amplitudes on evoked potentials)
• Musculoskeletal system: abnormalities in muscle fibers; altered nerve conduction velocity; reduced bone density
• Skin: aging skin
• Eyes: increased rate of cataracts (not caused by medications); degradation in motion discrimination
• Endocrine system: abnormal gonadal hormones; low estrogen; low androgen; thyroid dysfunction, elevated cortisol
• Metabolism: increased rates of obesity; glucose dysregulation even before antipsychotic treatment; increased insulin resistance; abnormal glucose tolerance; reduced insulin-like growth factor-1 levels
• Immune system: increased pro-inflammatory cytokines (interleukin [IL]-1B, IL-6, IL-3, IL-4, IL-10, IL-13, tumor necrosis factor-Symbol Stdα) and decrease in anti-inflammatory cytokines (IL-2, interferon [INF]-Symbol Stdα, INF-Symbol Stdγ) and vitamin D
• Cardiovascular: systolic hypertension, increased pulse pressure
• Oxidative stress and mitochondrial dysfunction: increase in reactive oxygen species in brain tissue and increased DNA and RNA oxidation markers
• Telomere dynamics: significantly higher rates of telomere loss.

The mitochondrial theory of aging.⁷ The origin of this theory dates back to the landmark work of Denham Harman more than 2 decades ago in which he proposed a connection between free radicals and aging, which is associated with cell mutations and cancer.⁸ He suggested that because mitochondrial DNA is not protected by histones as DNA in the nucleus is, it might be the main target for free radicals, making the mitochondria more susceptible to oxidative damage. Therefore, it is possible that the high oxidative stress of schizophrenia could contribute to mitochondrial dysfunction, which leads to further telomere erosion.⁹ Perhaps reducing oxidative stress in schizophrenia with a powerful antioxidant, such as the supplement N-acetylcysteine,¹⁰ could help repair the dysfunctional mitochondria found in patients with schizophrenia and might mitigate accelerated aging.

I would like to propose a bolder, even radical, “out-of-the-box” therapeutic strategy for accelerated aging: mitochondrial transplantation. In fact, “mitochondrial donation” and transplant has been performed on fetuses with genetically defective mitochondria, which has prevented rapid death after birth.¹¹

Similarities with progeria. The accumulating evidence for accelerated aging in schizophrenia has promoted some researchers to consider it a form of progeria¹² because of the accelerated aging features that patients with schizophrenia manifest. Patients with schizophrenia share some risk factors with patients with progeria, including high paternal age, prenatal stress, prenatal famine, low birth weight, and premature cognitive decline. Both progeria and schizophrenia are associated with increased apoptosis and cell senescence, which could reduce the risk of cancer but result in premature aging along with age-related medical disorders that lead to mortality in the elderly.

This is why collaborative care between psychiatrists and primary care providers is so vital for patients with schizophrenia from the onset of the illness during the teens and young adulthood, not after years of treatment and unhealthy lifestyle habits (smoking, sedentary living, high-fat and high-calorie diet), which add insult to injury, culminating in loss of 25 to 30 years of potential life. Preventative medical care starting when schizophrenia is first diagnosed is vital, in addition to comprehensive psychiatric care, because premature mortality is the worst outcome in medicine.

Henry A. Nasrallah, MD

Editor-in-Chief

This implies early senescence, segmental aging, and, in young adult patients, premature onset of multi-system medical illnesses associated with aging, including cardiovascular disease, cancer, brain atrophy, and cognitive decline. This might be the real reason why persons with schizophrenia die 25 to 30 years too early, not only because of an unhealthy lifestyle and iatrogenic cardio-metabolic adverse effects.

One of the most consistent observations pointing to accelerated aging in schizophrenia is shortened telomeres.^2,3 Telomeres are the terminal part of chromosomes (similar to the plastic aglets of shoelaces), which are known to shorten with each cell division because of “end replication losses.” Telomeres are measured in lymphocytes, which researchers regard as “windows to the brain” because they reflect brain aging.⁴ One study of lymphocytes in patients with schizophrenia found that they appear to be approximately 25 years older than the lymphocytes of healthy individuals!⁴

Possible causes of accelerated aging

Inflammation. The leading hypothesis for accelerated aging in schizophrenia is based on the inflammatory theory of aging. Schizophrenia has been strongly linked to immune dysregulation and neuroinflammation.⁵ Other components of the accelerated aging hypothesis include oxidative and nitrosative stress, which is associated with high levels of free radicals, and, importantly, mitochondrial dysfunction that fails to generate antioxidants (glutathione peroxidase, superoxide dismutase, and catalase) that can neutralize free radicals and reverse oxidative stress, as numerous studies have shown.

Clinically, and at a relatively young age, persons with schizophrenia show many physical features consistent with aging,⁶ including the following system changes:

• CNS: dilated ventricles, reduced brain volume and gray matter volume; hypofrontality, neurocognitive deficits such as executive functioning, working memory, and attention; neurophysiologic (low amplitudes on evoked potentials)
• Musculoskeletal system: abnormalities in muscle fibers; altered nerve conduction velocity; reduced bone density
• Skin: aging skin
• Eyes: increased rate of cataracts (not caused by medications); degradation in motion discrimination
• Endocrine system: abnormal gonadal hormones; low estrogen; low androgen; thyroid dysfunction, elevated cortisol
• Metabolism: increased rates of obesity; glucose dysregulation even before antipsychotic treatment; increased insulin resistance; abnormal glucose tolerance; reduced insulin-like growth factor-1 levels
• Immune system: increased pro-inflammatory cytokines (interleukin [IL]-1B, IL-6, IL-3, IL-4, IL-10, IL-13, tumor necrosis factor-Symbol Stdα) and decrease in anti-inflammatory cytokines (IL-2, interferon [INF]-Symbol Stdα, INF-Symbol Stdγ) and vitamin D
• Cardiovascular: systolic hypertension, increased pulse pressure
• Oxidative stress and mitochondrial dysfunction: increase in reactive oxygen species in brain tissue and increased DNA and RNA oxidation markers
• Telomere dynamics: significantly higher rates of telomere loss.

The mitochondrial theory of aging.⁷ The origin of this theory dates back to the landmark work of Denham Harman more than 2 decades ago in which he proposed a connection between free radicals and aging, which is associated with cell mutations and cancer.⁸ He suggested that because mitochondrial DNA is not protected by histones as DNA in the nucleus is, it might be the main target for free radicals, making the mitochondria more susceptible to oxidative damage. Therefore, it is possible that the high oxidative stress of schizophrenia could contribute to mitochondrial dysfunction, which leads to further telomere erosion.⁹ Perhaps reducing oxidative stress in schizophrenia with a powerful antioxidant, such as the supplement N-acetylcysteine,¹⁰ could help repair the dysfunctional mitochondria found in patients with schizophrenia and might mitigate accelerated aging.

I would like to propose a bolder, even radical, “out-of-the-box” therapeutic strategy for accelerated aging: mitochondrial transplantation. In fact, “mitochondrial donation” and transplant has been performed on fetuses with genetically defective mitochondria, which has prevented rapid death after birth.¹¹

Similarities with progeria. The accumulating evidence for accelerated aging in schizophrenia has promoted some researchers to consider it a form of progeria¹² because of the accelerated aging features that patients with schizophrenia manifest. Patients with schizophrenia share some risk factors with patients with progeria, including high paternal age, prenatal stress, prenatal famine, low birth weight, and premature cognitive decline. Both progeria and schizophrenia are associated with increased apoptosis and cell senescence, which could reduce the risk of cancer but result in premature aging along with age-related medical disorders that lead to mortality in the elderly.

This is why collaborative care between psychiatrists and primary care providers is so vital for patients with schizophrenia from the onset of the illness during the teens and young adulthood, not after years of treatment and unhealthy lifestyle habits (smoking, sedentary living, high-fat and high-calorie diet), which add insult to injury, culminating in loss of 25 to 30 years of potential life. Preventative medical care starting when schizophrenia is first diagnosed is vital, in addition to comprehensive psychiatric care, because premature mortality is the worst outcome in medicine.

Henry A. Nasrallah, MD

Editor-in-Chief

Catatonia is a neuropsychiatric condition with varying presentations that involve behavioral, motoric, cognitive, affective, and, occasionally, autonomic disturbances. Underlying causes of the syndrome include:

• mood disorders
• psychotic disorders
• neurologic disease
• general medical conditions
• metabolic abnormalities
• drug intoxication or withdrawal.

• deep vein thrombosis and pulmonary embolism
• pressure sores or ulcers
• muscle contractures
• nutritional deficiencies and dehydration from decreased oral intake.¹

Prompt recognition, assessment, and treatment are vital.

We recommend the following systematic approach to evaluate and treat catatonia (Table).

Assess

Appropriate assessment of catatonia requires recognition of the array of potential underlying causes of the syndrome.

Obtain a complete history, including:

• recent changes in behavior
• past psychiatric illness and hospitalization
• past or current neurologic or medical disease
• prescription and illicit drug use.

Collateral informants, such as family members and caregivers, could provide valuable information. This history could reveal causative factors and identify appropriate targets for treatment.

Physical and mental status examinations can help characterize the type and severity of motoric and behavioral symptoms, such as rigidity, waxy flexibility, negativism, automatic obedience, ambitendency, and perseveration. Monitoring vital signs is crucial because of the risk of medical complications and malignant catatonia, which can be lethal if not treated.

Laboratory testing and imaging might be indicated to rule out medical causes, such as infection, metabolic disturbances, drug intoxication and withdrawal, and acute neurologic etiologies.

Identify and rate symptom severity. After determining that a patient has catatonia, consider using a standardized instrument, such as the Bush Francis Catatonia Rating Scale (BFCRS),² to assess the patient’s type of symptoms and degree of impairment. Scores obtained on such instruments can be tracked as the patient receives treatment. Although the BFCRS is imperfect because of ambiguous symptom descriptions and because symptoms can remain after effective treatment, it is the most widely researched catatonia scale.

Treat and monitor

Although there are no published data from large-scale, randomized, controlled trials, clinical experience shows that the mainstays of treatment still are benzodiazepines and electroconvulsive therapy (ECT). A benzodiazepine challenge of IV lorazepam, 2 mg, can lead to rapid, substantial symptomatic relief with relatively low risk of harm. An estimated 50% to 70% of patients with catatonia respond within 5 days to IV lorazepam, 2 mg, every 3 to 8 hours.³

When patients do not respond to benzodiazepines, consider ECT. For patients with medical, neurologic, and toxic metabolic causes of catatonia, treat the underlying disturbance first.

Catatonia is a neuropsychiatric condition with varying presentations that involve behavioral, motoric, cognitive, affective, and, occasionally, autonomic disturbances. Underlying causes of the syndrome include:

• mood disorders
• psychotic disorders
• neurologic disease
• general medical conditions
• metabolic abnormalities
• drug intoxication or withdrawal.

• deep vein thrombosis and pulmonary embolism
• pressure sores or ulcers
• muscle contractures
• nutritional deficiencies and dehydration from decreased oral intake.¹

Prompt recognition, assessment, and treatment are vital.

We recommend the following systematic approach to evaluate and treat catatonia (Table).

Assess

Appropriate assessment of catatonia requires recognition of the array of potential underlying causes of the syndrome.

Obtain a complete history, including:

• recent changes in behavior
• past psychiatric illness and hospitalization
• past or current neurologic or medical disease
• prescription and illicit drug use.

Collateral informants, such as family members and caregivers, could provide valuable information. This history could reveal causative factors and identify appropriate targets for treatment.

Physical and mental status examinations can help characterize the type and severity of motoric and behavioral symptoms, such as rigidity, waxy flexibility, negativism, automatic obedience, ambitendency, and perseveration. Monitoring vital signs is crucial because of the risk of medical complications and malignant catatonia, which can be lethal if not treated.

Laboratory testing and imaging might be indicated to rule out medical causes, such as infection, metabolic disturbances, drug intoxication and withdrawal, and acute neurologic etiologies.

Identify and rate symptom severity. After determining that a patient has catatonia, consider using a standardized instrument, such as the Bush Francis Catatonia Rating Scale (BFCRS),² to assess the patient’s type of symptoms and degree of impairment. Scores obtained on such instruments can be tracked as the patient receives treatment. Although the BFCRS is imperfect because of ambiguous symptom descriptions and because symptoms can remain after effective treatment, it is the most widely researched catatonia scale.

Treat and monitor

Although there are no published data from large-scale, randomized, controlled trials, clinical experience shows that the mainstays of treatment still are benzodiazepines and electroconvulsive therapy (ECT). A benzodiazepine challenge of IV lorazepam, 2 mg, can lead to rapid, substantial symptomatic relief with relatively low risk of harm. An estimated 50% to 70% of patients with catatonia respond within 5 days to IV lorazepam, 2 mg, every 3 to 8 hours.³

When patients do not respond to benzodiazepines, consider ECT. For patients with medical, neurologic, and toxic metabolic causes of catatonia, treat the underlying disturbance first.

Catatonia is a neuropsychiatric condition with varying presentations that involve behavioral, motoric, cognitive, affective, and, occasionally, autonomic disturbances. Underlying causes of the syndrome include:

• mood disorders
• psychotic disorders
• neurologic disease
• general medical conditions
• metabolic abnormalities
• drug intoxication or withdrawal.

• deep vein thrombosis and pulmonary embolism
• pressure sores or ulcers
• muscle contractures
• nutritional deficiencies and dehydration from decreased oral intake.¹

Prompt recognition, assessment, and treatment are vital.

We recommend the following systematic approach to evaluate and treat catatonia (Table).

Assess

Appropriate assessment of catatonia requires recognition of the array of potential underlying causes of the syndrome.

Obtain a complete history, including:

• recent changes in behavior
• past psychiatric illness and hospitalization
• past or current neurologic or medical disease
• prescription and illicit drug use.

Collateral informants, such as family members and caregivers, could provide valuable information. This history could reveal causative factors and identify appropriate targets for treatment.

Physical and mental status examinations can help characterize the type and severity of motoric and behavioral symptoms, such as rigidity, waxy flexibility, negativism, automatic obedience, ambitendency, and perseveration. Monitoring vital signs is crucial because of the risk of medical complications and malignant catatonia, which can be lethal if not treated.

Laboratory testing and imaging might be indicated to rule out medical causes, such as infection, metabolic disturbances, drug intoxication and withdrawal, and acute neurologic etiologies.

Identify and rate symptom severity. After determining that a patient has catatonia, consider using a standardized instrument, such as the Bush Francis Catatonia Rating Scale (BFCRS),² to assess the patient’s type of symptoms and degree of impairment. Scores obtained on such instruments can be tracked as the patient receives treatment. Although the BFCRS is imperfect because of ambiguous symptom descriptions and because symptoms can remain after effective treatment, it is the most widely researched catatonia scale.

Treat and monitor

Although there are no published data from large-scale, randomized, controlled trials, clinical experience shows that the mainstays of treatment still are benzodiazepines and electroconvulsive therapy (ECT). A benzodiazepine challenge of IV lorazepam, 2 mg, can lead to rapid, substantial symptomatic relief with relatively low risk of harm. An estimated 50% to 70% of patients with catatonia respond within 5 days to IV lorazepam, 2 mg, every 3 to 8 hours.³

When patients do not respond to benzodiazepines, consider ECT. For patients with medical, neurologic, and toxic metabolic causes of catatonia, treat the underlying disturbance first.

Interval colorectal cancers were proximally located and had DNA mismatch repair deficiency significantly more often than did colorectal cancers in colonoscopy-naive patients, researchers reported in the November issue of Gastroenterology.

The findings underscore the need to effectively visualize the large colon to avoid missing lesions during colonoscopy, said Elena M. Stoffel, MD, MPH, of the University of Michigan Health System, Ann Arbor, and her associates. “Studies consistently show that colonoscopy affords less protection against proximal cancers, and DNA mismatch repair deficiency tumors are more frequent among proximal cancers,” they noted. But the proximal and distal colon also have different embryologic origins and gene expression profiles, “prompting some to suggest that these might be considered as two distinct organs. Whether the precursors of postcolonoscopy colorectal cancers are simply harder to detect or resect endoscopically, or whether their behavior differs on the basis of anatomic location or molecular subtype remains unclear,” they added.

Courtesy Wikimedia Commons/nephron/Creative Commons License

A variety of quality-related factors contribute to the risk of postcolonoscopy or interval colorectal cancer, as do clinical characteristics such as older age at diagnosis, proximal tumor location, family history of colorectal cancer, and previous polypectomy, the investigators noted. To further explore the clinical and molecular correlates of postcolonoscopy tumors, they conducted a cross-sectional study of 10,365 colorectal cancers diagnosed in Denmark between 2007 and 2011 (Gastroenterology. 2016 Jul 18. doi: 10.1053/j.gastro.2016.07.010). A total of 725 (7%) of the colorectal cancers occurred after colonoscopy, the researchers determined. These lesions were significantly more often located in the proximal colon (odds ratio, 2.34; 95% confidence interval, 1.90-2.89) and were more likely to have DNA mismatch repair deficiency (OR, 1.26; 95% CI, 1.00-59) when compared with colorectal cancers diagnosed in patients with no prior colonoscopy. However, they also were significantly less likely to be metastatic at presentation (OR, 0.65; 95% CI, 0.48-0.89). Interval colorectal cancers were particularly likely to be located in the proximal colon and/or to have DNA mismatch repair deficiency when diagnosed 3-6 years after colonoscopy, but the excess burden of these characteristics persisted up to 10 years after colonoscopy, the researchers said.

Molecular analyses of 85 postcolonoscopy colorectal cancers from one hospital indicated that 24% had DNA mismatch repair deficiency. When considering only those tumors diagnosed within 10 years after colonoscopy, 27% had KRAS/NRAS mutations, 19% had BRAF mutations, and 19% had PIK3CA mutations. The 7% of tumors with molecular features of Lynch syndrome all occurred within 10 years after index colonoscopy and accounted for a third of cases of DNA mismatch repair deficiency, reflecting the role of this mutation pathway in Lynch syndrome and its tendency to rapidly progress, the investigators said.

Notably, 38% of colorectal cancers diagnosed within a year after colonoscopy involved an incomplete examination, compared with only 16% of cases diagnosed within 1-10 years after colonoscopy, they also reported. This finding and the clinical and molecular correlates of the interval cancers “supports the popular assumption that many cancers diagnosed soon after colonoscopy result from missed lesions,” they concluded. “However, the heterogeneity in clinical and molecular features of cancers diagnosed at different time intervals suggests postcolonoscopy colorectal cancers are likely multifactorial in their etiology and clinical behavior.”

The study was supported by the Danish Cancer Society, the Lundbeck Foundation, the Novo Nordisk Foundation, the National Institutes of Health, M.D. Anderson Cancer Center, and a University of Texas Frederick Becker Distinguished University Chair in Cancer Research. The investigators had no disclosures.

Interval colorectal cancers were proximally located and had DNA mismatch repair deficiency significantly more often than did colorectal cancers in colonoscopy-naive patients, researchers reported in the November issue of Gastroenterology.

The findings underscore the need to effectively visualize the large colon to avoid missing lesions during colonoscopy, said Elena M. Stoffel, MD, MPH, of the University of Michigan Health System, Ann Arbor, and her associates. “Studies consistently show that colonoscopy affords less protection against proximal cancers, and DNA mismatch repair deficiency tumors are more frequent among proximal cancers,” they noted. But the proximal and distal colon also have different embryologic origins and gene expression profiles, “prompting some to suggest that these might be considered as two distinct organs. Whether the precursors of postcolonoscopy colorectal cancers are simply harder to detect or resect endoscopically, or whether their behavior differs on the basis of anatomic location or molecular subtype remains unclear,” they added.

Courtesy Wikimedia Commons/nephron/Creative Commons License

A variety of quality-related factors contribute to the risk of postcolonoscopy or interval colorectal cancer, as do clinical characteristics such as older age at diagnosis, proximal tumor location, family history of colorectal cancer, and previous polypectomy, the investigators noted. To further explore the clinical and molecular correlates of postcolonoscopy tumors, they conducted a cross-sectional study of 10,365 colorectal cancers diagnosed in Denmark between 2007 and 2011 (Gastroenterology. 2016 Jul 18. doi: 10.1053/j.gastro.2016.07.010). A total of 725 (7%) of the colorectal cancers occurred after colonoscopy, the researchers determined. These lesions were significantly more often located in the proximal colon (odds ratio, 2.34; 95% confidence interval, 1.90-2.89) and were more likely to have DNA mismatch repair deficiency (OR, 1.26; 95% CI, 1.00-59) when compared with colorectal cancers diagnosed in patients with no prior colonoscopy. However, they also were significantly less likely to be metastatic at presentation (OR, 0.65; 95% CI, 0.48-0.89). Interval colorectal cancers were particularly likely to be located in the proximal colon and/or to have DNA mismatch repair deficiency when diagnosed 3-6 years after colonoscopy, but the excess burden of these characteristics persisted up to 10 years after colonoscopy, the researchers said.

Molecular analyses of 85 postcolonoscopy colorectal cancers from one hospital indicated that 24% had DNA mismatch repair deficiency. When considering only those tumors diagnosed within 10 years after colonoscopy, 27% had KRAS/NRAS mutations, 19% had BRAF mutations, and 19% had PIK3CA mutations. The 7% of tumors with molecular features of Lynch syndrome all occurred within 10 years after index colonoscopy and accounted for a third of cases of DNA mismatch repair deficiency, reflecting the role of this mutation pathway in Lynch syndrome and its tendency to rapidly progress, the investigators said.

Notably, 38% of colorectal cancers diagnosed within a year after colonoscopy involved an incomplete examination, compared with only 16% of cases diagnosed within 1-10 years after colonoscopy, they also reported. This finding and the clinical and molecular correlates of the interval cancers “supports the popular assumption that many cancers diagnosed soon after colonoscopy result from missed lesions,” they concluded. “However, the heterogeneity in clinical and molecular features of cancers diagnosed at different time intervals suggests postcolonoscopy colorectal cancers are likely multifactorial in their etiology and clinical behavior.”

The study was supported by the Danish Cancer Society, the Lundbeck Foundation, the Novo Nordisk Foundation, the National Institutes of Health, M.D. Anderson Cancer Center, and a University of Texas Frederick Becker Distinguished University Chair in Cancer Research. The investigators had no disclosures.

Interval colorectal cancers were proximally located and had DNA mismatch repair deficiency significantly more often than did colorectal cancers in colonoscopy-naive patients, researchers reported in the November issue of Gastroenterology.

The findings underscore the need to effectively visualize the large colon to avoid missing lesions during colonoscopy, said Elena M. Stoffel, MD, MPH, of the University of Michigan Health System, Ann Arbor, and her associates. “Studies consistently show that colonoscopy affords less protection against proximal cancers, and DNA mismatch repair deficiency tumors are more frequent among proximal cancers,” they noted. But the proximal and distal colon also have different embryologic origins and gene expression profiles, “prompting some to suggest that these might be considered as two distinct organs. Whether the precursors of postcolonoscopy colorectal cancers are simply harder to detect or resect endoscopically, or whether their behavior differs on the basis of anatomic location or molecular subtype remains unclear,” they added.

Courtesy Wikimedia Commons/nephron/Creative Commons License

A variety of quality-related factors contribute to the risk of postcolonoscopy or interval colorectal cancer, as do clinical characteristics such as older age at diagnosis, proximal tumor location, family history of colorectal cancer, and previous polypectomy, the investigators noted. To further explore the clinical and molecular correlates of postcolonoscopy tumors, they conducted a cross-sectional study of 10,365 colorectal cancers diagnosed in Denmark between 2007 and 2011 (Gastroenterology. 2016 Jul 18. doi: 10.1053/j.gastro.2016.07.010). A total of 725 (7%) of the colorectal cancers occurred after colonoscopy, the researchers determined. These lesions were significantly more often located in the proximal colon (odds ratio, 2.34; 95% confidence interval, 1.90-2.89) and were more likely to have DNA mismatch repair deficiency (OR, 1.26; 95% CI, 1.00-59) when compared with colorectal cancers diagnosed in patients with no prior colonoscopy. However, they also were significantly less likely to be metastatic at presentation (OR, 0.65; 95% CI, 0.48-0.89). Interval colorectal cancers were particularly likely to be located in the proximal colon and/or to have DNA mismatch repair deficiency when diagnosed 3-6 years after colonoscopy, but the excess burden of these characteristics persisted up to 10 years after colonoscopy, the researchers said.

Molecular analyses of 85 postcolonoscopy colorectal cancers from one hospital indicated that 24% had DNA mismatch repair deficiency. When considering only those tumors diagnosed within 10 years after colonoscopy, 27% had KRAS/NRAS mutations, 19% had BRAF mutations, and 19% had PIK3CA mutations. The 7% of tumors with molecular features of Lynch syndrome all occurred within 10 years after index colonoscopy and accounted for a third of cases of DNA mismatch repair deficiency, reflecting the role of this mutation pathway in Lynch syndrome and its tendency to rapidly progress, the investigators said.

Notably, 38% of colorectal cancers diagnosed within a year after colonoscopy involved an incomplete examination, compared with only 16% of cases diagnosed within 1-10 years after colonoscopy, they also reported. This finding and the clinical and molecular correlates of the interval cancers “supports the popular assumption that many cancers diagnosed soon after colonoscopy result from missed lesions,” they concluded. “However, the heterogeneity in clinical and molecular features of cancers diagnosed at different time intervals suggests postcolonoscopy colorectal cancers are likely multifactorial in their etiology and clinical behavior.”

The study was supported by the Danish Cancer Society, the Lundbeck Foundation, the Novo Nordisk Foundation, the National Institutes of Health, M.D. Anderson Cancer Center, and a University of Texas Frederick Becker Distinguished University Chair in Cancer Research. The investigators had no disclosures.

CASE 1 ›

A 3-year-old boy was brought to our emergency department for evaluation of skin lesions that he’d had for 7 days. The boy would sometimes scratch the lesions, which began on his right flank as erythematous micropapules and later spread to his right lateral thigh and inner arm (FIGURE 1). His lymph nodes were not palpable.

The boy’s parents had been told to use a topical corticosteroid, but the rash did not improve. His family denied fever or other previous infectious or systemic symptoms, and said that he hadn’t come into contact with any irritants or allergenic substances.

CASE 2 ›

A 13-year-old girl came to our emergency department with a pruriginous rash on her right leg and abdomen that she’d had for 4 days (FIGURE 2). The millimetric papules had also spread to the right side of her trunk, her right arm and armpit, and her inner thigh. Before the rash, she’d had a fever, otalgia, and conjunctivitis. We noted redness of her left conjunctiva, eardrum, and pharynx. The girl’s lymph nodes were not palpable. Serologic examinations for Epstein-Barr virus, cytomegalovirus, rubella, parvovirus B19, and Mycoplasma were negative.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Both of these patients were given a diagnosis of asymmetric periflexural exanthem of childhood (APEC), based on the appearance and distribution of the rashes.

A rare condition that mostly affects young children

APEC is a rash of unknown cause, although epidemiologic and clinical findings support a viral etiology. Cases of this rash were first reported in 1992 by Bodemer et al, and a year later, Taïeb et al reported new cases, establishing the term “asymmetric periflexural exanthem.”^1,2 Several viruses have been related to APEC (including adenovirus, parvovirus B19, parainfluenza 2 and 3, and human herpesvirus 7), but none of these has been consistently associated with the rash.^3-5

Asymmetric periflexual exanthem of childhood is occasionally pruritic and can be preceded by short respiratory or gastrointestinal prodromes or a low-grade fever.APEC tends to affect children between one and 5 years of age, but adult cases have been reported.^6,7 The condition occurs slightly more frequently among females and more often in winter and spring.^8,9 APEC is a rare condition; since 1992, there have only been about 300 cases reported in the literature.¹⁰

What you’ll see. The erythematous rash appears as an asymmetrical or unilateral papular, scarlatiniform, or eczematous exanthema. It initially affects the axilla or groin and may then progress to the extremities and trunk. Minor lesions infrequently present on the contralateral side. Most children who are affected by APEC are otherwise healthy and asymptomatic at presentation. The exanthem is occasionally pruritic and can be preceded by short respiratory or gastrointestinal prodromes or a low-grade fever.^2,9 If the rash predominantly affects the lateral thoracic wall, it may be referred to as unilateral laterothoracic exanthem.¹¹ Regional lymphadenopathies can often be found, and there is no systemic involvement.

The differential diagnosis for this type of exanthem includes drug eruptions, pityriasis rosea, miliaria, scarlet fever, papular acrodermatitis of childhood, and other viral rashes. The asymmetric distribution of APEC helps to distinguish the condition. Other possible asymmetric skin lesions, such as contact dermatitis, tinea corporis, or lichen striatus, can be differentiated by the characteristics of the cutaneous lesions. Contact dermatitis lesions are more vesicular, pruritic, and related to the contact area. Tinea corporis lesions tend to be smaller, circular, well-limited, and often have pustules. Lichen striatus starts as small pink-, red-, or flesh-colored spots that join together to form a dull red and slightly scaly linear band over the course of one or 2 weeks.¹² Because APEC is self-limiting, a skin biopsy is usually not necessary.¹³

Lesions usually persist for one to 6 weeks and resolve with no sequelae. Only symptomatic treatment is required.⁹ Topical emollients, topical corticosteroids, or oral antihistamines can be used, if necessary.

Our patients. Both patients were treated with oral antihistamines and the rashes completely resolved within 2 to 3 weeks.

CORRESPONDENCE
Celia Horcajada-Reales, MD, Hospital Gregorio Marañón, Calle del Dr. Esquerdo, 46, 28007 Madrid, Spain; [email protected].

CASE 1 ›

A 3-year-old boy was brought to our emergency department for evaluation of skin lesions that he’d had for 7 days. The boy would sometimes scratch the lesions, which began on his right flank as erythematous micropapules and later spread to his right lateral thigh and inner arm (FIGURE 1). His lymph nodes were not palpable.

The boy’s parents had been told to use a topical corticosteroid, but the rash did not improve. His family denied fever or other previous infectious or systemic symptoms, and said that he hadn’t come into contact with any irritants or allergenic substances.

CASE 2 ›

A 13-year-old girl came to our emergency department with a pruriginous rash on her right leg and abdomen that she’d had for 4 days (FIGURE 2). The millimetric papules had also spread to the right side of her trunk, her right arm and armpit, and her inner thigh. Before the rash, she’d had a fever, otalgia, and conjunctivitis. We noted redness of her left conjunctiva, eardrum, and pharynx. The girl’s lymph nodes were not palpable. Serologic examinations for Epstein-Barr virus, cytomegalovirus, rubella, parvovirus B19, and Mycoplasma were negative.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Both of these patients were given a diagnosis of asymmetric periflexural exanthem of childhood (APEC), based on the appearance and distribution of the rashes.

A rare condition that mostly affects young children

APEC is a rash of unknown cause, although epidemiologic and clinical findings support a viral etiology. Cases of this rash were first reported in 1992 by Bodemer et al, and a year later, Taïeb et al reported new cases, establishing the term “asymmetric periflexural exanthem.”^1,2 Several viruses have been related to APEC (including adenovirus, parvovirus B19, parainfluenza 2 and 3, and human herpesvirus 7), but none of these has been consistently associated with the rash.^3-5

Asymmetric periflexual exanthem of childhood is occasionally pruritic and can be preceded by short respiratory or gastrointestinal prodromes or a low-grade fever.APEC tends to affect children between one and 5 years of age, but adult cases have been reported.^6,7 The condition occurs slightly more frequently among females and more often in winter and spring.^8,9 APEC is a rare condition; since 1992, there have only been about 300 cases reported in the literature.¹⁰

What you’ll see. The erythematous rash appears as an asymmetrical or unilateral papular, scarlatiniform, or eczematous exanthema. It initially affects the axilla or groin and may then progress to the extremities and trunk. Minor lesions infrequently present on the contralateral side. Most children who are affected by APEC are otherwise healthy and asymptomatic at presentation. The exanthem is occasionally pruritic and can be preceded by short respiratory or gastrointestinal prodromes or a low-grade fever.^2,9 If the rash predominantly affects the lateral thoracic wall, it may be referred to as unilateral laterothoracic exanthem.¹¹ Regional lymphadenopathies can often be found, and there is no systemic involvement.

The differential diagnosis for this type of exanthem includes drug eruptions, pityriasis rosea, miliaria, scarlet fever, papular acrodermatitis of childhood, and other viral rashes. The asymmetric distribution of APEC helps to distinguish the condition. Other possible asymmetric skin lesions, such as contact dermatitis, tinea corporis, or lichen striatus, can be differentiated by the characteristics of the cutaneous lesions. Contact dermatitis lesions are more vesicular, pruritic, and related to the contact area. Tinea corporis lesions tend to be smaller, circular, well-limited, and often have pustules. Lichen striatus starts as small pink-, red-, or flesh-colored spots that join together to form a dull red and slightly scaly linear band over the course of one or 2 weeks.¹² Because APEC is self-limiting, a skin biopsy is usually not necessary.¹³

Lesions usually persist for one to 6 weeks and resolve with no sequelae. Only symptomatic treatment is required.⁹ Topical emollients, topical corticosteroids, or oral antihistamines can be used, if necessary.

Our patients. Both patients were treated with oral antihistamines and the rashes completely resolved within 2 to 3 weeks.

CORRESPONDENCE
Celia Horcajada-Reales, MD, Hospital Gregorio Marañón, Calle del Dr. Esquerdo, 46, 28007 Madrid, Spain; [email protected].

CASE 1 ›

A 3-year-old boy was brought to our emergency department for evaluation of skin lesions that he’d had for 7 days. The boy would sometimes scratch the lesions, which began on his right flank as erythematous micropapules and later spread to his right lateral thigh and inner arm (FIGURE 1). His lymph nodes were not palpable.

The boy’s parents had been told to use a topical corticosteroid, but the rash did not improve. His family denied fever or other previous infectious or systemic symptoms, and said that he hadn’t come into contact with any irritants or allergenic substances.

CASE 2 ›

A 13-year-old girl came to our emergency department with a pruriginous rash on her right leg and abdomen that she’d had for 4 days (FIGURE 2). The millimetric papules had also spread to the right side of her trunk, her right arm and armpit, and her inner thigh. Before the rash, she’d had a fever, otalgia, and conjunctivitis. We noted redness of her left conjunctiva, eardrum, and pharynx. The girl’s lymph nodes were not palpable. Serologic examinations for Epstein-Barr virus, cytomegalovirus, rubella, parvovirus B19, and Mycoplasma were negative.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Both of these patients were given a diagnosis of asymmetric periflexural exanthem of childhood (APEC), based on the appearance and distribution of the rashes.

A rare condition that mostly affects young children

APEC is a rash of unknown cause, although epidemiologic and clinical findings support a viral etiology. Cases of this rash were first reported in 1992 by Bodemer et al, and a year later, Taïeb et al reported new cases, establishing the term “asymmetric periflexural exanthem.”^1,2 Several viruses have been related to APEC (including adenovirus, parvovirus B19, parainfluenza 2 and 3, and human herpesvirus 7), but none of these has been consistently associated with the rash.^3-5

Asymmetric periflexual exanthem of childhood is occasionally pruritic and can be preceded by short respiratory or gastrointestinal prodromes or a low-grade fever.APEC tends to affect children between one and 5 years of age, but adult cases have been reported.^6,7 The condition occurs slightly more frequently among females and more often in winter and spring.^8,9 APEC is a rare condition; since 1992, there have only been about 300 cases reported in the literature.¹⁰

What you’ll see. The erythematous rash appears as an asymmetrical or unilateral papular, scarlatiniform, or eczematous exanthema. It initially affects the axilla or groin and may then progress to the extremities and trunk. Minor lesions infrequently present on the contralateral side. Most children who are affected by APEC are otherwise healthy and asymptomatic at presentation. The exanthem is occasionally pruritic and can be preceded by short respiratory or gastrointestinal prodromes or a low-grade fever.^2,9 If the rash predominantly affects the lateral thoracic wall, it may be referred to as unilateral laterothoracic exanthem.¹¹ Regional lymphadenopathies can often be found, and there is no systemic involvement.

The differential diagnosis for this type of exanthem includes drug eruptions, pityriasis rosea, miliaria, scarlet fever, papular acrodermatitis of childhood, and other viral rashes. The asymmetric distribution of APEC helps to distinguish the condition. Other possible asymmetric skin lesions, such as contact dermatitis, tinea corporis, or lichen striatus, can be differentiated by the characteristics of the cutaneous lesions. Contact dermatitis lesions are more vesicular, pruritic, and related to the contact area. Tinea corporis lesions tend to be smaller, circular, well-limited, and often have pustules. Lichen striatus starts as small pink-, red-, or flesh-colored spots that join together to form a dull red and slightly scaly linear band over the course of one or 2 weeks.¹² Because APEC is self-limiting, a skin biopsy is usually not necessary.¹³

Lesions usually persist for one to 6 weeks and resolve with no sequelae. Only symptomatic treatment is required.⁹ Topical emollients, topical corticosteroids, or oral antihistamines can be used, if necessary.

Our patients. Both patients were treated with oral antihistamines and the rashes completely resolved within 2 to 3 weeks.

CORRESPONDENCE
Celia Horcajada-Reales, MD, Hospital Gregorio Marañón, Calle del Dr. Esquerdo, 46, 28007 Madrid, Spain; [email protected].

A 62-year-old man presented to the emergency department (ED) with a swollen, red, and painful right lower leg. He’d had bilateral lower leg swelling for 2 months, but the left leg became increasingly painful and red over the past 3 days. The patient also had a 3-day history of a diffuse rash that began on his right upper arm and spread to his left arm, both palms, both legs, and his back. It was mildly pruritic, but not painful.

The patient indicated that he had recently sought care from his primary care physician for lower respiratory symptoms. He had just completed a 5-day course of azithromycin and prednisone (50 mg/d for 5 days) the day before his ED visit.

A lower extremity venous ultrasound revealed that the patient had a deep vein thrombosis (DVT). Computed tomography (CT) imaging of the chest with contrast revealed pulmonary emboli. He was treated with enoxaparin and warfarin. We diagnosed the rash based on the patient’s history and the appearance of the rash, which was comprised of blanching and erythematous macules with central clearing (FIGURE 1). (There were no blisters or mucosal involvement.)

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Erythema multiforme

The clinical exam was consistent with the diagnosis of erythema multiforme (EM). A diagnosis of EM can usually be made based on the clinical exam alone.¹ Typical targetoid lesions have a round shape and 3 concentric zones: A central dusky area of epidermal necrosis that may involve bullae, a paler pink or edematous zone, and a peripheral erythematous ring.² Atypical lesions, such as raised papules, may also be seen.²

The skin lesions of EM usually appear symmetrically on the distal extremities and spread in a centripetal manner.¹ Palms, soles, and mucosa can be involved.¹ EM with mucosal involvement is called “erythema multiforme major,” and EM without mucosal disease (as in our patient’s case) is called “erythema multiforme minor.”²

EM is an acute, immune-mediated eruption thought to be caused by a cell-mediated hypersensitivity to certain infections or drugs.² Ninety percent of cases are associated with an infection; herpes simplex virus (HSV) is the most common infectious agent.³  Mycoplasma pneumoniae is another culprit, especially in children. Medications are inciting factors about 10% of the time; nonsteroidal anti-inflammatory drugs, sulfonamides, antiepileptics, and antibiotics have been linked to EM eruptions.³

Herpes simplex virus is the most common infectious trigger for erythema multiforme.Interestingly, while azithromycin—the medication our patient had taken most recently—can cause EM, it has been mainly linked to cases of Stevens-Johnson syndrome (SJS).⁴ So, while we suspect that azithromycin was the trigger in our patient’s case, we can’t be sure. It’s also possible that Mycoplasma pneumoniae was the trigger for our patient’s EM. However, Mycoplasma pneumoniae is more common in adolescents.

Differential includes life-threatening conditions like SJS

The differential diagnosis for a non-vesicular palmar rash is discussed in the TABLE.^1,5-12 There is a wide spectrum of possible etiologies—from infectious and rheumatologic disorders to chronic liver disease. Histologic testing may be useful in differentiating EM from other diseases, but in most cases, it is not required to make a diagnosis.¹ Laboratory testing may reveal leukocytosis, an elevated erythrocyte sedimentation rate, and elevated liver function test results, but these are nonspecific.¹

It’s important to differentiate EM from life-threatening conditions like SJS and toxic epidermal necrolysis (TEN).⁵ EM is characterized by typical and atypical targetoid lesions with minimal mucosal involvement.^6,7 SJS is characterized by flat atypical targetoid lesions, confluent purpuric macules, severe mucosal erosions, and <10% epidermal detachment.^6,7 TEN is characterized by severe mucosal erosions and >30% epidermal detachment.^6,7

Lesions resolve on their own, but topical steroids can provide relief

It's important to differentiate erythema multiforme from Stevens-Johnson syndrome and toxic epidermal necrolysis.EM is a self-limiting disease; lesions resolve within about 2 weeks.³ Management begins by treating any suspected infection or discontinuing any suspected drugs.¹ In patients with co-existing or recurrent HSV infection, early treatment with an oral antiviral (such as acyclovir) may lessen the number and duration of lesions.^1,6 In addition, oral antihistamines and topical steroids may be used to provide symptomatic relief.^1,6 Use of oral corticosteroids can be considered in severe mucosal disease, although such use is considered controversial due to a lack of evidence.^1,6

Our patient remained hospitalized for 4 days. As noted earlier, his DVT and pulmonary embolism were treated with enoxaparin and the patient was sent home with a prescription for warfarin. Regarding the EM, his rash and itching improved significantly during the hospitalization (without any specific treatment) and was mostly resolved at a follow-up visit 6 days after discharge.

CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, Colorado 80238; [email protected].

A 62-year-old man presented to the emergency department (ED) with a swollen, red, and painful right lower leg. He’d had bilateral lower leg swelling for 2 months, but the left leg became increasingly painful and red over the past 3 days. The patient also had a 3-day history of a diffuse rash that began on his right upper arm and spread to his left arm, both palms, both legs, and his back. It was mildly pruritic, but not painful.

The patient indicated that he had recently sought care from his primary care physician for lower respiratory symptoms. He had just completed a 5-day course of azithromycin and prednisone (50 mg/d for 5 days) the day before his ED visit.

A lower extremity venous ultrasound revealed that the patient had a deep vein thrombosis (DVT). Computed tomography (CT) imaging of the chest with contrast revealed pulmonary emboli. He was treated with enoxaparin and warfarin. We diagnosed the rash based on the patient’s history and the appearance of the rash, which was comprised of blanching and erythematous macules with central clearing (FIGURE 1). (There were no blisters or mucosal involvement.)

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Erythema multiforme

The clinical exam was consistent with the diagnosis of erythema multiforme (EM). A diagnosis of EM can usually be made based on the clinical exam alone.¹ Typical targetoid lesions have a round shape and 3 concentric zones: A central dusky area of epidermal necrosis that may involve bullae, a paler pink or edematous zone, and a peripheral erythematous ring.² Atypical lesions, such as raised papules, may also be seen.²

The skin lesions of EM usually appear symmetrically on the distal extremities and spread in a centripetal manner.¹ Palms, soles, and mucosa can be involved.¹ EM with mucosal involvement is called “erythema multiforme major,” and EM without mucosal disease (as in our patient’s case) is called “erythema multiforme minor.”²

EM is an acute, immune-mediated eruption thought to be caused by a cell-mediated hypersensitivity to certain infections or drugs.² Ninety percent of cases are associated with an infection; herpes simplex virus (HSV) is the most common infectious agent.³  Mycoplasma pneumoniae is another culprit, especially in children. Medications are inciting factors about 10% of the time; nonsteroidal anti-inflammatory drugs, sulfonamides, antiepileptics, and antibiotics have been linked to EM eruptions.³

Herpes simplex virus is the most common infectious trigger for erythema multiforme.Interestingly, while azithromycin—the medication our patient had taken most recently—can cause EM, it has been mainly linked to cases of Stevens-Johnson syndrome (SJS).⁴ So, while we suspect that azithromycin was the trigger in our patient’s case, we can’t be sure. It’s also possible that Mycoplasma pneumoniae was the trigger for our patient’s EM. However, Mycoplasma pneumoniae is more common in adolescents.

Differential includes life-threatening conditions like SJS

The differential diagnosis for a non-vesicular palmar rash is discussed in the TABLE.^1,5-12 There is a wide spectrum of possible etiologies—from infectious and rheumatologic disorders to chronic liver disease. Histologic testing may be useful in differentiating EM from other diseases, but in most cases, it is not required to make a diagnosis.¹ Laboratory testing may reveal leukocytosis, an elevated erythrocyte sedimentation rate, and elevated liver function test results, but these are nonspecific.¹

It’s important to differentiate EM from life-threatening conditions like SJS and toxic epidermal necrolysis (TEN).⁵ EM is characterized by typical and atypical targetoid lesions with minimal mucosal involvement.^6,7 SJS is characterized by flat atypical targetoid lesions, confluent purpuric macules, severe mucosal erosions, and <10% epidermal detachment.^6,7 TEN is characterized by severe mucosal erosions and >30% epidermal detachment.^6,7

Lesions resolve on their own, but topical steroids can provide relief

It's important to differentiate erythema multiforme from Stevens-Johnson syndrome and toxic epidermal necrolysis.EM is a self-limiting disease; lesions resolve within about 2 weeks.³ Management begins by treating any suspected infection or discontinuing any suspected drugs.¹ In patients with co-existing or recurrent HSV infection, early treatment with an oral antiviral (such as acyclovir) may lessen the number and duration of lesions.^1,6 In addition, oral antihistamines and topical steroids may be used to provide symptomatic relief.^1,6 Use of oral corticosteroids can be considered in severe mucosal disease, although such use is considered controversial due to a lack of evidence.^1,6

Our patient remained hospitalized for 4 days. As noted earlier, his DVT and pulmonary embolism were treated with enoxaparin and the patient was sent home with a prescription for warfarin. Regarding the EM, his rash and itching improved significantly during the hospitalization (without any specific treatment) and was mostly resolved at a follow-up visit 6 days after discharge.

CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, Colorado 80238; [email protected].

A 62-year-old man presented to the emergency department (ED) with a swollen, red, and painful right lower leg. He’d had bilateral lower leg swelling for 2 months, but the left leg became increasingly painful and red over the past 3 days. The patient also had a 3-day history of a diffuse rash that began on his right upper arm and spread to his left arm, both palms, both legs, and his back. It was mildly pruritic, but not painful.

The patient indicated that he had recently sought care from his primary care physician for lower respiratory symptoms. He had just completed a 5-day course of azithromycin and prednisone (50 mg/d for 5 days) the day before his ED visit.

A lower extremity venous ultrasound revealed that the patient had a deep vein thrombosis (DVT). Computed tomography (CT) imaging of the chest with contrast revealed pulmonary emboli. He was treated with enoxaparin and warfarin. We diagnosed the rash based on the patient’s history and the appearance of the rash, which was comprised of blanching and erythematous macules with central clearing (FIGURE 1). (There were no blisters or mucosal involvement.)

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Erythema multiforme

The clinical exam was consistent with the diagnosis of erythema multiforme (EM). A diagnosis of EM can usually be made based on the clinical exam alone.¹ Typical targetoid lesions have a round shape and 3 concentric zones: A central dusky area of epidermal necrosis that may involve bullae, a paler pink or edematous zone, and a peripheral erythematous ring.² Atypical lesions, such as raised papules, may also be seen.²

The skin lesions of EM usually appear symmetrically on the distal extremities and spread in a centripetal manner.¹ Palms, soles, and mucosa can be involved.¹ EM with mucosal involvement is called “erythema multiforme major,” and EM without mucosal disease (as in our patient’s case) is called “erythema multiforme minor.”²

EM is an acute, immune-mediated eruption thought to be caused by a cell-mediated hypersensitivity to certain infections or drugs.² Ninety percent of cases are associated with an infection; herpes simplex virus (HSV) is the most common infectious agent.³  Mycoplasma pneumoniae is another culprit, especially in children. Medications are inciting factors about 10% of the time; nonsteroidal anti-inflammatory drugs, sulfonamides, antiepileptics, and antibiotics have been linked to EM eruptions.³

Herpes simplex virus is the most common infectious trigger for erythema multiforme.Interestingly, while azithromycin—the medication our patient had taken most recently—can cause EM, it has been mainly linked to cases of Stevens-Johnson syndrome (SJS).⁴ So, while we suspect that azithromycin was the trigger in our patient’s case, we can’t be sure. It’s also possible that Mycoplasma pneumoniae was the trigger for our patient’s EM. However, Mycoplasma pneumoniae is more common in adolescents.

Differential includes life-threatening conditions like SJS

The differential diagnosis for a non-vesicular palmar rash is discussed in the TABLE.^1,5-12 There is a wide spectrum of possible etiologies—from infectious and rheumatologic disorders to chronic liver disease. Histologic testing may be useful in differentiating EM from other diseases, but in most cases, it is not required to make a diagnosis.¹ Laboratory testing may reveal leukocytosis, an elevated erythrocyte sedimentation rate, and elevated liver function test results, but these are nonspecific.¹

It’s important to differentiate EM from life-threatening conditions like SJS and toxic epidermal necrolysis (TEN).⁵ EM is characterized by typical and atypical targetoid lesions with minimal mucosal involvement.^6,7 SJS is characterized by flat atypical targetoid lesions, confluent purpuric macules, severe mucosal erosions, and <10% epidermal detachment.^6,7 TEN is characterized by severe mucosal erosions and >30% epidermal detachment.^6,7

Lesions resolve on their own, but topical steroids can provide relief

It's important to differentiate erythema multiforme from Stevens-Johnson syndrome and toxic epidermal necrolysis.EM is a self-limiting disease; lesions resolve within about 2 weeks.³ Management begins by treating any suspected infection or discontinuing any suspected drugs.¹ In patients with co-existing or recurrent HSV infection, early treatment with an oral antiviral (such as acyclovir) may lessen the number and duration of lesions.^1,6 In addition, oral antihistamines and topical steroids may be used to provide symptomatic relief.^1,6 Use of oral corticosteroids can be considered in severe mucosal disease, although such use is considered controversial due to a lack of evidence.^1,6

Our patient remained hospitalized for 4 days. As noted earlier, his DVT and pulmonary embolism were treated with enoxaparin and the patient was sent home with a prescription for warfarin. Regarding the EM, his rash and itching improved significantly during the hospitalization (without any specific treatment) and was mostly resolved at a follow-up visit 6 days after discharge.

CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, Colorado 80238; [email protected].

The study¹ that served as the basis for the PURL entitled, “Ramipril for claudication?” (J Fam Pract. 2013;62:579-580), has been retracted from the Journal of the American Medical Association.² Therefore we, on behalf of all of the authors of the PURL, are retracting the PURL, as well.

According to JAMA’s retraction statement, the first author of the article admitted to data fabrication following an internal investigation.² The source article does not provide subgroup analysis to determine how much of an effect the fabricated data may have had on the final reported outcome. However, a separately reported (and also retracted) sub-analysis of this study indicates that 165/212 (77.8%) patients were enrolled from the site of the first author.³

The question remains: Does ramipril work for symptoms of claudication?

The question remains: Does ramipril work for symptoms of claudication? A completely separate group of researchers conducted a similar, but smaller, randomized clinical trial of ramipril in patients with intermittent claudication.⁴ In this study, 33 patients were randomized to ramipril or placebo for a 24-week trial. The ramipril group (n=14) improved maximum treadmill walking distance by an adjusted mean of 131 meters (m) (95% confidence interval [CI], 62-199; P=.001), improved treadmill intermittent claudication distance by 122 m (95% CI, 56-188; P=.001), and improved patient-reported walking distance by 159 m (95% CI, 66-313; P=.043).

The 2004 Heart Outcomes Prevention Evaluation (HOPE) study indicates that ramipril maintains a mortality benefit for patients with intermittent claudication.⁵ A subgroup of this study included 1725 patients with baseline peripheral artery disease who were randomized to ramipril at 10 mg, which yielded a relative risk (RR) of 0.75 (95% CI, 0.61-0.92) for the primary outcome (cardiovascular mortality, myocardial infarction, stroke). This alone validates the use of ramipril in patients with intermittent claudication. But with the retraction of the large randomized controlled trial, we are not sure how much it may improve walk distances. Further studies might better clarify if ramipril provides symptomatic benefit by reducing claudication symptoms, in addition to the known cardiovascular mortality benefit.

Luke Stephens, MD, MSPH
Park Ridge, IL

James J. Stevermer, MD, MSPH
Columbia, MO

The study¹ that served as the basis for the PURL entitled, “Ramipril for claudication?” (J Fam Pract. 2013;62:579-580), has been retracted from the Journal of the American Medical Association.² Therefore we, on behalf of all of the authors of the PURL, are retracting the PURL, as well.

According to JAMA’s retraction statement, the first author of the article admitted to data fabrication following an internal investigation.² The source article does not provide subgroup analysis to determine how much of an effect the fabricated data may have had on the final reported outcome. However, a separately reported (and also retracted) sub-analysis of this study indicates that 165/212 (77.8%) patients were enrolled from the site of the first author.³

The question remains: Does ramipril work for symptoms of claudication?

The question remains: Does ramipril work for symptoms of claudication? A completely separate group of researchers conducted a similar, but smaller, randomized clinical trial of ramipril in patients with intermittent claudication.⁴ In this study, 33 patients were randomized to ramipril or placebo for a 24-week trial. The ramipril group (n=14) improved maximum treadmill walking distance by an adjusted mean of 131 meters (m) (95% confidence interval [CI], 62-199; P=.001), improved treadmill intermittent claudication distance by 122 m (95% CI, 56-188; P=.001), and improved patient-reported walking distance by 159 m (95% CI, 66-313; P=.043).

The 2004 Heart Outcomes Prevention Evaluation (HOPE) study indicates that ramipril maintains a mortality benefit for patients with intermittent claudication.⁵ A subgroup of this study included 1725 patients with baseline peripheral artery disease who were randomized to ramipril at 10 mg, which yielded a relative risk (RR) of 0.75 (95% CI, 0.61-0.92) for the primary outcome (cardiovascular mortality, myocardial infarction, stroke). This alone validates the use of ramipril in patients with intermittent claudication. But with the retraction of the large randomized controlled trial, we are not sure how much it may improve walk distances. Further studies might better clarify if ramipril provides symptomatic benefit by reducing claudication symptoms, in addition to the known cardiovascular mortality benefit.

Luke Stephens, MD, MSPH
Park Ridge, IL

James J. Stevermer, MD, MSPH
Columbia, MO

The study¹ that served as the basis for the PURL entitled, “Ramipril for claudication?” (J Fam Pract. 2013;62:579-580), has been retracted from the Journal of the American Medical Association.² Therefore we, on behalf of all of the authors of the PURL, are retracting the PURL, as well.

According to JAMA’s retraction statement, the first author of the article admitted to data fabrication following an internal investigation.² The source article does not provide subgroup analysis to determine how much of an effect the fabricated data may have had on the final reported outcome. However, a separately reported (and also retracted) sub-analysis of this study indicates that 165/212 (77.8%) patients were enrolled from the site of the first author.³

The question remains: Does ramipril work for symptoms of claudication?

The question remains: Does ramipril work for symptoms of claudication? A completely separate group of researchers conducted a similar, but smaller, randomized clinical trial of ramipril in patients with intermittent claudication.⁴ In this study, 33 patients were randomized to ramipril or placebo for a 24-week trial. The ramipril group (n=14) improved maximum treadmill walking distance by an adjusted mean of 131 meters (m) (95% confidence interval [CI], 62-199; P=.001), improved treadmill intermittent claudication distance by 122 m (95% CI, 56-188; P=.001), and improved patient-reported walking distance by 159 m (95% CI, 66-313; P=.043).

The 2004 Heart Outcomes Prevention Evaluation (HOPE) study indicates that ramipril maintains a mortality benefit for patients with intermittent claudication.⁵ A subgroup of this study included 1725 patients with baseline peripheral artery disease who were randomized to ramipril at 10 mg, which yielded a relative risk (RR) of 0.75 (95% CI, 0.61-0.92) for the primary outcome (cardiovascular mortality, myocardial infarction, stroke). This alone validates the use of ramipril in patients with intermittent claudication. But with the retraction of the large randomized controlled trial, we are not sure how much it may improve walk distances. Further studies might better clarify if ramipril provides symptomatic benefit by reducing claudication symptoms, in addition to the known cardiovascular mortality benefit.

Luke Stephens, MD, MSPH
Park Ridge, IL

James J. Stevermer, MD, MSPH
Columbia, MO

The article, “Bone disease in patients with kidney disease: A tricky interplay” (J Fam Pract. 2016;65:606-612), incorrectly stated: “Elevations of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) lead to hyperphosphatemia and hypocalcemia because of decreased urinary excretion of phosphorus.” In fact, FGF23 normally acts to lower blood phosphate levels. Furthermore, an elevated phosphorus level causes an increase in serum calcium levels and not hypocalcemia. This sentence, and the 2 that followed it, should have read:

“Elevations of FGF23 lower blood phosphate levels by inhibiting phosphate reabsorption in the kidneys, thus increasing urinary excretion of phosphorus. Secondary hyperparathyroidism, driven by hypocalcemia, responds to normalize serum calcium levels by increasing the number and size of osteoclasts actively breaking down bone matrix. This increased level of bone breakdown escalates fracture risk.”

This information has been corrected in the online version of the article.

The article, “Bone disease in patients with kidney disease: A tricky interplay” (J Fam Pract. 2016;65:606-612), incorrectly stated: “Elevations of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) lead to hyperphosphatemia and hypocalcemia because of decreased urinary excretion of phosphorus.” In fact, FGF23 normally acts to lower blood phosphate levels. Furthermore, an elevated phosphorus level causes an increase in serum calcium levels and not hypocalcemia. This sentence, and the 2 that followed it, should have read:

“Elevations of FGF23 lower blood phosphate levels by inhibiting phosphate reabsorption in the kidneys, thus increasing urinary excretion of phosphorus. Secondary hyperparathyroidism, driven by hypocalcemia, responds to normalize serum calcium levels by increasing the number and size of osteoclasts actively breaking down bone matrix. This increased level of bone breakdown escalates fracture risk.”

This information has been corrected in the online version of the article.

The article, “Bone disease in patients with kidney disease: A tricky interplay” (J Fam Pract. 2016;65:606-612), incorrectly stated: “Elevations of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) lead to hyperphosphatemia and hypocalcemia because of decreased urinary excretion of phosphorus.” In fact, FGF23 normally acts to lower blood phosphate levels. Furthermore, an elevated phosphorus level causes an increase in serum calcium levels and not hypocalcemia. This sentence, and the 2 that followed it, should have read:

“Elevations of FGF23 lower blood phosphate levels by inhibiting phosphate reabsorption in the kidneys, thus increasing urinary excretion of phosphorus. Secondary hyperparathyroidism, driven by hypocalcemia, responds to normalize serum calcium levels by increasing the number and size of osteoclasts actively breaking down bone matrix. This increased level of bone breakdown escalates fracture risk.”

This information has been corrected in the online version of the article.

CE/CME No: CR-1611

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Understand the prevalence and risks of Chagas disease in the United States.
• Explain the pathophysiology of Chagas disease, including the vector and transmission routes of the disease.
• Describe the clinical presentation of both the acute and chronic forms of the disease and learn when to suspect an infection.
• Outline a plan for diagnosis and treatment of Chagas disease.
• Educate women with Chagas disease about the risk of transmission for future offspring.

FACULTY

Jessica McDonald works in the Emergency Medicine Department at Dekalb Medical Center, Atlanta. Jill Mattingly is Academic Coordinator and Clinical Assistant Professor in the Physician Assistant Program at Mercer University, Atlanta.
The authors have no financial relationships to disclose.

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of November 2016.

Article begins on next page >>

Chagas disease, a parasitic infection, is increasingly being detected in the United States, most likely due to immigration from endemic countries in South and Central America. Approximately 300,000 persons in the US have chronic Chagas disease, and up to 30% of them will develop clinically evident cardiovascular and/or gastrointestinal disease. Here’s practical guidance to help you recognize the features of symptomatic Chagas disease and follow up with appropriate evaluation and management.

Chagas disease, also known as American trypanosomiasis, is caused by the protozoan parasite Trypanosoma cruzi.¹ It is most commonly spread by triatomine bugs infected with T cruzi and is endemic in many parts of Mexico and Central and South America.² Chagas disease was first described in 1909 by Brazilian physician Carlos Chagas.³ Since its discovery, it has often been considered a disease affecting only the poor living in endemic areas of Latin America. However, 6 million to 7 million people are infected with T cruzi worldwide, and estimates suggest that Mexico and the US rank third and seventh, respectively, in the number of persons with T cruzi infection in the Western Hemisphere.^1,4

An estimated 300,000 persons in the US have Chagas disease; most of them are not aware that they are infected.^5,6 The increasing presence of the disease in the US, which traditionally has been considered a nonendemic area, is due to immigration from endemic areas, with subsequent infections occurring through mechanisms that do not require contact with the triatomine vector (eg, congenital transmission).¹ Between 1981 and 2005, more than 7 million people from T cruzi-endemic countries in Latin America moved to the US and became legal residents.³

Early detection and treatment of Chagas disease is important because up to 30% of patients with chronic infection will develop a heart disorder, which can range in severity from conduction system abnormalities to dilated cardiomyopathy.⁴ In some areas of southern Mexico, Chagas disease is the most common cause of dilated cardiomyopathy.¹ Equally concerning is the fact that untreated mothers with Chagas disease can transmit T cruzi to their infants.^1,3 An estimated 315 babies are born with congenital Chagas disease each year in the US, an incidence equivalent to that of phenylketonuria.⁷ It is estimated that congenital transmission is responsible for up to one-quarter of new infections worldwide.¹ Unfortunately, obstetricians are not well informed about the risk factors for congenital Chagas disease, and very limited screening of at-risk women is performed. In a 2008 survey exploring health care providers’ knowledge of and understanding about Chagas disease, obstetricians and gynecologists had the greatest knowledge deficits about the disease, although considerable deficits were also seen among other specialties.¹

KISSING BUG DISEASE: ETIOLOGY/PATHOPHYSIOLOGY

Exposure to the protozoan parasite T cruzi, the cause of Chagas disease, typically occurs following the bite of a triatomine bug. Also known as “kissing bugs” because they usually bite exposed areas of the skin such as the face, triatomine bugs feed on human blood, typically at night, and act as a vector for the parasite.⁸ The parasite lives in the feces and urine of the triatomine bugs and is excreted near the bite during or shortly after a blood meal. The bitten person will then unknowingly smear the infected feces into the bite wound, eyes, mouth, or any opening in the skin, which gives the parasites systemic access.⁴ Once in the host’s bloodstream, the parasite replicates in host cells, a process that ends in cell lysis and hematogenous spread. At this point, the parasites can be seen on peripheral blood smear. Noninfected triatomine insects become infected and continue the cycle when they feed on an infected human host (see Figure 1).³ Persons of lower socioeconomic status living in endemic areas in Latin America are at a higher risk for contracting Chagas disease because “kissing bugs” commonly live in wall or roof cracks of poorly built homes. Populations living in poverty are also at risk due to minimal access to health care and prenatal care.⁴ Transmission of T cruzi not involving triatomine vectors occurs congenitally or through blood transfusions, consumption of contaminated food, and organ donations.⁴

Acute phase

Infection with the T cruzi parasite is followed by an asymptomatic incubation period of one to two weeks, which is then followed by an acute phase that can last eight to 12 weeks.⁵ The acute phase is characterized by a large amount of parasites in the bloodstream (see Table 1). The patient is often asymptomatic but can have nonspecific symptoms such as fever, headache, lymphadenopathy, shortness of breath, myalgia, swelling, and abdominal or chest pain.⁴ Because symptoms during the acute phase are typically mild, many patients do not seek medical attention until they transition into the chronic phase.⁴ Infants are more likely to experience severe symptoms, including myocarditis or meningoencephalitis, and thus are more likely to present during the acute phase.⁹

If the patient acquired the infection through an organ transplant, the acute phase symptoms can be delayed, on average, up to 112 days.5 These patients will have more noticeable symptoms, including hepatosplenomegaly, myocarditis, and congestive heart failure. Due to the known risk for transmission through organ transplants, donors are often screened for Chagas disease. Unfortunately, this screening is selective and often inconsistent.⁵ Therefore, the presence of the previously mentioned symptoms in a person who recently received an organ transplant should raise suspicion of Chagas disease.⁵

Chronic phase

Patients not treated during the acute phase will pass into the chronic phase of Chagas disease.⁵ This may occur due to reactivation of T cruzi infection via immunosuppression.⁹ At this time, the previously asymptomatic patient will have typical signs and symptoms of chronic disease, along with nodules, panniculitis, and myocarditis.^4,9,10 During the chronic phase, parasites are undetectable by microscopy, but the patient can still spread the disease to the vector as well as to others congenitally and through organ donation and blood transfusions.^5,9

Patients with chronic T cruzi infection who remain without signs or symptoms of infection are considered to have the indeterminate form of chronic disease. Many patients will remain in the indeterminate form throughout their lives, but between 20% and 30% will progress to the determinate form of chronic disease over years to decades.³ The determinate form is characterized by clinically evident disease and is classically divided into cardiac Chagas disease and digestive Chagas disease.⁵ Symptoms of the chronic phase depend on the genotype of T cruzi that caused the infection. The AG genotype has a higher incidence of digestive disease.¹¹

Cardiac Chagas disease is believed to occur due to parasite invasion and persistence in cardiac tissue, leading to immune-mediated myocardial injury.⁵ Chagas cardiomyopathy is characterized by chronic myocarditis affecting all cardiac chambers and disturbances in the electrical conduction system; patients also often develop apical aneurysms. Longstanding cardiac Chagas disease can lead to more serious complications, such as episodes of ventricular tachycardia, heart block, thromboembolic phenomena, severe bradycardia, dilated cardiomyopathy, and congestive heart failure. Patients may complain of presyncope, syncope, and episodes of palpitations. They are also at high risk for sudden cardiac death.⁵ Patients with cardiomyopathy or cardiac insufficiency secondary to Chagas disease have a worse prognosis than those with idiopathic cardiomyopathy or decompensated heart failure due to other etiologies.¹²

Less common than cardiac Chagas disease, digestive Chagas disease occurs mostly in Argentina, Bolivia, Chile, Paraguay, Uruguay, and parts of Peru and Brazil; it is rarely seen in northern South America, Central America, or Mexico.⁵ The parasite causes gastrointestinal symptoms by damaging intramural neurons, resulting in denervation of hollow viscera. Since it affects the esophagus and colon, patients may present with dysphagia, odynophagia, cough, reflux, weight loss, constipation, and abdominal pain.⁵

The physical examination of a patient with suspected Chagas disease can be crucial to the diagnosis. As noted, there are often few specific symptoms or physical exam findings during the acute phase. However, in some patients, swelling and inflammation may be evident at the site of inoculation, often on the face or extremities. This finding is called a chagoma. The Romaña sign, characterized by painless unilateral swelling of the upper and lower eyelid, can also be seen if the infection occurred through the conjunctiva.⁵ A nonpruritic morbilliform rash, called schizotrypanides, may be a presenting symptom in patients with acute disease.¹³ Children younger than 2 years of age are at increased risk for a severe acute infection, with signs and symptoms of pericardial effusion, myocarditis, and meningoencephalitis. Children can also develop generalized edema and lymphadenopathy. Those children who develop severe manifestations during acute infection have an increased risk for mortality.⁵

Chronic chagasic cardiomyopathy may present with signs of left-sided heart failure (pulmonary edema, dyspnea at rest or exertion), biventricular heart failure (hepatomegaly, peripheral edema, jugular venous distention), or thromboembolic events to the brain, lower extremities, and lungs.¹³ Chronic chagasic megaesophagus may lead to weight loss, esophageal dysmotility, pneumonitis due to aspiration of food trapped in the esophagus and stomach, salivary gland enlargement, and erosive esophagitis, which increases the risk for esophageal cancer. Chronic chagasic megacolon can present as an intestinal obstruction, volvulus, abdominal distention, or fecaloma.¹³

Clinicians should be alert to the possibility of congenital T cruzi infection in children born to women who emigrated from an endemic area or who visited an area with a high prevalence of Chagas disease. Most newborns with T cruzi infection are asymptomatic, but in some cases a thorough neonatal exam can lead to the diagnosis. Manifestations of symptomatic congenital infection include hepatosplenomegaly, low birth weight, premature birth, and low Apgar scores.⁵ Lab tests may reveal thrombocytopenia and anemia. Neonates with severe disease may also have respiratory distress, meningoencephalitis, and gastrointestinal problems.⁵

LABORATORY WORK-UP

Laboratory work-up for Chagas disease depends on the provider’s awareness of the disease and its symptoms. All patients should undergo routine blood work, including complete blood count (CBC) with differential, comprehensive metabolic panel (CMP), and liver function tests to rule out other etiologies that manifest with similar symptoms. If the patient presents during the acute phase, microscopy of blood smears with Giemsa stain should be done to visualize the parasites. In the patient who presents during the chronic phase with cardiac symptoms, measurement of B-type natriuretic peptide, troponin, C-reactive protein, and the erythrocyte sedimentation rate can be used to rule out other differential diagnoses. Electrocardiogram (ECG) may show a right bundle-branch block or left anterior fascicular block.⁵ Echocardiogram may show left ventricular wall motion abnormalities and/or cardiomyopathy with congestive heart failure.^5,10 A work-up for di­gestive Chagas disease may include a barium swallow, kidney-ureter-bladder x-ray, or MRI/CT of the abdomen.¹⁴

Accurate diagnosis of Chagas disease requires a thorough history and physical exam, as well as a high index of suspicion. Recent travel to an endemic area of Chagas disease in combination with the typical signs and symptoms—such as fever, headache, lymphadenopathy, shortness of breath, myalgia, swelling, and abdominal or chest pain—should prompt the provider to perform more specific tests.⁴ Inquiry about past medical history, blood transfusions, and surgeries is also imperative to make the correct diagnosis.⁵

The approach to diagnosis of Chagas disease depends on whether the patient presents during the acute or chronic phase. During the acute phase, the count of the trypomastigote, the mature extracellular form of the parasite T cruzi, is at its highest, making this the best time to obtain an accurate diagnosis if an infection is suspected.³ Microscopy of fresh preparations of anticoagulated blood or buffy coat may show motile parasites.¹⁰ Other options include visualization of parasites in a blood smear with Giemsa stain or hemoculture. Hemoculture is a sensitive test but takes several weeks to show growth of the parasites. Therefore, polymerase chain reaction (PCR) assay is the preferred diagnostic test due to its high sensitivity and quick turnaround time.⁵

Because no diagnostic gold standard exists for chronic disease, confidently diagnosing Chagas in the United States can be difficult.⁵ Past the acute phase (about three months after infection), microscopy and PCR cannot be used due to low parasi­temia. If an infection with T cruzi is suspected but nine to 14 weeks have passed since exposure, serology is the method of choice for diagnosis. The enzyme-linked immunosorbent assay (ELISA) and immunofluorescent-antibody assay (IFA) are most often used to identify immunoglobulin (Ig) G antibodies to the parasite.

The difficulty of diagnosing Chagas disease in the chronic phase lies in the fact that neither ELISA or IFA alone is sensitive or specific enough to confirm the diagnosis.⁵ In order to make a serologic diagnosis of infection, positive results are needed from two serologic tests based on two different antigens or by using two different techniques (eg, ELISA or IFA). If the two tests are discordant, a third test must be done to determine the patient’s infection status. The radioimmunoprecipitation assay (RIPA) and trypomastigote excreted-secreted antigen immunoblot (TESA-blot) have been traditionally used as confirmatory tests, but even they do not have high sensitivity and specificity. A case of indeterminate Chagas disease is confirmed with positive serologic testing in a patient without symptoms and with normal ECG, chest x-ray, and imaging of the colon and esophagus.¹⁵

The preferred protocol for diagnosis of congenital Chagas disease first requires positive serologic testing confirming the infection in the mother (see Figure 2).¹⁶ Once that is determined, microscopic and PCR-based examinations of cord blood and peripheral blood specimens are carried out during the first one to two months of the infant’s life.¹⁰ PCR is the preferred test for early congenital Chagas disease, recipients of organ transplants, and after accidental exposure since results can determine if the patient is infected earlier than trypomastigotes (developmental stage of trypanosomes) can be seen on a peripheral blood smear.⁵

If there is a suspicion of Chagas disease, the patient should be referred to an infectious disease specialist for diagnosis and treatment. Nifurtimox and benz­nidazole are the only drugs that have been shown to improve the course of Chagas disease.⁵ However, neither drug is approved by the FDA, and both can only be obtained from the CDC, which makes treatment a challenge.⁹ In addition, up to 30% of patients terminate treatment due to the many adverse effects of these drugs.¹⁷

The dosage regimen for nifurtimox is 8-10 mg/kg/d divided into three doses for 90 days.¹⁰ Anorexia, weight loss, nausea, vomiting, and abdominal pain occur in up to 70% of patients.⁵ Irritability, insomnia, disorientation, and tremors can also occur. Neurotoxicity leading to peripheral neuropathy is dose dependent and requires treatment termination.⁵

Benznidazole is better tolerated and is active against the trypomastigotes as well as the amastigotes or intracellular form of the parasite.¹⁰ The dosage regimen for benznidazole is 5-7 mg/kg/d divided into two doses for 60 days.¹⁰ Dermatologic reactions such as rash, photosensitivity, and exfoliative dermatitis are the most common adverse effects. Peripheral neuropathy and bone marrow suppression are dose dependent and require therapy cessation.⁵

The CDC recommends treatment for all cases of acute disease (including congenital disease) regardless of age, and for chronic disease in patients up to age 50 who have not progressed to cardiomyopathy. In patients older than 50, treatment should be determined after weighing the potential risks and benefits (see Table 2).¹⁸

The success of treatment is determined in part by the phase of the disease. Cure rates in patients treated with either nifurtimox or benznidazole during the acute phase range from 65% to 80%.¹⁷ Chronic disease shows less of a response to traditional antiparasitic drug regimens, but higher rates of success are seen in younger patients.⁵ According to current estimates, successful treatment of chronic disease is limited to 15% to 30% patients.¹⁷ Treatment of congenital Chagas disease should begin as soon as the diagnosis is confirmed, and cure rates are greater than 90% if patients are treated within the first year of life.¹⁰ Treating congenital Chagas disease is important because the infection can be passed to future generations even if the disease never manifests with symptoms.¹⁹ However, if an expecting mother has known Chagas disease, antiparasitic medications are not recommended during the pregnancy because of a lack of fetal safety data for the two antiparasitic agents.²⁰ Instead, it is recommended that women of childbearing age be treated before pregnancy, as rates of congenital infection are 25 times lower in women who are treated than in those who are not.²¹

PRE- AND POSTEXPOSURE PATIENT EDUCATION

Patient education mainly focuses on how to prevent Chagas disease and prognosis once diagnosed. During travel to endemic areas, the use of insecticides and residing in well-built households are the most important prevention measures. No vaccine is available, and primary chemoprophylaxis of persons visiting endemic areas is not recommended due to the low risk for infection and concerns about adverse effects.¹³

The survival rate of those who remain in the indeterminate phase is the same as that of the general population. However, findings that most strongly predict mortality include ventricular tachycardia, cardiomegaly, congestive heart failure (NYHA class III/IV), left ventricular systolic dysfunction, and male sex.¹⁰ Patients diagnosed with Chagas disease should be strongly encouraged not to donate blood or organs.¹⁰ Some organ and blood donation organizations selectively or universally screen donated specimens; however, this screening is not required by law.⁵ Family members of those diagnosed with the disease should also be tested, especially if the patient is a woman who has children or who plans to become pregnant.¹⁰

In patients confirmed to have Chagas disease but without symptoms and a normal ECG, further initial evaluation is not required.¹⁰ An annual history, physical exam, and ECG should be done. Those who have symptoms or ECG changes should have a complete cardiac work-up, including a 24-hour ambulatory ECG, exercise stress test, and echocardiogram to determine functional capacity. A barium swallow, barium enema, esophageal manometry, and endoscopy may be indicated in patients with gastrointestinal symptoms of Chagas disease but otherwise are not recommended. Patients taking antiparasitic drugs should have a CBC and CMP at the start of treatment and then bimonthly until the end of treatment to monitor for rare bone marrow suppression. Nifurtimox and benznidazole are also known to be mutagenic and increase the risk for lymphoma in animal studies, but this risk has not been documented in humans.¹⁰

CONCLUSION

Chagas disease is considered one of the neglected tropical diseases due to its high prevalence, chronic course, debilitating symptoms, and association with poverty.⁷ It is evident that incidence and prevalence of Chagas disease in the US are increasing due to recent immigration and mother-to-child transmission. Therefore, family practice clinicians must be able to recognize the red flags that suggest a T cruzi infection.^5,9 Enhanced awareness of Chagas disease among health care providers will lead to better symptom control and cure rates for affected patients and may also prevent congenital infections. These efforts could serve to remove Chagas disease from the list of neglected tropical diseases.

CE/CME No: CR-1611

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Understand the prevalence and risks of Chagas disease in the United States.
• Explain the pathophysiology of Chagas disease, including the vector and transmission routes of the disease.
• Describe the clinical presentation of both the acute and chronic forms of the disease and learn when to suspect an infection.
• Outline a plan for diagnosis and treatment of Chagas disease.
• Educate women with Chagas disease about the risk of transmission for future offspring.

FACULTY

Jessica McDonald works in the Emergency Medicine Department at Dekalb Medical Center, Atlanta. Jill Mattingly is Academic Coordinator and Clinical Assistant Professor in the Physician Assistant Program at Mercer University, Atlanta.
The authors have no financial relationships to disclose.

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of November 2016.

Article begins on next page >>

Chagas disease, a parasitic infection, is increasingly being detected in the United States, most likely due to immigration from endemic countries in South and Central America. Approximately 300,000 persons in the US have chronic Chagas disease, and up to 30% of them will develop clinically evident cardiovascular and/or gastrointestinal disease. Here’s practical guidance to help you recognize the features of symptomatic Chagas disease and follow up with appropriate evaluation and management.

Chagas disease, also known as American trypanosomiasis, is caused by the protozoan parasite Trypanosoma cruzi.¹ It is most commonly spread by triatomine bugs infected with T cruzi and is endemic in many parts of Mexico and Central and South America.² Chagas disease was first described in 1909 by Brazilian physician Carlos Chagas.³ Since its discovery, it has often been considered a disease affecting only the poor living in endemic areas of Latin America. However, 6 million to 7 million people are infected with T cruzi worldwide, and estimates suggest that Mexico and the US rank third and seventh, respectively, in the number of persons with T cruzi infection in the Western Hemisphere.^1,4

An estimated 300,000 persons in the US have Chagas disease; most of them are not aware that they are infected.^5,6 The increasing presence of the disease in the US, which traditionally has been considered a nonendemic area, is due to immigration from endemic areas, with subsequent infections occurring through mechanisms that do not require contact with the triatomine vector (eg, congenital transmission).¹ Between 1981 and 2005, more than 7 million people from T cruzi-endemic countries in Latin America moved to the US and became legal residents.³

Early detection and treatment of Chagas disease is important because up to 30% of patients with chronic infection will develop a heart disorder, which can range in severity from conduction system abnormalities to dilated cardiomyopathy.⁴ In some areas of southern Mexico, Chagas disease is the most common cause of dilated cardiomyopathy.¹ Equally concerning is the fact that untreated mothers with Chagas disease can transmit T cruzi to their infants.^1,3 An estimated 315 babies are born with congenital Chagas disease each year in the US, an incidence equivalent to that of phenylketonuria.⁷ It is estimated that congenital transmission is responsible for up to one-quarter of new infections worldwide.¹ Unfortunately, obstetricians are not well informed about the risk factors for congenital Chagas disease, and very limited screening of at-risk women is performed. In a 2008 survey exploring health care providers’ knowledge of and understanding about Chagas disease, obstetricians and gynecologists had the greatest knowledge deficits about the disease, although considerable deficits were also seen among other specialties.¹

KISSING BUG DISEASE: ETIOLOGY/PATHOPHYSIOLOGY

Exposure to the protozoan parasite T cruzi, the cause of Chagas disease, typically occurs following the bite of a triatomine bug. Also known as “kissing bugs” because they usually bite exposed areas of the skin such as the face, triatomine bugs feed on human blood, typically at night, and act as a vector for the parasite.⁸ The parasite lives in the feces and urine of the triatomine bugs and is excreted near the bite during or shortly after a blood meal. The bitten person will then unknowingly smear the infected feces into the bite wound, eyes, mouth, or any opening in the skin, which gives the parasites systemic access.⁴ Once in the host’s bloodstream, the parasite replicates in host cells, a process that ends in cell lysis and hematogenous spread. At this point, the parasites can be seen on peripheral blood smear. Noninfected triatomine insects become infected and continue the cycle when they feed on an infected human host (see Figure 1).³ Persons of lower socioeconomic status living in endemic areas in Latin America are at a higher risk for contracting Chagas disease because “kissing bugs” commonly live in wall or roof cracks of poorly built homes. Populations living in poverty are also at risk due to minimal access to health care and prenatal care.⁴ Transmission of T cruzi not involving triatomine vectors occurs congenitally or through blood transfusions, consumption of contaminated food, and organ donations.⁴

Acute phase

Infection with the T cruzi parasite is followed by an asymptomatic incubation period of one to two weeks, which is then followed by an acute phase that can last eight to 12 weeks.⁵ The acute phase is characterized by a large amount of parasites in the bloodstream (see Table 1). The patient is often asymptomatic but can have nonspecific symptoms such as fever, headache, lymphadenopathy, shortness of breath, myalgia, swelling, and abdominal or chest pain.⁴ Because symptoms during the acute phase are typically mild, many patients do not seek medical attention until they transition into the chronic phase.⁴ Infants are more likely to experience severe symptoms, including myocarditis or meningoencephalitis, and thus are more likely to present during the acute phase.⁹

If the patient acquired the infection through an organ transplant, the acute phase symptoms can be delayed, on average, up to 112 days.5 These patients will have more noticeable symptoms, including hepatosplenomegaly, myocarditis, and congestive heart failure. Due to the known risk for transmission through organ transplants, donors are often screened for Chagas disease. Unfortunately, this screening is selective and often inconsistent.⁵ Therefore, the presence of the previously mentioned symptoms in a person who recently received an organ transplant should raise suspicion of Chagas disease.⁵

Chronic phase

Patients not treated during the acute phase will pass into the chronic phase of Chagas disease.⁵ This may occur due to reactivation of T cruzi infection via immunosuppression.⁹ At this time, the previously asymptomatic patient will have typical signs and symptoms of chronic disease, along with nodules, panniculitis, and myocarditis.^4,9,10 During the chronic phase, parasites are undetectable by microscopy, but the patient can still spread the disease to the vector as well as to others congenitally and through organ donation and blood transfusions.^5,9

Patients with chronic T cruzi infection who remain without signs or symptoms of infection are considered to have the indeterminate form of chronic disease. Many patients will remain in the indeterminate form throughout their lives, but between 20% and 30% will progress to the determinate form of chronic disease over years to decades.³ The determinate form is characterized by clinically evident disease and is classically divided into cardiac Chagas disease and digestive Chagas disease.⁵ Symptoms of the chronic phase depend on the genotype of T cruzi that caused the infection. The AG genotype has a higher incidence of digestive disease.¹¹

Cardiac Chagas disease is believed to occur due to parasite invasion and persistence in cardiac tissue, leading to immune-mediated myocardial injury.⁵ Chagas cardiomyopathy is characterized by chronic myocarditis affecting all cardiac chambers and disturbances in the electrical conduction system; patients also often develop apical aneurysms. Longstanding cardiac Chagas disease can lead to more serious complications, such as episodes of ventricular tachycardia, heart block, thromboembolic phenomena, severe bradycardia, dilated cardiomyopathy, and congestive heart failure. Patients may complain of presyncope, syncope, and episodes of palpitations. They are also at high risk for sudden cardiac death.⁵ Patients with cardiomyopathy or cardiac insufficiency secondary to Chagas disease have a worse prognosis than those with idiopathic cardiomyopathy or decompensated heart failure due to other etiologies.¹²

Less common than cardiac Chagas disease, digestive Chagas disease occurs mostly in Argentina, Bolivia, Chile, Paraguay, Uruguay, and parts of Peru and Brazil; it is rarely seen in northern South America, Central America, or Mexico.⁵ The parasite causes gastrointestinal symptoms by damaging intramural neurons, resulting in denervation of hollow viscera. Since it affects the esophagus and colon, patients may present with dysphagia, odynophagia, cough, reflux, weight loss, constipation, and abdominal pain.⁵

The physical examination of a patient with suspected Chagas disease can be crucial to the diagnosis. As noted, there are often few specific symptoms or physical exam findings during the acute phase. However, in some patients, swelling and inflammation may be evident at the site of inoculation, often on the face or extremities. This finding is called a chagoma. The Romaña sign, characterized by painless unilateral swelling of the upper and lower eyelid, can also be seen if the infection occurred through the conjunctiva.⁵ A nonpruritic morbilliform rash, called schizotrypanides, may be a presenting symptom in patients with acute disease.¹³ Children younger than 2 years of age are at increased risk for a severe acute infection, with signs and symptoms of pericardial effusion, myocarditis, and meningoencephalitis. Children can also develop generalized edema and lymphadenopathy. Those children who develop severe manifestations during acute infection have an increased risk for mortality.⁵

Chronic chagasic cardiomyopathy may present with signs of left-sided heart failure (pulmonary edema, dyspnea at rest or exertion), biventricular heart failure (hepatomegaly, peripheral edema, jugular venous distention), or thromboembolic events to the brain, lower extremities, and lungs.¹³ Chronic chagasic megaesophagus may lead to weight loss, esophageal dysmotility, pneumonitis due to aspiration of food trapped in the esophagus and stomach, salivary gland enlargement, and erosive esophagitis, which increases the risk for esophageal cancer. Chronic chagasic megacolon can present as an intestinal obstruction, volvulus, abdominal distention, or fecaloma.¹³

Clinicians should be alert to the possibility of congenital T cruzi infection in children born to women who emigrated from an endemic area or who visited an area with a high prevalence of Chagas disease. Most newborns with T cruzi infection are asymptomatic, but in some cases a thorough neonatal exam can lead to the diagnosis. Manifestations of symptomatic congenital infection include hepatosplenomegaly, low birth weight, premature birth, and low Apgar scores.⁵ Lab tests may reveal thrombocytopenia and anemia. Neonates with severe disease may also have respiratory distress, meningoencephalitis, and gastrointestinal problems.⁵

LABORATORY WORK-UP

Laboratory work-up for Chagas disease depends on the provider’s awareness of the disease and its symptoms. All patients should undergo routine blood work, including complete blood count (CBC) with differential, comprehensive metabolic panel (CMP), and liver function tests to rule out other etiologies that manifest with similar symptoms. If the patient presents during the acute phase, microscopy of blood smears with Giemsa stain should be done to visualize the parasites. In the patient who presents during the chronic phase with cardiac symptoms, measurement of B-type natriuretic peptide, troponin, C-reactive protein, and the erythrocyte sedimentation rate can be used to rule out other differential diagnoses. Electrocardiogram (ECG) may show a right bundle-branch block or left anterior fascicular block.⁵ Echocardiogram may show left ventricular wall motion abnormalities and/or cardiomyopathy with congestive heart failure.^5,10 A work-up for di­gestive Chagas disease may include a barium swallow, kidney-ureter-bladder x-ray, or MRI/CT of the abdomen.¹⁴

Accurate diagnosis of Chagas disease requires a thorough history and physical exam, as well as a high index of suspicion. Recent travel to an endemic area of Chagas disease in combination with the typical signs and symptoms—such as fever, headache, lymphadenopathy, shortness of breath, myalgia, swelling, and abdominal or chest pain—should prompt the provider to perform more specific tests.⁴ Inquiry about past medical history, blood transfusions, and surgeries is also imperative to make the correct diagnosis.⁵

The approach to diagnosis of Chagas disease depends on whether the patient presents during the acute or chronic phase. During the acute phase, the count of the trypomastigote, the mature extracellular form of the parasite T cruzi, is at its highest, making this the best time to obtain an accurate diagnosis if an infection is suspected.³ Microscopy of fresh preparations of anticoagulated blood or buffy coat may show motile parasites.¹⁰ Other options include visualization of parasites in a blood smear with Giemsa stain or hemoculture. Hemoculture is a sensitive test but takes several weeks to show growth of the parasites. Therefore, polymerase chain reaction (PCR) assay is the preferred diagnostic test due to its high sensitivity and quick turnaround time.⁵

Because no diagnostic gold standard exists for chronic disease, confidently diagnosing Chagas in the United States can be difficult.⁵ Past the acute phase (about three months after infection), microscopy and PCR cannot be used due to low parasi­temia. If an infection with T cruzi is suspected but nine to 14 weeks have passed since exposure, serology is the method of choice for diagnosis. The enzyme-linked immunosorbent assay (ELISA) and immunofluorescent-antibody assay (IFA) are most often used to identify immunoglobulin (Ig) G antibodies to the parasite.

The difficulty of diagnosing Chagas disease in the chronic phase lies in the fact that neither ELISA or IFA alone is sensitive or specific enough to confirm the diagnosis.⁵ In order to make a serologic diagnosis of infection, positive results are needed from two serologic tests based on two different antigens or by using two different techniques (eg, ELISA or IFA). If the two tests are discordant, a third test must be done to determine the patient’s infection status. The radioimmunoprecipitation assay (RIPA) and trypomastigote excreted-secreted antigen immunoblot (TESA-blot) have been traditionally used as confirmatory tests, but even they do not have high sensitivity and specificity. A case of indeterminate Chagas disease is confirmed with positive serologic testing in a patient without symptoms and with normal ECG, chest x-ray, and imaging of the colon and esophagus.¹⁵

The preferred protocol for diagnosis of congenital Chagas disease first requires positive serologic testing confirming the infection in the mother (see Figure 2).¹⁶ Once that is determined, microscopic and PCR-based examinations of cord blood and peripheral blood specimens are carried out during the first one to two months of the infant’s life.¹⁰ PCR is the preferred test for early congenital Chagas disease, recipients of organ transplants, and after accidental exposure since results can determine if the patient is infected earlier than trypomastigotes (developmental stage of trypanosomes) can be seen on a peripheral blood smear.⁵

If there is a suspicion of Chagas disease, the patient should be referred to an infectious disease specialist for diagnosis and treatment. Nifurtimox and benz­nidazole are the only drugs that have been shown to improve the course of Chagas disease.⁵ However, neither drug is approved by the FDA, and both can only be obtained from the CDC, which makes treatment a challenge.⁹ In addition, up to 30% of patients terminate treatment due to the many adverse effects of these drugs.¹⁷

The dosage regimen for nifurtimox is 8-10 mg/kg/d divided into three doses for 90 days.¹⁰ Anorexia, weight loss, nausea, vomiting, and abdominal pain occur in up to 70% of patients.⁵ Irritability, insomnia, disorientation, and tremors can also occur. Neurotoxicity leading to peripheral neuropathy is dose dependent and requires treatment termination.⁵

Benznidazole is better tolerated and is active against the trypomastigotes as well as the amastigotes or intracellular form of the parasite.¹⁰ The dosage regimen for benznidazole is 5-7 mg/kg/d divided into two doses for 60 days.¹⁰ Dermatologic reactions such as rash, photosensitivity, and exfoliative dermatitis are the most common adverse effects. Peripheral neuropathy and bone marrow suppression are dose dependent and require therapy cessation.⁵

The CDC recommends treatment for all cases of acute disease (including congenital disease) regardless of age, and for chronic disease in patients up to age 50 who have not progressed to cardiomyopathy. In patients older than 50, treatment should be determined after weighing the potential risks and benefits (see Table 2).¹⁸

The success of treatment is determined in part by the phase of the disease. Cure rates in patients treated with either nifurtimox or benznidazole during the acute phase range from 65% to 80%.¹⁷ Chronic disease shows less of a response to traditional antiparasitic drug regimens, but higher rates of success are seen in younger patients.⁵ According to current estimates, successful treatment of chronic disease is limited to 15% to 30% patients.¹⁷ Treatment of congenital Chagas disease should begin as soon as the diagnosis is confirmed, and cure rates are greater than 90% if patients are treated within the first year of life.¹⁰ Treating congenital Chagas disease is important because the infection can be passed to future generations even if the disease never manifests with symptoms.¹⁹ However, if an expecting mother has known Chagas disease, antiparasitic medications are not recommended during the pregnancy because of a lack of fetal safety data for the two antiparasitic agents.²⁰ Instead, it is recommended that women of childbearing age be treated before pregnancy, as rates of congenital infection are 25 times lower in women who are treated than in those who are not.²¹

PRE- AND POSTEXPOSURE PATIENT EDUCATION

Patient education mainly focuses on how to prevent Chagas disease and prognosis once diagnosed. During travel to endemic areas, the use of insecticides and residing in well-built households are the most important prevention measures. No vaccine is available, and primary chemoprophylaxis of persons visiting endemic areas is not recommended due to the low risk for infection and concerns about adverse effects.¹³

The survival rate of those who remain in the indeterminate phase is the same as that of the general population. However, findings that most strongly predict mortality include ventricular tachycardia, cardiomegaly, congestive heart failure (NYHA class III/IV), left ventricular systolic dysfunction, and male sex.¹⁰ Patients diagnosed with Chagas disease should be strongly encouraged not to donate blood or organs.¹⁰ Some organ and blood donation organizations selectively or universally screen donated specimens; however, this screening is not required by law.⁵ Family members of those diagnosed with the disease should also be tested, especially if the patient is a woman who has children or who plans to become pregnant.¹⁰

In patients confirmed to have Chagas disease but without symptoms and a normal ECG, further initial evaluation is not required.¹⁰ An annual history, physical exam, and ECG should be done. Those who have symptoms or ECG changes should have a complete cardiac work-up, including a 24-hour ambulatory ECG, exercise stress test, and echocardiogram to determine functional capacity. A barium swallow, barium enema, esophageal manometry, and endoscopy may be indicated in patients with gastrointestinal symptoms of Chagas disease but otherwise are not recommended. Patients taking antiparasitic drugs should have a CBC and CMP at the start of treatment and then bimonthly until the end of treatment to monitor for rare bone marrow suppression. Nifurtimox and benznidazole are also known to be mutagenic and increase the risk for lymphoma in animal studies, but this risk has not been documented in humans.¹⁰

CONCLUSION

Chagas disease is considered one of the neglected tropical diseases due to its high prevalence, chronic course, debilitating symptoms, and association with poverty.⁷ It is evident that incidence and prevalence of Chagas disease in the US are increasing due to recent immigration and mother-to-child transmission. Therefore, family practice clinicians must be able to recognize the red flags that suggest a T cruzi infection.^5,9 Enhanced awareness of Chagas disease among health care providers will lead to better symptom control and cure rates for affected patients and may also prevent congenital infections. These efforts could serve to remove Chagas disease from the list of neglected tropical diseases.

CE/CME No: CR-1611

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Understand the prevalence and risks of Chagas disease in the United States.
• Explain the pathophysiology of Chagas disease, including the vector and transmission routes of the disease.
• Describe the clinical presentation of both the acute and chronic forms of the disease and learn when to suspect an infection.
• Outline a plan for diagnosis and treatment of Chagas disease.
• Educate women with Chagas disease about the risk of transmission for future offspring.

FACULTY

Jessica McDonald works in the Emergency Medicine Department at Dekalb Medical Center, Atlanta. Jill Mattingly is Academic Coordinator and Clinical Assistant Professor in the Physician Assistant Program at Mercer University, Atlanta.
The authors have no financial relationships to disclose.

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of November 2016.

Article begins on next page >>

Chagas disease, a parasitic infection, is increasingly being detected in the United States, most likely due to immigration from endemic countries in South and Central America. Approximately 300,000 persons in the US have chronic Chagas disease, and up to 30% of them will develop clinically evident cardiovascular and/or gastrointestinal disease. Here’s practical guidance to help you recognize the features of symptomatic Chagas disease and follow up with appropriate evaluation and management.

Chagas disease, also known as American trypanosomiasis, is caused by the protozoan parasite Trypanosoma cruzi.¹ It is most commonly spread by triatomine bugs infected with T cruzi and is endemic in many parts of Mexico and Central and South America.² Chagas disease was first described in 1909 by Brazilian physician Carlos Chagas.³ Since its discovery, it has often been considered a disease affecting only the poor living in endemic areas of Latin America. However, 6 million to 7 million people are infected with T cruzi worldwide, and estimates suggest that Mexico and the US rank third and seventh, respectively, in the number of persons with T cruzi infection in the Western Hemisphere.^1,4

An estimated 300,000 persons in the US have Chagas disease; most of them are not aware that they are infected.^5,6 The increasing presence of the disease in the US, which traditionally has been considered a nonendemic area, is due to immigration from endemic areas, with subsequent infections occurring through mechanisms that do not require contact with the triatomine vector (eg, congenital transmission).¹ Between 1981 and 2005, more than 7 million people from T cruzi-endemic countries in Latin America moved to the US and became legal residents.³

Early detection and treatment of Chagas disease is important because up to 30% of patients with chronic infection will develop a heart disorder, which can range in severity from conduction system abnormalities to dilated cardiomyopathy.⁴ In some areas of southern Mexico, Chagas disease is the most common cause of dilated cardiomyopathy.¹ Equally concerning is the fact that untreated mothers with Chagas disease can transmit T cruzi to their infants.^1,3 An estimated 315 babies are born with congenital Chagas disease each year in the US, an incidence equivalent to that of phenylketonuria.⁷ It is estimated that congenital transmission is responsible for up to one-quarter of new infections worldwide.¹ Unfortunately, obstetricians are not well informed about the risk factors for congenital Chagas disease, and very limited screening of at-risk women is performed. In a 2008 survey exploring health care providers’ knowledge of and understanding about Chagas disease, obstetricians and gynecologists had the greatest knowledge deficits about the disease, although considerable deficits were also seen among other specialties.¹

KISSING BUG DISEASE: ETIOLOGY/PATHOPHYSIOLOGY

Exposure to the protozoan parasite T cruzi, the cause of Chagas disease, typically occurs following the bite of a triatomine bug. Also known as “kissing bugs” because they usually bite exposed areas of the skin such as the face, triatomine bugs feed on human blood, typically at night, and act as a vector for the parasite.⁸ The parasite lives in the feces and urine of the triatomine bugs and is excreted near the bite during or shortly after a blood meal. The bitten person will then unknowingly smear the infected feces into the bite wound, eyes, mouth, or any opening in the skin, which gives the parasites systemic access.⁴ Once in the host’s bloodstream, the parasite replicates in host cells, a process that ends in cell lysis and hematogenous spread. At this point, the parasites can be seen on peripheral blood smear. Noninfected triatomine insects become infected and continue the cycle when they feed on an infected human host (see Figure 1).³ Persons of lower socioeconomic status living in endemic areas in Latin America are at a higher risk for contracting Chagas disease because “kissing bugs” commonly live in wall or roof cracks of poorly built homes. Populations living in poverty are also at risk due to minimal access to health care and prenatal care.⁴ Transmission of T cruzi not involving triatomine vectors occurs congenitally or through blood transfusions, consumption of contaminated food, and organ donations.⁴

Acute phase

Infection with the T cruzi parasite is followed by an asymptomatic incubation period of one to two weeks, which is then followed by an acute phase that can last eight to 12 weeks.⁵ The acute phase is characterized by a large amount of parasites in the bloodstream (see Table 1). The patient is often asymptomatic but can have nonspecific symptoms such as fever, headache, lymphadenopathy, shortness of breath, myalgia, swelling, and abdominal or chest pain.⁴ Because symptoms during the acute phase are typically mild, many patients do not seek medical attention until they transition into the chronic phase.⁴ Infants are more likely to experience severe symptoms, including myocarditis or meningoencephalitis, and thus are more likely to present during the acute phase.⁹

If the patient acquired the infection through an organ transplant, the acute phase symptoms can be delayed, on average, up to 112 days.5 These patients will have more noticeable symptoms, including hepatosplenomegaly, myocarditis, and congestive heart failure. Due to the known risk for transmission through organ transplants, donors are often screened for Chagas disease. Unfortunately, this screening is selective and often inconsistent.⁵ Therefore, the presence of the previously mentioned symptoms in a person who recently received an organ transplant should raise suspicion of Chagas disease.⁵

Chronic phase

Patients not treated during the acute phase will pass into the chronic phase of Chagas disease.⁵ This may occur due to reactivation of T cruzi infection via immunosuppression.⁹ At this time, the previously asymptomatic patient will have typical signs and symptoms of chronic disease, along with nodules, panniculitis, and myocarditis.^4,9,10 During the chronic phase, parasites are undetectable by microscopy, but the patient can still spread the disease to the vector as well as to others congenitally and through organ donation and blood transfusions.^5,9

Patients with chronic T cruzi infection who remain without signs or symptoms of infection are considered to have the indeterminate form of chronic disease. Many patients will remain in the indeterminate form throughout their lives, but between 20% and 30% will progress to the determinate form of chronic disease over years to decades.³ The determinate form is characterized by clinically evident disease and is classically divided into cardiac Chagas disease and digestive Chagas disease.⁵ Symptoms of the chronic phase depend on the genotype of T cruzi that caused the infection. The AG genotype has a higher incidence of digestive disease.¹¹

Cardiac Chagas disease is believed to occur due to parasite invasion and persistence in cardiac tissue, leading to immune-mediated myocardial injury.⁵ Chagas cardiomyopathy is characterized by chronic myocarditis affecting all cardiac chambers and disturbances in the electrical conduction system; patients also often develop apical aneurysms. Longstanding cardiac Chagas disease can lead to more serious complications, such as episodes of ventricular tachycardia, heart block, thromboembolic phenomena, severe bradycardia, dilated cardiomyopathy, and congestive heart failure. Patients may complain of presyncope, syncope, and episodes of palpitations. They are also at high risk for sudden cardiac death.⁵ Patients with cardiomyopathy or cardiac insufficiency secondary to Chagas disease have a worse prognosis than those with idiopathic cardiomyopathy or decompensated heart failure due to other etiologies.¹²

Less common than cardiac Chagas disease, digestive Chagas disease occurs mostly in Argentina, Bolivia, Chile, Paraguay, Uruguay, and parts of Peru and Brazil; it is rarely seen in northern South America, Central America, or Mexico.⁵ The parasite causes gastrointestinal symptoms by damaging intramural neurons, resulting in denervation of hollow viscera. Since it affects the esophagus and colon, patients may present with dysphagia, odynophagia, cough, reflux, weight loss, constipation, and abdominal pain.⁵

The physical examination of a patient with suspected Chagas disease can be crucial to the diagnosis. As noted, there are often few specific symptoms or physical exam findings during the acute phase. However, in some patients, swelling and inflammation may be evident at the site of inoculation, often on the face or extremities. This finding is called a chagoma. The Romaña sign, characterized by painless unilateral swelling of the upper and lower eyelid, can also be seen if the infection occurred through the conjunctiva.⁵ A nonpruritic morbilliform rash, called schizotrypanides, may be a presenting symptom in patients with acute disease.¹³ Children younger than 2 years of age are at increased risk for a severe acute infection, with signs and symptoms of pericardial effusion, myocarditis, and meningoencephalitis. Children can also develop generalized edema and lymphadenopathy. Those children who develop severe manifestations during acute infection have an increased risk for mortality.⁵

Chronic chagasic cardiomyopathy may present with signs of left-sided heart failure (pulmonary edema, dyspnea at rest or exertion), biventricular heart failure (hepatomegaly, peripheral edema, jugular venous distention), or thromboembolic events to the brain, lower extremities, and lungs.¹³ Chronic chagasic megaesophagus may lead to weight loss, esophageal dysmotility, pneumonitis due to aspiration of food trapped in the esophagus and stomach, salivary gland enlargement, and erosive esophagitis, which increases the risk for esophageal cancer. Chronic chagasic megacolon can present as an intestinal obstruction, volvulus, abdominal distention, or fecaloma.¹³

Clinicians should be alert to the possibility of congenital T cruzi infection in children born to women who emigrated from an endemic area or who visited an area with a high prevalence of Chagas disease. Most newborns with T cruzi infection are asymptomatic, but in some cases a thorough neonatal exam can lead to the diagnosis. Manifestations of symptomatic congenital infection include hepatosplenomegaly, low birth weight, premature birth, and low Apgar scores.⁵ Lab tests may reveal thrombocytopenia and anemia. Neonates with severe disease may also have respiratory distress, meningoencephalitis, and gastrointestinal problems.⁵

LABORATORY WORK-UP

Laboratory work-up for Chagas disease depends on the provider’s awareness of the disease and its symptoms. All patients should undergo routine blood work, including complete blood count (CBC) with differential, comprehensive metabolic panel (CMP), and liver function tests to rule out other etiologies that manifest with similar symptoms. If the patient presents during the acute phase, microscopy of blood smears with Giemsa stain should be done to visualize the parasites. In the patient who presents during the chronic phase with cardiac symptoms, measurement of B-type natriuretic peptide, troponin, C-reactive protein, and the erythrocyte sedimentation rate can be used to rule out other differential diagnoses. Electrocardiogram (ECG) may show a right bundle-branch block or left anterior fascicular block.⁵ Echocardiogram may show left ventricular wall motion abnormalities and/or cardiomyopathy with congestive heart failure.^5,10 A work-up for di­gestive Chagas disease may include a barium swallow, kidney-ureter-bladder x-ray, or MRI/CT of the abdomen.¹⁴

Accurate diagnosis of Chagas disease requires a thorough history and physical exam, as well as a high index of suspicion. Recent travel to an endemic area of Chagas disease in combination with the typical signs and symptoms—such as fever, headache, lymphadenopathy, shortness of breath, myalgia, swelling, and abdominal or chest pain—should prompt the provider to perform more specific tests.⁴ Inquiry about past medical history, blood transfusions, and surgeries is also imperative to make the correct diagnosis.⁵

The approach to diagnosis of Chagas disease depends on whether the patient presents during the acute or chronic phase. During the acute phase, the count of the trypomastigote, the mature extracellular form of the parasite T cruzi, is at its highest, making this the best time to obtain an accurate diagnosis if an infection is suspected.³ Microscopy of fresh preparations of anticoagulated blood or buffy coat may show motile parasites.¹⁰ Other options include visualization of parasites in a blood smear with Giemsa stain or hemoculture. Hemoculture is a sensitive test but takes several weeks to show growth of the parasites. Therefore, polymerase chain reaction (PCR) assay is the preferred diagnostic test due to its high sensitivity and quick turnaround time.⁵

Because no diagnostic gold standard exists for chronic disease, confidently diagnosing Chagas in the United States can be difficult.⁵ Past the acute phase (about three months after infection), microscopy and PCR cannot be used due to low parasi­temia. If an infection with T cruzi is suspected but nine to 14 weeks have passed since exposure, serology is the method of choice for diagnosis. The enzyme-linked immunosorbent assay (ELISA) and immunofluorescent-antibody assay (IFA) are most often used to identify immunoglobulin (Ig) G antibodies to the parasite.

The difficulty of diagnosing Chagas disease in the chronic phase lies in the fact that neither ELISA or IFA alone is sensitive or specific enough to confirm the diagnosis.⁵ In order to make a serologic diagnosis of infection, positive results are needed from two serologic tests based on two different antigens or by using two different techniques (eg, ELISA or IFA). If the two tests are discordant, a third test must be done to determine the patient’s infection status. The radioimmunoprecipitation assay (RIPA) and trypomastigote excreted-secreted antigen immunoblot (TESA-blot) have been traditionally used as confirmatory tests, but even they do not have high sensitivity and specificity. A case of indeterminate Chagas disease is confirmed with positive serologic testing in a patient without symptoms and with normal ECG, chest x-ray, and imaging of the colon and esophagus.¹⁵

The preferred protocol for diagnosis of congenital Chagas disease first requires positive serologic testing confirming the infection in the mother (see Figure 2).¹⁶ Once that is determined, microscopic and PCR-based examinations of cord blood and peripheral blood specimens are carried out during the first one to two months of the infant’s life.¹⁰ PCR is the preferred test for early congenital Chagas disease, recipients of organ transplants, and after accidental exposure since results can determine if the patient is infected earlier than trypomastigotes (developmental stage of trypanosomes) can be seen on a peripheral blood smear.⁵

If there is a suspicion of Chagas disease, the patient should be referred to an infectious disease specialist for diagnosis and treatment. Nifurtimox and benz­nidazole are the only drugs that have been shown to improve the course of Chagas disease.⁵ However, neither drug is approved by the FDA, and both can only be obtained from the CDC, which makes treatment a challenge.⁹ In addition, up to 30% of patients terminate treatment due to the many adverse effects of these drugs.¹⁷

The dosage regimen for nifurtimox is 8-10 mg/kg/d divided into three doses for 90 days.¹⁰ Anorexia, weight loss, nausea, vomiting, and abdominal pain occur in up to 70% of patients.⁵ Irritability, insomnia, disorientation, and tremors can also occur. Neurotoxicity leading to peripheral neuropathy is dose dependent and requires treatment termination.⁵

Benznidazole is better tolerated and is active against the trypomastigotes as well as the amastigotes or intracellular form of the parasite.¹⁰ The dosage regimen for benznidazole is 5-7 mg/kg/d divided into two doses for 60 days.¹⁰ Dermatologic reactions such as rash, photosensitivity, and exfoliative dermatitis are the most common adverse effects. Peripheral neuropathy and bone marrow suppression are dose dependent and require therapy cessation.⁵

The CDC recommends treatment for all cases of acute disease (including congenital disease) regardless of age, and for chronic disease in patients up to age 50 who have not progressed to cardiomyopathy. In patients older than 50, treatment should be determined after weighing the potential risks and benefits (see Table 2).¹⁸

The success of treatment is determined in part by the phase of the disease. Cure rates in patients treated with either nifurtimox or benznidazole during the acute phase range from 65% to 80%.¹⁷ Chronic disease shows less of a response to traditional antiparasitic drug regimens, but higher rates of success are seen in younger patients.⁵ According to current estimates, successful treatment of chronic disease is limited to 15% to 30% patients.¹⁷ Treatment of congenital Chagas disease should begin as soon as the diagnosis is confirmed, and cure rates are greater than 90% if patients are treated within the first year of life.¹⁰ Treating congenital Chagas disease is important because the infection can be passed to future generations even if the disease never manifests with symptoms.¹⁹ However, if an expecting mother has known Chagas disease, antiparasitic medications are not recommended during the pregnancy because of a lack of fetal safety data for the two antiparasitic agents.²⁰ Instead, it is recommended that women of childbearing age be treated before pregnancy, as rates of congenital infection are 25 times lower in women who are treated than in those who are not.²¹

PRE- AND POSTEXPOSURE PATIENT EDUCATION

Patient education mainly focuses on how to prevent Chagas disease and prognosis once diagnosed. During travel to endemic areas, the use of insecticides and residing in well-built households are the most important prevention measures. No vaccine is available, and primary chemoprophylaxis of persons visiting endemic areas is not recommended due to the low risk for infection and concerns about adverse effects.¹³

The survival rate of those who remain in the indeterminate phase is the same as that of the general population. However, findings that most strongly predict mortality include ventricular tachycardia, cardiomegaly, congestive heart failure (NYHA class III/IV), left ventricular systolic dysfunction, and male sex.¹⁰ Patients diagnosed with Chagas disease should be strongly encouraged not to donate blood or organs.¹⁰ Some organ and blood donation organizations selectively or universally screen donated specimens; however, this screening is not required by law.⁵ Family members of those diagnosed with the disease should also be tested, especially if the patient is a woman who has children or who plans to become pregnant.¹⁰

In patients confirmed to have Chagas disease but without symptoms and a normal ECG, further initial evaluation is not required.¹⁰ An annual history, physical exam, and ECG should be done. Those who have symptoms or ECG changes should have a complete cardiac work-up, including a 24-hour ambulatory ECG, exercise stress test, and echocardiogram to determine functional capacity. A barium swallow, barium enema, esophageal manometry, and endoscopy may be indicated in patients with gastrointestinal symptoms of Chagas disease but otherwise are not recommended. Patients taking antiparasitic drugs should have a CBC and CMP at the start of treatment and then bimonthly until the end of treatment to monitor for rare bone marrow suppression. Nifurtimox and benznidazole are also known to be mutagenic and increase the risk for lymphoma in animal studies, but this risk has not been documented in humans.¹⁰

CONCLUSION

Chagas disease is considered one of the neglected tropical diseases due to its high prevalence, chronic course, debilitating symptoms, and association with poverty.⁷ It is evident that incidence and prevalence of Chagas disease in the US are increasing due to recent immigration and mother-to-child transmission. Therefore, family practice clinicians must be able to recognize the red flags that suggest a T cruzi infection.^5,9 Enhanced awareness of Chagas disease among health care providers will lead to better symptom control and cure rates for affected patients and may also prevent congenital infections. These efforts could serve to remove Chagas disease from the list of neglected tropical diseases.

EVIDENCE SUMMARY

The TABLE^1-4 shows the major results of the meta-analyses for the various medical therapy trials.

Two systematic reviews with meta-analyses evaluated treatment with INS for CRS with nasal polyps (40 RCTs; 3624 patients, mean age 48 years, 64% male) and without polyps (10 RCTs; 590 patients, mean age 39 years, 51% male).^1,2 Trials reported sinonasal symptom outcomes differently and couldn’t be combined. In addition to reducing rate of polyp occurrence, for both CRS with and without polyps, key findings were:

• Global symptom scores were better for INS than placebo.
• Proportion of patients responding was greater for INS than with placebo.

There was no significant difference between adverse event rates with INS and placebo.

A systematic review and meta-analysis (8 RCTs, 389 patients) compared different SI regimens for CRS.³ The standardized mean difference was used to combine trials using various symptom outcomes. Key findings included the following:

• SI was better than no treatment.
• SI adjunctive therapy (with an antihistamine) improved disease-specific quality-of-life scores.
• SI was less effective than INS therapy for symptom improvement.

Hypertonic and isotonic saline yielded similar symptom scores. No adverse effects were reported.

One meta-analysis evaluated patient-reported outcomes with 12 weeks of macrolide therapy compared to placebo using the results of the SinoNasal Outcome Test (SNOT). The SNOT is a quality-of-life questionnaire that lists symptoms and the social-emotional consequences of CRS; a negative change in the SNOT score, on a 0 to 5 scale, indicates improvement. Overall the SNOT score improved 8% with macrolide therapy—statistically significant, but of uncertain clinical importance.⁴

Surgery improves nasal obstruction, pain, and postnasal discharge

A systematic review of 21 studies (prospective RCTs, prospective controlled clinical trials, cohort studies, case series, and retrospective record reviews) with a total of 2070 patients analyzed the effectiveness of endoscopic sinus surgery alone for improving CRS symptoms.⁵ Mean duration of post-operative follow-up was 14 months. Meta-analysis was performed separately for each symptom and the standard mean difference of the symptom severity score before and after surgery was reported as the effect size (ES) for the outcome measure (an ES of 0.2 is considered small; 0.6, moderate; 1.2, large; and 2, very large).

All symptoms improved compared to their preoperative severity scores. Nasal obstruction improved the most (ES=1.73; 95% CI, 1.45-2.02). Large symptom improvement was also observed for facial pain (ES=1.13; 95% CI, 0.96-1.31) and postnasal discharge (ES=1.19; 95% CI, 0.96-1.43).

Surgery and medical therapy may provide comparable symptom relief

A recent Cochrane review of 4 low-quality RCTs including 378 patients compared surgical with medical interventions for CRS with nasal polyps. Study heterogeneity and selective outcome reporting prevented meta-analysis.

The 3 comparison groups were endoscopic sinus surgery vs systemic steroids + INS; polypectomy vs systemic steroid + INS; and endoscopic surgery + INS vs antibiotic + “high-dose” INS. Overall, neither surgery nor medical therapy was superior in terms of patient-reported symptom scores or quality-of-life measures.⁶

EVIDENCE SUMMARY

The TABLE^1-4 shows the major results of the meta-analyses for the various medical therapy trials.

Two systematic reviews with meta-analyses evaluated treatment with INS for CRS with nasal polyps (40 RCTs; 3624 patients, mean age 48 years, 64% male) and without polyps (10 RCTs; 590 patients, mean age 39 years, 51% male).^1,2 Trials reported sinonasal symptom outcomes differently and couldn’t be combined. In addition to reducing rate of polyp occurrence, for both CRS with and without polyps, key findings were:

• Global symptom scores were better for INS than placebo.
• Proportion of patients responding was greater for INS than with placebo.

There was no significant difference between adverse event rates with INS and placebo.

A systematic review and meta-analysis (8 RCTs, 389 patients) compared different SI regimens for CRS.³ The standardized mean difference was used to combine trials using various symptom outcomes. Key findings included the following:

• SI was better than no treatment.
• SI adjunctive therapy (with an antihistamine) improved disease-specific quality-of-life scores.
• SI was less effective than INS therapy for symptom improvement.

Hypertonic and isotonic saline yielded similar symptom scores. No adverse effects were reported.

One meta-analysis evaluated patient-reported outcomes with 12 weeks of macrolide therapy compared to placebo using the results of the SinoNasal Outcome Test (SNOT). The SNOT is a quality-of-life questionnaire that lists symptoms and the social-emotional consequences of CRS; a negative change in the SNOT score, on a 0 to 5 scale, indicates improvement. Overall the SNOT score improved 8% with macrolide therapy—statistically significant, but of uncertain clinical importance.⁴

Surgery improves nasal obstruction, pain, and postnasal discharge

A systematic review of 21 studies (prospective RCTs, prospective controlled clinical trials, cohort studies, case series, and retrospective record reviews) with a total of 2070 patients analyzed the effectiveness of endoscopic sinus surgery alone for improving CRS symptoms.⁵ Mean duration of post-operative follow-up was 14 months. Meta-analysis was performed separately for each symptom and the standard mean difference of the symptom severity score before and after surgery was reported as the effect size (ES) for the outcome measure (an ES of 0.2 is considered small; 0.6, moderate; 1.2, large; and 2, very large).

All symptoms improved compared to their preoperative severity scores. Nasal obstruction improved the most (ES=1.73; 95% CI, 1.45-2.02). Large symptom improvement was also observed for facial pain (ES=1.13; 95% CI, 0.96-1.31) and postnasal discharge (ES=1.19; 95% CI, 0.96-1.43).

Surgery and medical therapy may provide comparable symptom relief

A recent Cochrane review of 4 low-quality RCTs including 378 patients compared surgical with medical interventions for CRS with nasal polyps. Study heterogeneity and selective outcome reporting prevented meta-analysis.

The 3 comparison groups were endoscopic sinus surgery vs systemic steroids + INS; polypectomy vs systemic steroid + INS; and endoscopic surgery + INS vs antibiotic + “high-dose” INS. Overall, neither surgery nor medical therapy was superior in terms of patient-reported symptom scores or quality-of-life measures.⁶

EVIDENCE SUMMARY

The TABLE^1-4 shows the major results of the meta-analyses for the various medical therapy trials.

Two systematic reviews with meta-analyses evaluated treatment with INS for CRS with nasal polyps (40 RCTs; 3624 patients, mean age 48 years, 64% male) and without polyps (10 RCTs; 590 patients, mean age 39 years, 51% male).^1,2 Trials reported sinonasal symptom outcomes differently and couldn’t be combined. In addition to reducing rate of polyp occurrence, for both CRS with and without polyps, key findings were:

• Global symptom scores were better for INS than placebo.
• Proportion of patients responding was greater for INS than with placebo.

There was no significant difference between adverse event rates with INS and placebo.

A systematic review and meta-analysis (8 RCTs, 389 patients) compared different SI regimens for CRS.³ The standardized mean difference was used to combine trials using various symptom outcomes. Key findings included the following:

• SI was better than no treatment.
• SI adjunctive therapy (with an antihistamine) improved disease-specific quality-of-life scores.
• SI was less effective than INS therapy for symptom improvement.

Hypertonic and isotonic saline yielded similar symptom scores. No adverse effects were reported.

One meta-analysis evaluated patient-reported outcomes with 12 weeks of macrolide therapy compared to placebo using the results of the SinoNasal Outcome Test (SNOT). The SNOT is a quality-of-life questionnaire that lists symptoms and the social-emotional consequences of CRS; a negative change in the SNOT score, on a 0 to 5 scale, indicates improvement. Overall the SNOT score improved 8% with macrolide therapy—statistically significant, but of uncertain clinical importance.⁴

Surgery improves nasal obstruction, pain, and postnasal discharge

A systematic review of 21 studies (prospective RCTs, prospective controlled clinical trials, cohort studies, case series, and retrospective record reviews) with a total of 2070 patients analyzed the effectiveness of endoscopic sinus surgery alone for improving CRS symptoms.⁵ Mean duration of post-operative follow-up was 14 months. Meta-analysis was performed separately for each symptom and the standard mean difference of the symptom severity score before and after surgery was reported as the effect size (ES) for the outcome measure (an ES of 0.2 is considered small; 0.6, moderate; 1.2, large; and 2, very large).

All symptoms improved compared to their preoperative severity scores. Nasal obstruction improved the most (ES=1.73; 95% CI, 1.45-2.02). Large symptom improvement was also observed for facial pain (ES=1.13; 95% CI, 0.96-1.31) and postnasal discharge (ES=1.19; 95% CI, 0.96-1.43).

Surgery and medical therapy may provide comparable symptom relief

A recent Cochrane review of 4 low-quality RCTs including 378 patients compared surgical with medical interventions for CRS with nasal polyps. Study heterogeneity and selective outcome reporting prevented meta-analysis.

The 3 comparison groups were endoscopic sinus surgery vs systemic steroids + INS; polypectomy vs systemic steroid + INS; and endoscopic surgery + INS vs antibiotic + “high-dose” INS. Overall, neither surgery nor medical therapy was superior in terms of patient-reported symptom scores or quality-of-life measures.⁶