The Food and Drug Administration has granted breakthrough therapy designation to zanubrutinib as a treatment for adults with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Zanubrutinib (BGB-3111) is a Bruton’s tyrosine kinase inhibitor being developed by BeiGene as a potential treatment for B-cell malignancies.

Researchers have evaluated zanubrutinib in a phase 2 trial (NCT03206970) of patients with relapsed/refractory MCL. Results from this trial were presented at the 2018 annual meeting of the American Society of Hematology (Abstract 148).

As of March 27, 2018, 86 patients had been enrolled in the trial and received treatment. They had a median of two prior lines of therapy and they received zanubrutinib at 160 mg twice daily.

Eighty-five patients were evaluable for efficacy. The overall response rate was 83.5% (71/85), and the complete response rate was 58.8% (50/85). At a median follow-up of 24.1 weeks, the median duration of response and median progression-free survival had not been reached. The estimated 24-week progression-free survival rate was 82%. The most common adverse events (AEs) in this trial were decrease in neutrophil count (31.4%), rash (29.1%), upper respiratory tract infection (29.1%), and decrease in platelet count (22.1%). Common grade 3 or higher AEs included neutrophil count decrease (11.6%) and lung infection (5.8%).

Four patients had fatal treatment-emergent AEs. One death was caused by a traffic accident, one was due to cerebral hemorrhage, and one resulted from pneumonia. The fourth death occurred in a patient with infection, but the cause of death was unknown.

Breakthrough therapy designation is designed to expedite the development and review of a therapy for a serious or life-threatening disease, following preliminary clinical evidence indicating it demonstrates substantial improvement over existing therapies.

jensmith@mdedge.com

The Food and Drug Administration has granted breakthrough therapy designation to zanubrutinib as a treatment for adults with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Zanubrutinib (BGB-3111) is a Bruton’s tyrosine kinase inhibitor being developed by BeiGene as a potential treatment for B-cell malignancies.

Researchers have evaluated zanubrutinib in a phase 2 trial (NCT03206970) of patients with relapsed/refractory MCL. Results from this trial were presented at the 2018 annual meeting of the American Society of Hematology (Abstract 148).

As of March 27, 2018, 86 patients had been enrolled in the trial and received treatment. They had a median of two prior lines of therapy and they received zanubrutinib at 160 mg twice daily.

Eighty-five patients were evaluable for efficacy. The overall response rate was 83.5% (71/85), and the complete response rate was 58.8% (50/85). At a median follow-up of 24.1 weeks, the median duration of response and median progression-free survival had not been reached. The estimated 24-week progression-free survival rate was 82%. The most common adverse events (AEs) in this trial were decrease in neutrophil count (31.4%), rash (29.1%), upper respiratory tract infection (29.1%), and decrease in platelet count (22.1%). Common grade 3 or higher AEs included neutrophil count decrease (11.6%) and lung infection (5.8%).

Four patients had fatal treatment-emergent AEs. One death was caused by a traffic accident, one was due to cerebral hemorrhage, and one resulted from pneumonia. The fourth death occurred in a patient with infection, but the cause of death was unknown.

Breakthrough therapy designation is designed to expedite the development and review of a therapy for a serious or life-threatening disease, following preliminary clinical evidence indicating it demonstrates substantial improvement over existing therapies.

jensmith@mdedge.com

The Food and Drug Administration has granted breakthrough therapy designation to zanubrutinib as a treatment for adults with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Zanubrutinib (BGB-3111) is a Bruton’s tyrosine kinase inhibitor being developed by BeiGene as a potential treatment for B-cell malignancies.

Researchers have evaluated zanubrutinib in a phase 2 trial (NCT03206970) of patients with relapsed/refractory MCL. Results from this trial were presented at the 2018 annual meeting of the American Society of Hematology (Abstract 148).

As of March 27, 2018, 86 patients had been enrolled in the trial and received treatment. They had a median of two prior lines of therapy and they received zanubrutinib at 160 mg twice daily.

Eighty-five patients were evaluable for efficacy. The overall response rate was 83.5% (71/85), and the complete response rate was 58.8% (50/85). At a median follow-up of 24.1 weeks, the median duration of response and median progression-free survival had not been reached. The estimated 24-week progression-free survival rate was 82%. The most common adverse events (AEs) in this trial were decrease in neutrophil count (31.4%), rash (29.1%), upper respiratory tract infection (29.1%), and decrease in platelet count (22.1%). Common grade 3 or higher AEs included neutrophil count decrease (11.6%) and lung infection (5.8%).

Four patients had fatal treatment-emergent AEs. One death was caused by a traffic accident, one was due to cerebral hemorrhage, and one resulted from pneumonia. The fourth death occurred in a patient with infection, but the cause of death was unknown.

Breakthrough therapy designation is designed to expedite the development and review of a therapy for a serious or life-threatening disease, following preliminary clinical evidence indicating it demonstrates substantial improvement over existing therapies.

jensmith@mdedge.com

Diagnosis of any mental disorder significantly increased the risk for all other mental disorders, based on data from a population-based cohort study of almost 6 million individuals followed for nearly 84 million person-years.

Comorbidity among mental disorders has been acknowledged, but comprehensive data on comorbidities across all subsets of disease and a comprehensive risk assessment has been lacking, wrote Oleguer Plana-Ripoll, PhD, of Aarhus University in Denmark, and his colleagues.

In a study published in JAMA Psychiatry, the researchers included all individuals born in Denmark between Jan. 1, 1900, and Dec. 31, 2015, who were living in Denmark between Jan. 1, 2000, and Dec. 31, 2016. They used national health registries to identify mental disorders, and diagnoses were based on the International Statistical Classification of Diseases and Related Health Problems. The study population included 2,958,293 men and 2,982,485 women with an average age of 32 years at the start of the follow-up period; participants were followed for a total of 83.9 million person-years. Mental disorders were categorized in groups, and groups were paired for risk assessment.

Overall, the risk of developing all other mental disorders increased with the diagnosis of one mental disorder, most prominently in the first year after diagnosis, but the risk persisted for at least 15 years. In one model controlling for age, calendar time, and sex, hazard ratios ranged from 2.0 for prior intellectual disabilities paired with later eating disorders to 48.6 for prior developmental disorders paired with later intellectual disabilities.

The large sample size allowed for focus on absolute risk and the study was accompanied by an interactive website (http://www.nbepi.com) that allows clinicians (and potentially patients) to monitor possible emerging mental health comorbidities.

As one example of absolute risk assessment, the researchers determined that 40% of men and 50% of women diagnosed with a mood disorder before age 20 years would develop an incident neurotic disorder as defined by the 10th revision of the International Statistical Classification of Diseases and Related Health Problems within the next 15 years. “The provision of absolute risk estimates may facilitate the clinical translation of our findings, and lay the groundwork for future studies related to personalized medicine and the primary prevention of comorbidity,” Dr. Plana-Ripoll and his colleagues wrote.

The researchers acknowledged the study’s limitation of comorbidities to pairs of disorders versus three or more, the use of groups of disorders rather than specific disorders, and the limitation to mental disorders treated in secondary care settings. However, the data support findings from previous studies and “provide new insights into the complex nature of comorbidity and the comprehensive nature of the analysis will provide an important foundation for future research,” they said.

The research was supported by the Danish National Research Foundation. Dr. Plana-Ripoll had no financial conflicts to disclose. Some coauthors disclosed grants from the National Institutes of Health, Novo Nordisk Foundation, and the European Research Council, and some coauthors disclosed financial relationships with Sanofi Aventis, Johnson & Johnson, Sage Pharmaceuticals, Shire, and Takeda.

SOURCE: Plana-Ripoll O et al. JAMA Psychiatry. 2019 Jan 16. doi: 10.1001/jamapsychiatry.2018.3658.

Diagnosis of any mental disorder significantly increased the risk for all other mental disorders, based on data from a population-based cohort study of almost 6 million individuals followed for nearly 84 million person-years.

Comorbidity among mental disorders has been acknowledged, but comprehensive data on comorbidities across all subsets of disease and a comprehensive risk assessment has been lacking, wrote Oleguer Plana-Ripoll, PhD, of Aarhus University in Denmark, and his colleagues.

In a study published in JAMA Psychiatry, the researchers included all individuals born in Denmark between Jan. 1, 1900, and Dec. 31, 2015, who were living in Denmark between Jan. 1, 2000, and Dec. 31, 2016. They used national health registries to identify mental disorders, and diagnoses were based on the International Statistical Classification of Diseases and Related Health Problems. The study population included 2,958,293 men and 2,982,485 women with an average age of 32 years at the start of the follow-up period; participants were followed for a total of 83.9 million person-years. Mental disorders were categorized in groups, and groups were paired for risk assessment.

Overall, the risk of developing all other mental disorders increased with the diagnosis of one mental disorder, most prominently in the first year after diagnosis, but the risk persisted for at least 15 years. In one model controlling for age, calendar time, and sex, hazard ratios ranged from 2.0 for prior intellectual disabilities paired with later eating disorders to 48.6 for prior developmental disorders paired with later intellectual disabilities.

The large sample size allowed for focus on absolute risk and the study was accompanied by an interactive website (http://www.nbepi.com) that allows clinicians (and potentially patients) to monitor possible emerging mental health comorbidities.

As one example of absolute risk assessment, the researchers determined that 40% of men and 50% of women diagnosed with a mood disorder before age 20 years would develop an incident neurotic disorder as defined by the 10th revision of the International Statistical Classification of Diseases and Related Health Problems within the next 15 years. “The provision of absolute risk estimates may facilitate the clinical translation of our findings, and lay the groundwork for future studies related to personalized medicine and the primary prevention of comorbidity,” Dr. Plana-Ripoll and his colleagues wrote.

The researchers acknowledged the study’s limitation of comorbidities to pairs of disorders versus three or more, the use of groups of disorders rather than specific disorders, and the limitation to mental disorders treated in secondary care settings. However, the data support findings from previous studies and “provide new insights into the complex nature of comorbidity and the comprehensive nature of the analysis will provide an important foundation for future research,” they said.

The research was supported by the Danish National Research Foundation. Dr. Plana-Ripoll had no financial conflicts to disclose. Some coauthors disclosed grants from the National Institutes of Health, Novo Nordisk Foundation, and the European Research Council, and some coauthors disclosed financial relationships with Sanofi Aventis, Johnson & Johnson, Sage Pharmaceuticals, Shire, and Takeda.

SOURCE: Plana-Ripoll O et al. JAMA Psychiatry. 2019 Jan 16. doi: 10.1001/jamapsychiatry.2018.3658.

Diagnosis of any mental disorder significantly increased the risk for all other mental disorders, based on data from a population-based cohort study of almost 6 million individuals followed for nearly 84 million person-years.

Comorbidity among mental disorders has been acknowledged, but comprehensive data on comorbidities across all subsets of disease and a comprehensive risk assessment has been lacking, wrote Oleguer Plana-Ripoll, PhD, of Aarhus University in Denmark, and his colleagues.

In a study published in JAMA Psychiatry, the researchers included all individuals born in Denmark between Jan. 1, 1900, and Dec. 31, 2015, who were living in Denmark between Jan. 1, 2000, and Dec. 31, 2016. They used national health registries to identify mental disorders, and diagnoses were based on the International Statistical Classification of Diseases and Related Health Problems. The study population included 2,958,293 men and 2,982,485 women with an average age of 32 years at the start of the follow-up period; participants were followed for a total of 83.9 million person-years. Mental disorders were categorized in groups, and groups were paired for risk assessment.

Overall, the risk of developing all other mental disorders increased with the diagnosis of one mental disorder, most prominently in the first year after diagnosis, but the risk persisted for at least 15 years. In one model controlling for age, calendar time, and sex, hazard ratios ranged from 2.0 for prior intellectual disabilities paired with later eating disorders to 48.6 for prior developmental disorders paired with later intellectual disabilities.

The large sample size allowed for focus on absolute risk and the study was accompanied by an interactive website (http://www.nbepi.com) that allows clinicians (and potentially patients) to monitor possible emerging mental health comorbidities.

As one example of absolute risk assessment, the researchers determined that 40% of men and 50% of women diagnosed with a mood disorder before age 20 years would develop an incident neurotic disorder as defined by the 10th revision of the International Statistical Classification of Diseases and Related Health Problems within the next 15 years. “The provision of absolute risk estimates may facilitate the clinical translation of our findings, and lay the groundwork for future studies related to personalized medicine and the primary prevention of comorbidity,” Dr. Plana-Ripoll and his colleagues wrote.

The researchers acknowledged the study’s limitation of comorbidities to pairs of disorders versus three or more, the use of groups of disorders rather than specific disorders, and the limitation to mental disorders treated in secondary care settings. However, the data support findings from previous studies and “provide new insights into the complex nature of comorbidity and the comprehensive nature of the analysis will provide an important foundation for future research,” they said.

The research was supported by the Danish National Research Foundation. Dr. Plana-Ripoll had no financial conflicts to disclose. Some coauthors disclosed grants from the National Institutes of Health, Novo Nordisk Foundation, and the European Research Council, and some coauthors disclosed financial relationships with Sanofi Aventis, Johnson & Johnson, Sage Pharmaceuticals, Shire, and Takeda.

SOURCE: Plana-Ripoll O et al. JAMA Psychiatry. 2019 Jan 16. doi: 10.1001/jamapsychiatry.2018.3658.

To determine if a nationwide implementation of robotic minimally invasive surgery (MIS) influenced the risk of severe complications and survival among women with early-stage endometrial cancer, a group of researchers from the University of Southern Denmark studied the Danish Gynecological Cancer Database, a nationwide, mandatory prospective registration of new cases of women with endometrial cancer who received their surgical treatment in a public hospital.¹ Siv Joergensen, MD, reported results at the 47th AAGL Global Congress on Minimally Invasive Gynecology annual meeting on November 13, 2018, in Las Vegas, Nevada.

The transition to robotic MIS was undertaken in Denmark from 2008 to 2013, with the centralization of endometrial cancer treatment in 2012. Over the span of 10 years, the surgical approach to treatment changed from 97% open access surgery to 95% MIS.

For the prospective cohort study, more than 7,000 women with endometrial cancer who received a hysterectomy from January 2005 to June 2015 were grouped by those receiving surgical care before (group 1) and after (group 2) robotic MIS implementation in Denmark. A total of 5,654 women with FIGO Stage I–II endometrial cancer were included in the final study.

Severe complications were 7.3% in group 1 and 6.2% in group 2 (odds ratio, 1.38; 95% confidence interval [CI], 1.10–1.73). Five-year survival rates were significantly lower before robotic MIS was implemented (hazard ratio, 1.22; 95% CI, 1.05–1.41), and no difference was found between laparoscopic and robotic MIS.

The authors concluded that nationwide implementation of robotic MIS enabled a shift toward all types of MIS (with a 73% reduction in hysterectomies performed by laparotomy) and translated into reduced risk of severe complications and increased survival.

How do these results compare with those in the United States?

According to Erica Dun, MD, MPH, who provided commentary for Dr. Joergensen’s study, the United States adopted robotic MIS in the early 2000s. Around 2008, 14% of hysterectomies performed for early-stage endometrial cancer were done through a MIS approach.² In 2014, after a study in which Walker and colleagues found that laparoscopy was safe and feasible compared with laparotomy,³ the American College of Obstetricians and Gynecologists, jointly with the Society of Gynecologic Oncologists, stated that “MIS should be embraced as the standard surgical approach for comprehensive surgical staging in women with endometrial cancer.”⁴

Dr. Dun pointed out that Casarin and colleagues found in 2018 that 71.4% of surgeries performed in the United States for endometrial cancer were performed through MIS.⁵ That number rose to 86.5% MIS (72.5% robot-assisted) for centers of the National Comprehensive Cancer Network.⁶

Dr. Dun concluded that nationwide implementation of robotic MIS is feasible for gynecologic oncologists, and it is beneficial for patients.

To determine if a nationwide implementation of robotic minimally invasive surgery (MIS) influenced the risk of severe complications and survival among women with early-stage endometrial cancer, a group of researchers from the University of Southern Denmark studied the Danish Gynecological Cancer Database, a nationwide, mandatory prospective registration of new cases of women with endometrial cancer who received their surgical treatment in a public hospital.¹ Siv Joergensen, MD, reported results at the 47th AAGL Global Congress on Minimally Invasive Gynecology annual meeting on November 13, 2018, in Las Vegas, Nevada.

The transition to robotic MIS was undertaken in Denmark from 2008 to 2013, with the centralization of endometrial cancer treatment in 2012. Over the span of 10 years, the surgical approach to treatment changed from 97% open access surgery to 95% MIS.

For the prospective cohort study, more than 7,000 women with endometrial cancer who received a hysterectomy from January 2005 to June 2015 were grouped by those receiving surgical care before (group 1) and after (group 2) robotic MIS implementation in Denmark. A total of 5,654 women with FIGO Stage I–II endometrial cancer were included in the final study.

Severe complications were 7.3% in group 1 and 6.2% in group 2 (odds ratio, 1.38; 95% confidence interval [CI], 1.10–1.73). Five-year survival rates were significantly lower before robotic MIS was implemented (hazard ratio, 1.22; 95% CI, 1.05–1.41), and no difference was found between laparoscopic and robotic MIS.

The authors concluded that nationwide implementation of robotic MIS enabled a shift toward all types of MIS (with a 73% reduction in hysterectomies performed by laparotomy) and translated into reduced risk of severe complications and increased survival.

How do these results compare with those in the United States?

According to Erica Dun, MD, MPH, who provided commentary for Dr. Joergensen’s study, the United States adopted robotic MIS in the early 2000s. Around 2008, 14% of hysterectomies performed for early-stage endometrial cancer were done through a MIS approach.² In 2014, after a study in which Walker and colleagues found that laparoscopy was safe and feasible compared with laparotomy,³ the American College of Obstetricians and Gynecologists, jointly with the Society of Gynecologic Oncologists, stated that “MIS should be embraced as the standard surgical approach for comprehensive surgical staging in women with endometrial cancer.”⁴

Dr. Dun pointed out that Casarin and colleagues found in 2018 that 71.4% of surgeries performed in the United States for endometrial cancer were performed through MIS.⁵ That number rose to 86.5% MIS (72.5% robot-assisted) for centers of the National Comprehensive Cancer Network.⁶

Dr. Dun concluded that nationwide implementation of robotic MIS is feasible for gynecologic oncologists, and it is beneficial for patients.

To determine if a nationwide implementation of robotic minimally invasive surgery (MIS) influenced the risk of severe complications and survival among women with early-stage endometrial cancer, a group of researchers from the University of Southern Denmark studied the Danish Gynecological Cancer Database, a nationwide, mandatory prospective registration of new cases of women with endometrial cancer who received their surgical treatment in a public hospital.¹ Siv Joergensen, MD, reported results at the 47th AAGL Global Congress on Minimally Invasive Gynecology annual meeting on November 13, 2018, in Las Vegas, Nevada.

The transition to robotic MIS was undertaken in Denmark from 2008 to 2013, with the centralization of endometrial cancer treatment in 2012. Over the span of 10 years, the surgical approach to treatment changed from 97% open access surgery to 95% MIS.

For the prospective cohort study, more than 7,000 women with endometrial cancer who received a hysterectomy from January 2005 to June 2015 were grouped by those receiving surgical care before (group 1) and after (group 2) robotic MIS implementation in Denmark. A total of 5,654 women with FIGO Stage I–II endometrial cancer were included in the final study.

Severe complications were 7.3% in group 1 and 6.2% in group 2 (odds ratio, 1.38; 95% confidence interval [CI], 1.10–1.73). Five-year survival rates were significantly lower before robotic MIS was implemented (hazard ratio, 1.22; 95% CI, 1.05–1.41), and no difference was found between laparoscopic and robotic MIS.

The authors concluded that nationwide implementation of robotic MIS enabled a shift toward all types of MIS (with a 73% reduction in hysterectomies performed by laparotomy) and translated into reduced risk of severe complications and increased survival.

How do these results compare with those in the United States?

According to Erica Dun, MD, MPH, who provided commentary for Dr. Joergensen’s study, the United States adopted robotic MIS in the early 2000s. Around 2008, 14% of hysterectomies performed for early-stage endometrial cancer were done through a MIS approach.² In 2014, after a study in which Walker and colleagues found that laparoscopy was safe and feasible compared with laparotomy,³ the American College of Obstetricians and Gynecologists, jointly with the Society of Gynecologic Oncologists, stated that “MIS should be embraced as the standard surgical approach for comprehensive surgical staging in women with endometrial cancer.”⁴

Dr. Dun pointed out that Casarin and colleagues found in 2018 that 71.4% of surgeries performed in the United States for endometrial cancer were performed through MIS.⁵ That number rose to 86.5% MIS (72.5% robot-assisted) for centers of the National Comprehensive Cancer Network.⁶

Dr. Dun concluded that nationwide implementation of robotic MIS is feasible for gynecologic oncologists, and it is beneficial for patients.

Clinical question: How effective are intramuscular midazolam, olanzapine, ziprasidone, and haloperidol at sedating acutely agitated adults in the emergency department?

Background: Acute agitation is commonly seen in the ED and sometimes requires parenteral medications to keep patients and staff safe. Although many medications, including benzodiazepines and antipsychotics, are used, there is no consensus regarding which medications are most effective and safe for acute agitation.

Study design: Prospective observational study.

Setting: Emergency department of an inner-city Level 1 adult and pediatric trauma center.

Synopsis: This study enrolled 737 adults in the ED who presented with acute agitation and treated them with either haloperidol 5 mg, ziprasidone 20 mg, olanzapine 10 mg, midazolam 5 mg, or haloperidol 10 mg intramuscularly, based on predetermined 3-week blocks. The main outcome was the proportion of patients adequately sedated at 15 minutes, based on Altered Mental Status Scale score less than 1. A total of 650 patients (88%) were agitated from alcohol intoxication.

Dr. Jenkins is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.

Clinical question: How effective are intramuscular midazolam, olanzapine, ziprasidone, and haloperidol at sedating acutely agitated adults in the emergency department?

Background: Acute agitation is commonly seen in the ED and sometimes requires parenteral medications to keep patients and staff safe. Although many medications, including benzodiazepines and antipsychotics, are used, there is no consensus regarding which medications are most effective and safe for acute agitation.

Study design: Prospective observational study.

Setting: Emergency department of an inner-city Level 1 adult and pediatric trauma center.

Synopsis: This study enrolled 737 adults in the ED who presented with acute agitation and treated them with either haloperidol 5 mg, ziprasidone 20 mg, olanzapine 10 mg, midazolam 5 mg, or haloperidol 10 mg intramuscularly, based on predetermined 3-week blocks. The main outcome was the proportion of patients adequately sedated at 15 minutes, based on Altered Mental Status Scale score less than 1. A total of 650 patients (88%) were agitated from alcohol intoxication.

Dr. Jenkins is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.

Clinical question: How effective are intramuscular midazolam, olanzapine, ziprasidone, and haloperidol at sedating acutely agitated adults in the emergency department?

Background: Acute agitation is commonly seen in the ED and sometimes requires parenteral medications to keep patients and staff safe. Although many medications, including benzodiazepines and antipsychotics, are used, there is no consensus regarding which medications are most effective and safe for acute agitation.

Study design: Prospective observational study.

Setting: Emergency department of an inner-city Level 1 adult and pediatric trauma center.

Synopsis: This study enrolled 737 adults in the ED who presented with acute agitation and treated them with either haloperidol 5 mg, ziprasidone 20 mg, olanzapine 10 mg, midazolam 5 mg, or haloperidol 10 mg intramuscularly, based on predetermined 3-week blocks. The main outcome was the proportion of patients adequately sedated at 15 minutes, based on Altered Mental Status Scale score less than 1. A total of 650 patients (88%) were agitated from alcohol intoxication.

Dr. Jenkins is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.

Discussing confidentiality is essential to the appropriate health care of adolescents, especially prior to discussing sensitive subjects, reported John S. Santelli, MD, MPH, of Mailman School of Public Health, Columbia University, New York, N.Y., and his associates.

Rawpixel/Thinkstock

“Previous research has shown that when adolescents and young adults (AYAs) are not assured of confidentiality, they are less willing to discuss sensitive topics with their providers,” they wrote. The report is in Pediatrics.

According to national guidelines, although discussions concerning confidentiality can begin with parents in early adolescence, over time, the goal should be to allow fully for alone time for the AYA with you without parents present in the room.

You have a unique opportunity to help parents understand confidentiality and aid them in transitioning over time, with full respect and support for the developing adolescent-provider relationship, so that it can be fully realized by the time the adolescent reaches 13 years of age.

Using a nationally representative age-, race/ethnicity-, and income-matched sample of AYAs, the authors surveyed youth aged 13-26 years concerning preventive services received and discussions held with health care providers. Of the 1,918 individuals who completed the survey, the authors’ analysis was limited to the 1,509 (79%) youth who had seen their providers in the past 2 years.

The study focused on 11 youth-provider discussion topics. For 10 of the 11 topics, less than half of the young people said they had a discussion on the topic with a health care provider on their last visit. The most commonly discussed topics overall included mental health/emotional issues (55%), drug or alcohol use (46%), tobacco use (44%), and school performance (43%); the least common were gun safety (14%), sexual orientation (20%), and sexual or physical abuse (21%). There were more discussions concerning birth control among young women (from 26% at ages 13-14 to 54% by ages 23-26) compared with young men (13% at ages 13-14 to 12% by ages 23-26).

On average, young women reported discussing just 3.7 of the 11 topics during their last preventive care visit; young men similarly reported an average of 3.6 topics. Overall, the mean number of youth-provider discussions declined over time from 4.1 at ages 13-14 and 4.4 at ages 15-18 to 2.6 by ages 23-26.

Compared with white youth, who reported 3.3 topics at their last visit, Hispanic and African American youth reported discussing 4.2 topics. Similar differences were seen when comparing rural (2.7 topics) and urban or suburban youth (3.8 topics) or incomes greater than $75,000 (3.6 topics) compared with incomes of $25,000 or less (4.2 topics).

Youth who previously discussed confidentiality also reported discussing more topics (4.4), compared with those who had not talked about confidentiality (2.9).

Before the implementation of the Patient Protection and Affordable Care Act (ACA), which requires the provision of prevention services without cost sharing, less than half of adolescents visited a medical provider for annual preventive care visits, other studies have shown.

Although professional guidelines for adolescent preventive care recommend youth access to confidential services, “young people report that health care encounters often do not include an explanation of confidentiality by their health care provider.” Without the assurance of confidentiality, adolescents are more likely to not seek care or to opt not to disclose risky behaviors.

Current systems tend to rely on parent reporting regarding uses of services, and there is no mechanism in place for collection of data on discussion of sensitive health topics. The authors also noted a lack of time available for dialogue during visits as well as an absence of screening questionnaires prior to visits that might invite opportunities to disclose information on sensitive topics.

“Young people who reported ever having talked about confidentiality with their regular provider were more likely to engage in health discussions with providers,” emphasized Dr. Santelli and his associates. “The use of a health checklist and/or questionnaire and having spent more time with their provider during the visit were consistently associated with more of these discussions.”

You can build rapport with AYAs during preventive care visits that include screening and counseling. Immunizations, screening, and treatment of sexually transmitted infections, and dispensing of reproductive and sexual health services, including contraception, offer good opportunities for these discussions. Other sensitive topics are tobacco, alcohol, and drug use; depression and mental health; and obesity and physical activity.

Dr. Santelli and his associates consider the results of their research to serve as a “valuable addition to the literature.” They did, however, note several limitations. Because the data are cross-sectional, they cannot demonstrate causality. The use of self-report data may have contributed to underreporting of risk behaviors because adolescents were interviewed directly following parents on the same computer. Survey questions did account for the existence of youth-provider discussions, but the researchers were not able to measure the impact or quality of the resulting conversations.

It is important to note that because providers were not interviewed, the time pressures and other expected barriers were not fully accounted for in this research, Dr. Santelli and his colleagues cautioned. “Future research should ask specifically about provider-level barriers to providing preventive care to better understand their impact,” they advised.

Ultimately, the clinicians who are providing care to youth and their families will need support in implementing such changes, especially where education in the importance of discussion confidentiality and private time are concerned, they added.

The authors had no relevant financial disclosures. The study was funded by an unrestricted research grant from the Merck Foundation.

SOURCE: Santelli J et. al. Pediatrics. 2019. doi: 10.1542/peds.2018-1403.

Discussing confidentiality is essential to the appropriate health care of adolescents, especially prior to discussing sensitive subjects, reported John S. Santelli, MD, MPH, of Mailman School of Public Health, Columbia University, New York, N.Y., and his associates.

Rawpixel/Thinkstock

“Previous research has shown that when adolescents and young adults (AYAs) are not assured of confidentiality, they are less willing to discuss sensitive topics with their providers,” they wrote. The report is in Pediatrics.

According to national guidelines, although discussions concerning confidentiality can begin with parents in early adolescence, over time, the goal should be to allow fully for alone time for the AYA with you without parents present in the room.

You have a unique opportunity to help parents understand confidentiality and aid them in transitioning over time, with full respect and support for the developing adolescent-provider relationship, so that it can be fully realized by the time the adolescent reaches 13 years of age.

Using a nationally representative age-, race/ethnicity-, and income-matched sample of AYAs, the authors surveyed youth aged 13-26 years concerning preventive services received and discussions held with health care providers. Of the 1,918 individuals who completed the survey, the authors’ analysis was limited to the 1,509 (79%) youth who had seen their providers in the past 2 years.

The study focused on 11 youth-provider discussion topics. For 10 of the 11 topics, less than half of the young people said they had a discussion on the topic with a health care provider on their last visit. The most commonly discussed topics overall included mental health/emotional issues (55%), drug or alcohol use (46%), tobacco use (44%), and school performance (43%); the least common were gun safety (14%), sexual orientation (20%), and sexual or physical abuse (21%). There were more discussions concerning birth control among young women (from 26% at ages 13-14 to 54% by ages 23-26) compared with young men (13% at ages 13-14 to 12% by ages 23-26).

On average, young women reported discussing just 3.7 of the 11 topics during their last preventive care visit; young men similarly reported an average of 3.6 topics. Overall, the mean number of youth-provider discussions declined over time from 4.1 at ages 13-14 and 4.4 at ages 15-18 to 2.6 by ages 23-26.

Compared with white youth, who reported 3.3 topics at their last visit, Hispanic and African American youth reported discussing 4.2 topics. Similar differences were seen when comparing rural (2.7 topics) and urban or suburban youth (3.8 topics) or incomes greater than $75,000 (3.6 topics) compared with incomes of $25,000 or less (4.2 topics).

Youth who previously discussed confidentiality also reported discussing more topics (4.4), compared with those who had not talked about confidentiality (2.9).

Before the implementation of the Patient Protection and Affordable Care Act (ACA), which requires the provision of prevention services without cost sharing, less than half of adolescents visited a medical provider for annual preventive care visits, other studies have shown.

Although professional guidelines for adolescent preventive care recommend youth access to confidential services, “young people report that health care encounters often do not include an explanation of confidentiality by their health care provider.” Without the assurance of confidentiality, adolescents are more likely to not seek care or to opt not to disclose risky behaviors.

Current systems tend to rely on parent reporting regarding uses of services, and there is no mechanism in place for collection of data on discussion of sensitive health topics. The authors also noted a lack of time available for dialogue during visits as well as an absence of screening questionnaires prior to visits that might invite opportunities to disclose information on sensitive topics.

“Young people who reported ever having talked about confidentiality with their regular provider were more likely to engage in health discussions with providers,” emphasized Dr. Santelli and his associates. “The use of a health checklist and/or questionnaire and having spent more time with their provider during the visit were consistently associated with more of these discussions.”

You can build rapport with AYAs during preventive care visits that include screening and counseling. Immunizations, screening, and treatment of sexually transmitted infections, and dispensing of reproductive and sexual health services, including contraception, offer good opportunities for these discussions. Other sensitive topics are tobacco, alcohol, and drug use; depression and mental health; and obesity and physical activity.

Dr. Santelli and his associates consider the results of their research to serve as a “valuable addition to the literature.” They did, however, note several limitations. Because the data are cross-sectional, they cannot demonstrate causality. The use of self-report data may have contributed to underreporting of risk behaviors because adolescents were interviewed directly following parents on the same computer. Survey questions did account for the existence of youth-provider discussions, but the researchers were not able to measure the impact or quality of the resulting conversations.

It is important to note that because providers were not interviewed, the time pressures and other expected barriers were not fully accounted for in this research, Dr. Santelli and his colleagues cautioned. “Future research should ask specifically about provider-level barriers to providing preventive care to better understand their impact,” they advised.

Ultimately, the clinicians who are providing care to youth and their families will need support in implementing such changes, especially where education in the importance of discussion confidentiality and private time are concerned, they added.

The authors had no relevant financial disclosures. The study was funded by an unrestricted research grant from the Merck Foundation.

SOURCE: Santelli J et. al. Pediatrics. 2019. doi: 10.1542/peds.2018-1403.

Discussing confidentiality is essential to the appropriate health care of adolescents, especially prior to discussing sensitive subjects, reported John S. Santelli, MD, MPH, of Mailman School of Public Health, Columbia University, New York, N.Y., and his associates.

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“Previous research has shown that when adolescents and young adults (AYAs) are not assured of confidentiality, they are less willing to discuss sensitive topics with their providers,” they wrote. The report is in Pediatrics.

According to national guidelines, although discussions concerning confidentiality can begin with parents in early adolescence, over time, the goal should be to allow fully for alone time for the AYA with you without parents present in the room.

You have a unique opportunity to help parents understand confidentiality and aid them in transitioning over time, with full respect and support for the developing adolescent-provider relationship, so that it can be fully realized by the time the adolescent reaches 13 years of age.

Using a nationally representative age-, race/ethnicity-, and income-matched sample of AYAs, the authors surveyed youth aged 13-26 years concerning preventive services received and discussions held with health care providers. Of the 1,918 individuals who completed the survey, the authors’ analysis was limited to the 1,509 (79%) youth who had seen their providers in the past 2 years.

The study focused on 11 youth-provider discussion topics. For 10 of the 11 topics, less than half of the young people said they had a discussion on the topic with a health care provider on their last visit. The most commonly discussed topics overall included mental health/emotional issues (55%), drug or alcohol use (46%), tobacco use (44%), and school performance (43%); the least common were gun safety (14%), sexual orientation (20%), and sexual or physical abuse (21%). There were more discussions concerning birth control among young women (from 26% at ages 13-14 to 54% by ages 23-26) compared with young men (13% at ages 13-14 to 12% by ages 23-26).

On average, young women reported discussing just 3.7 of the 11 topics during their last preventive care visit; young men similarly reported an average of 3.6 topics. Overall, the mean number of youth-provider discussions declined over time from 4.1 at ages 13-14 and 4.4 at ages 15-18 to 2.6 by ages 23-26.

Compared with white youth, who reported 3.3 topics at their last visit, Hispanic and African American youth reported discussing 4.2 topics. Similar differences were seen when comparing rural (2.7 topics) and urban or suburban youth (3.8 topics) or incomes greater than $75,000 (3.6 topics) compared with incomes of $25,000 or less (4.2 topics).

Youth who previously discussed confidentiality also reported discussing more topics (4.4), compared with those who had not talked about confidentiality (2.9).

Before the implementation of the Patient Protection and Affordable Care Act (ACA), which requires the provision of prevention services without cost sharing, less than half of adolescents visited a medical provider for annual preventive care visits, other studies have shown.

Although professional guidelines for adolescent preventive care recommend youth access to confidential services, “young people report that health care encounters often do not include an explanation of confidentiality by their health care provider.” Without the assurance of confidentiality, adolescents are more likely to not seek care or to opt not to disclose risky behaviors.

Current systems tend to rely on parent reporting regarding uses of services, and there is no mechanism in place for collection of data on discussion of sensitive health topics. The authors also noted a lack of time available for dialogue during visits as well as an absence of screening questionnaires prior to visits that might invite opportunities to disclose information on sensitive topics.

“Young people who reported ever having talked about confidentiality with their regular provider were more likely to engage in health discussions with providers,” emphasized Dr. Santelli and his associates. “The use of a health checklist and/or questionnaire and having spent more time with their provider during the visit were consistently associated with more of these discussions.”

You can build rapport with AYAs during preventive care visits that include screening and counseling. Immunizations, screening, and treatment of sexually transmitted infections, and dispensing of reproductive and sexual health services, including contraception, offer good opportunities for these discussions. Other sensitive topics are tobacco, alcohol, and drug use; depression and mental health; and obesity and physical activity.

Dr. Santelli and his associates consider the results of their research to serve as a “valuable addition to the literature.” They did, however, note several limitations. Because the data are cross-sectional, they cannot demonstrate causality. The use of self-report data may have contributed to underreporting of risk behaviors because adolescents were interviewed directly following parents on the same computer. Survey questions did account for the existence of youth-provider discussions, but the researchers were not able to measure the impact or quality of the resulting conversations.

It is important to note that because providers were not interviewed, the time pressures and other expected barriers were not fully accounted for in this research, Dr. Santelli and his colleagues cautioned. “Future research should ask specifically about provider-level barriers to providing preventive care to better understand their impact,” they advised.

Ultimately, the clinicians who are providing care to youth and their families will need support in implementing such changes, especially where education in the importance of discussion confidentiality and private time are concerned, they added.

The authors had no relevant financial disclosures. The study was funded by an unrestricted research grant from the Merck Foundation.

SOURCE: Santelli J et. al. Pediatrics. 2019. doi: 10.1542/peds.2018-1403.

The Food and Drug Administration has smoothed the way to OTC naloxone by releasing “drug facts label” templates for manufacturers to use when submitting their products for consideration.

Drug facts labels (DFLs) are required for all OTC drugs, and it’s usually up to manufacturers to develop and test their own to ensure that consumers understand how to use their products.

“Some stakeholders have identified the requirement ... as a barrier to development of OTC naloxone products,” so the agency developed two DFLs on its own – one for nasal spray naloxone, the other for auto-injectors – and completed the necessary label comprehension testing, according to an announcement from FDA Commissioner Scott Gottlieb, MD.

There’s not much else manufactures have to do, except deal with the details of their own products. They “can now focus their efforts on ... how well consumers understand the product-specific information that hasn’t been already tested in the model” DFLs, according to the announcement.

As deaths from opioid abuse continue to climb, the FDA is committed to increasing access to naloxone, which currently requires a prescription. The new DFLs “should jump-start the development of OTC naloxone products ... I personally urge companies to take notice of this pathway that the FDA has opened for them and come to the Agency with applications as soon as possible,” Dr. Gottlieb said.

Comprehension was assessed in more than 700 people, including heroin and prescription opioid users, their friends and families, and adolescents. “Overall, the study demonstrated that” the DFLs are “well-understood by consumers” and acceptable “for use by manufacturers in support of their ... development programs,” according to the announcement.

In a press statement, the American Medical Association applauded the agency’s move “to provide labeling that would allow for over-the-counter availability of naloxone, a move that will save people from opioid-related overdose ... The action should spur efforts by naloxone manufacturers to submit applications for their products to receive over-the-counter status.”

aotto@mdedge.com

The Food and Drug Administration has smoothed the way to OTC naloxone by releasing “drug facts label” templates for manufacturers to use when submitting their products for consideration.

Drug facts labels (DFLs) are required for all OTC drugs, and it’s usually up to manufacturers to develop and test their own to ensure that consumers understand how to use their products.

“Some stakeholders have identified the requirement ... as a barrier to development of OTC naloxone products,” so the agency developed two DFLs on its own – one for nasal spray naloxone, the other for auto-injectors – and completed the necessary label comprehension testing, according to an announcement from FDA Commissioner Scott Gottlieb, MD.

There’s not much else manufactures have to do, except deal with the details of their own products. They “can now focus their efforts on ... how well consumers understand the product-specific information that hasn’t been already tested in the model” DFLs, according to the announcement.

As deaths from opioid abuse continue to climb, the FDA is committed to increasing access to naloxone, which currently requires a prescription. The new DFLs “should jump-start the development of OTC naloxone products ... I personally urge companies to take notice of this pathway that the FDA has opened for them and come to the Agency with applications as soon as possible,” Dr. Gottlieb said.

Comprehension was assessed in more than 700 people, including heroin and prescription opioid users, their friends and families, and adolescents. “Overall, the study demonstrated that” the DFLs are “well-understood by consumers” and acceptable “for use by manufacturers in support of their ... development programs,” according to the announcement.

In a press statement, the American Medical Association applauded the agency’s move “to provide labeling that would allow for over-the-counter availability of naloxone, a move that will save people from opioid-related overdose ... The action should spur efforts by naloxone manufacturers to submit applications for their products to receive over-the-counter status.”

aotto@mdedge.com

The Food and Drug Administration has smoothed the way to OTC naloxone by releasing “drug facts label” templates for manufacturers to use when submitting their products for consideration.

Drug facts labels (DFLs) are required for all OTC drugs, and it’s usually up to manufacturers to develop and test their own to ensure that consumers understand how to use their products.

“Some stakeholders have identified the requirement ... as a barrier to development of OTC naloxone products,” so the agency developed two DFLs on its own – one for nasal spray naloxone, the other for auto-injectors – and completed the necessary label comprehension testing, according to an announcement from FDA Commissioner Scott Gottlieb, MD.

There’s not much else manufactures have to do, except deal with the details of their own products. They “can now focus their efforts on ... how well consumers understand the product-specific information that hasn’t been already tested in the model” DFLs, according to the announcement.

As deaths from opioid abuse continue to climb, the FDA is committed to increasing access to naloxone, which currently requires a prescription. The new DFLs “should jump-start the development of OTC naloxone products ... I personally urge companies to take notice of this pathway that the FDA has opened for them and come to the Agency with applications as soon as possible,” Dr. Gottlieb said.

Comprehension was assessed in more than 700 people, including heroin and prescription opioid users, their friends and families, and adolescents. “Overall, the study demonstrated that” the DFLs are “well-understood by consumers” and acceptable “for use by manufacturers in support of their ... development programs,” according to the announcement.

In a press statement, the American Medical Association applauded the agency’s move “to provide labeling that would allow for over-the-counter availability of naloxone, a move that will save people from opioid-related overdose ... The action should spur efforts by naloxone manufacturers to submit applications for their products to receive over-the-counter status.”

aotto@mdedge.com

Anti-vaccination protesters targeted Monique A. Tello, MD, MPH, in late summer 2018 by leaving bad online ratings and writing false and defamatory comments in her online profiles. Dr. Tell wrote about her experience in a blog post where she opened up about how difficult the process has been, and how she has found support in a community of her colleagues.
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Anti-vaccination protesters targeted Monique A. Tello, MD, MPH, in late summer 2018 by leaving bad online ratings and writing false and defamatory comments in her online profiles. Dr. Tell wrote about her experience in a blog post where she opened up about how difficult the process has been, and how she has found support in a community of her colleagues.
Apple Podcasts
Google Podcasts
Spotify

Anti-vaccination protesters targeted Monique A. Tello, MD, MPH, in late summer 2018 by leaving bad online ratings and writing false and defamatory comments in her online profiles. Dr. Tell wrote about her experience in a blog post where she opened up about how difficult the process has been, and how she has found support in a community of her colleagues.
Apple Podcasts
Google Podcasts
Spotify

Young women who delay starting contraception when they start sexual activity are at increased risk of unwanted pregnancy. Also today, disease-modifying therapies and stem cell transplants both reduce disease progression in MS, the American Academy of Pediatrics guidelines on hemangioma should empower primary care clinicians, and a treat-to-target approach for CVD risk factors decreased atherosclerosis in patients with rheumatoid arthritis.

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Google Podcasts

Spotify

Young women who delay starting contraception when they start sexual activity are at increased risk of unwanted pregnancy. Also today, disease-modifying therapies and stem cell transplants both reduce disease progression in MS, the American Academy of Pediatrics guidelines on hemangioma should empower primary care clinicians, and a treat-to-target approach for CVD risk factors decreased atherosclerosis in patients with rheumatoid arthritis.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify

Young women who delay starting contraception when they start sexual activity are at increased risk of unwanted pregnancy. Also today, disease-modifying therapies and stem cell transplants both reduce disease progression in MS, the American Academy of Pediatrics guidelines on hemangioma should empower primary care clinicians, and a treat-to-target approach for CVD risk factors decreased atherosclerosis in patients with rheumatoid arthritis.

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Apple Podcasts

Google Podcasts

Spotify

Aplastic anemia is a clinical and pathological entity of bone marrow failure that causes progressive loss of hematopoietic progenitor stem cells (HPSC), resulting in pancytopenia.¹ Patients may present along a spectrum, ranging from being asymptomatic with incidental findings on peripheral blood testing to having life-threatening neutropenic infections or bleeding. Aplastic anemia results from either inherited or acquired causes, and the pathophysiology and treatment approach vary significantly between these 2 causes. Therefore, recognition of inherited marrow failure diseases, such as Fanconi anemia and telomere biology disorders, is critical to establishing the management plan. This article reviews the epidemiology, pathophysiology, clinical presentation, and diagnosis of aplastic anemia. Treatment of aplastic anemia is reviewed in a separate article.

Epidemiology

Aplastic anemia is a rare disorder, with an incidence of approximately 1.5 to 7 cases per million individuals per year.^2,3 A recent Scandinavian study reported that the incidence of aplastic anemia among the Swedish population is 2.3 cases per million individuals per year, with a median age at diagnosis of 60 years and a slight female predominance (52% versus 48%, respectively).² This data is congruent with prior observations made in Barcelona, where the incidence was 2.34 cases per million individuals per year, albeit with a slightly higher incidence in males compared to females (2.54 versus 2.16, respectively).⁴ The incidence of aplastic anemia varies globally, with a disproportionate increase in incidence seen among Asian populations, with rates as high as 8.8 per million individuals per year.^3-5 This variation in incidence in Asia versus other countries has not been well explained. There appears to be a bimodal distribution, with incidence peaks seen in young adults and in older adults.^2,3,6

Pathophysiology

Acquired Aplastic Anemia

The leading hypothesis as to the cause of most cases of acquired aplastic anemia is that a dysregulated immune system destroys hematopoietic progenitor cells. Inciting etiologies implicated in the development of acquired aplastic anemia include pregnancy, infection, medications, and exposure to certain chemicals, such as benzene.^1,7 The historical understanding of acquired aplastic anemia implicates cytotoxic T-lymphocyte–mediated destruction of CD34+ hematopoietic stem cells.^1,8,9 This hypothesis served as the basis for treatment of acquired aplastic anemia with immunosuppressive therapy, predominantly anti-thymocyte globulin (ATG) combined with cyclosporine A.^1,8 More recent work has focused on cytokine interactions, particularly the suppressive role of interferon (IFN)-γ on hematopoietic stem cells independent of T-lymphocyte–mediated hematopoietic destruction, which has been demonstrated in a murine model.⁸ The interaction of IFN-γ with the hematopoietic stem cells pool is dynamic. IFN-γ levels are elevated during an acute inflammatory response such as a viral infection, providing further basis for the immune-mediated nature of the acquired disease.¹⁰ Specifically, in vitro studies suggest the effects of IFN-γ on HPSC may be secondary to interruption of thrombopoietin and its respective signaling pathways, which play a key role in hematopoietic stem cell renewal.¹¹ Eltrombopag, a thrombopoietin receptor antagonist, has shown promise in the treatment of refractory aplastic anemia, with studies indicating that its effectiveness is independent of IFN-γ levels.^11,12

Inherited Aplastic Anemia

The inherited marrow failure syndromes (IMFSs) are a group of disorders characterized by cellular maintenance and repair defects, leading to cytopenias, increased cancer risk, structural defects, and risk of end organ damage, such as liver cirrhosis and pulmonary fibrosis.^13-15 The most common diseases include Fanconi anemia, dyskeratosis congenita/telomere biology disorders, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, but with the advent of whole exome sequencing new syndromes continue to be discovered. While classically these disorders present in children, adult presentations of these syndromes are now commonplace. Broadly, the pathophysiology of inherited aplastic anemia relates to the defective hematopoietic progenitor cells and an accelerated decline of the hematopoietic stem cell compartment.

The most common IMFS, Fanconi anemia and telomere biology disorders, are associated with numerous mutations in DNA damage repair pathways and telomere maintenance pathways. TERT, DKC, and TERC mutations are most commonly associated with dyskeratosis congenita, but may also be found infrequently in patients with aplastic anemia presenting at an older age in the absence of the classic phenotypical features.^1,16,17 The recognition of an underlying genetic disorder or telomere biology disorder leading to constitutional aplastic anemia is significant, as these conditions are associated not only with marrow failure, but also endocrinopathies, organ fibrosis, and solid organ malignancies.^13-15 In particular, mutations in the TERT and TERC genes have been associated with dyskeratosis congenita as well as pulmonary fibrosis and cirrhosis.^18,19 The implications of early diagnosis of an IMFS lie in the approach to treatment and prognosis.

Clonal Disorders and Secondary Malignancies

Myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML) are 2 clonal disorders that may arise from a background of aplastic anemia.^9,20,21 Hypoplastic MDS can be difficult to differentiate from aplastic anemia at diagnosis based on morphology alone, although recent work has demonstrated that molecular testing for somatic mutations in ASXL1, DNMT3A, and BCOR can aid in differentiating a subset of aplastic anemia patients who are more likely to progress to MDS.²¹ Clonal populations of cells harboring 6p uniparental disomy are seen in more than 10% of patients with aplastic anemia on cytogenetic analysis, which can help differentiate the diseases.⁹ Yoshizato and colleagues found lower rates of ASXL1 and DNMT3A mutations in patients with aplastic anemia as compared with patients with MDS or AML. In this study, patients with aplastic anemia had higher rates of mutations in PIGA (reflecting the increased paroxysmal nocturnal hemoglobinuria [PNH] clonality seen in aplastic anemia) and BCOR.⁹ Mutations were also found in genes commonly mutated in MDS and AML, including TET2, RUNX1, TP53, and JAK2, albeit at lower frequencies.⁹ These mutations as a whole have not predicted response to therapy or prognosis. However, when performing survival analysis in patients with specific mutations, those commonly encountered in MDS/AML (ASXL1, DNMT3A, TP53, RUNX1, CSMD1) are associated with faster progression to overt MDS/AML and decreased overall survival (OS),^20,21 suggesting these mutations may represent early clonality that can lead to clonal evolution and the development of secondary malignancies. Conversely, mutations in BCOR and BCORL appear to identify patients who may have a favorable outcome in response to immunosuppressive therapy and, similar to patients with PIGA mutations, improved OS.⁹

Paroxysmal Nocturnal Hemoglobinuria

In addition to having an increased risk of myelodysplasia and malignancy due to the development of a dominant pre-malignant clone, patients with aplastic anemia often harbor progenitor cell clones associated with PNH.^1,17 PNH clones have been identified in more than 50% of patients with aplastic anemia.^22,23 PNH represents a clonal disorder of hematopoiesis in which cells harbor X-linked somatic mutations in the PIGA gene; this gene encodes a protein responsible for the synthesis of glycosylphosphatidylinositol (GPI) anchors on the cell surface.^22,24 The lack of these cell surface proteins, specifically CD55 (also known as decay accelerating factor) and CD59 (also known as membrane inhibitor of reactive lysis), predisposes red cells to increased complement-mediated lysis.²⁵ The exact mechanism for the development of these clones in patients with aplastic anemia is not fully understood. Current theories hypothesize that these clones are protected from the immune-mediated destruction of normal hematopoietic stem cells due to the absence of the cell surface proteins.^1,20 The role of these clones over time in patients with aplastic anemia is less clear, though recent work demonstrated that despite differences in clonality over the disease course, aplastic anemia patients with small PNH clones are less likely to develop overt hemolysis and larger PNH clones compared to patients harboring larger (≥ 50%) PNH clones at diagnosis.^23,26,27 Additionally, PNH clones in patients with aplastic anemia infrequently become clinically significant.²⁷ It should be noted that these conditions exist along a continuum; that is, patients with aplastic anemia may develop PNH clones, while conversely patients with PNH may develop aplastic anemia.²⁰ Patients with PNH clones should be followed via peripheral blood flow cytometry in addition to complete blood count to track clonal stability and identify clinically significant PNH among aplastic anemia patients.²⁸

Patients with aplastic anemia typically are diagnosed either due to asymptomatic cytopenias found on peripheral blood sampling, symptomatic anemia, bleeding secondary to thrombocytopenia, or wound healing and infectious complications related to neutropenia.²⁹ A thorough history to understand the timing of symptoms, recent infectious symptoms/exposure, habits, and chemical or toxin exposures (including medications, travel, and supplements) helps guide diagnostic testing. Family history is also critical, with attention given to premature graying, pulmonary, renal, and liver disease, and blood disorders.

Patients with an IMFS, (eg, Fanconi anemia or dyskeratosis congenita) may have associated phenotypical findings such as urogenital abnormalities or short stature; in addition, those with dyskeratosis congenita may present with the classic triad of oral leukoplakia, lacy skin pigmentation, and dystrophic nails.⁷ However, in patients with IMFS, classic phenotypical findings may be lacking in up to 30% to 40% of patients.⁷ As described previously, while congenital malformations are common in Fanconi anemia and dyskeratosis congenita, a third of patients may have no or only subtle phenotypical abnormalities, including alterations in skin or hair pigmentation, skeletal and growth abnormalities, and endocrine disorders.³⁰ The International Fanconi Anemia Registry identified central nervous system, genitourinary, skin and musculoskeletal, ophthalmic, and gastrointestinal system malformations among children with Fanconi anemia.^31,32 Patients with dyskeratosis congenita may present with pulmonary fibrosis, hepatic cirrhosis, or premature graying, as highlighted in a recent study by DiNardo and colleagues.³³ Therefore, physicians must have a heightened index of suspicion in patients with subtle phenotypical findings and associated cytopenias.

Diagnosis

Differential Diagnosis

The diagnosis of aplastic anemia should be suspected in any patient presenting with pancytopenia. Aplastic anemia is a diagnosis of exclusion.³⁴ Other conditions associated with peripheral blood pancytopenia should be considered including infections (HIV, hepatitis, parvovirus B19, cytomegalovirus, Epstein-Barr virus, varicella-zoster virus), nutritional deficiencies (vitamin B12, folate, copper, zinc), autoimmune disease (systemic lupus erythematosus, rheumatoid arthritis, hemophagocytic lymphohistiocytosis), hypersplenism, marrow-occupying diseases (eg, leukemia, lymphoma, MDS), solid malignancies, and fibrosis (Table).⁷

Diagnostic Evaluation

The workup for aplastic anemia should include a thorough history and physical exam to search simultaneously for alternative diagnoses and clues pointing to potential etiologic agents.⁷ Diagnostic tests to be performed include a complete blood count with differential, reticulocyte count, immature platelet fraction, flow cytometry (to rule out lymphoproliferative disorders and atypical myeloid cells and to evaluate for PNH), and bone marrow biopsy with subsequent cytogenetic, immunohistochemical, and molecular testing.³⁵ The typical findings in aplastic anemia include peripheral blood pancytopenia without dysplastic features and bone marrow biopsy demonstrating a hypocellular marrow.⁷ A relative lymphocytosis in the peripheral blood is common.⁷ In patients with a significant PNH clone, a macrocytosis along with elevated lactate dehydrogenase and elevated reticulocyte and granulocyte counts may be present.³⁶

The diagnosis (based on the Camitta criteria³⁷ and modified Camitta criteria³⁸ for severe aplastic anemia) requires 2 of the following findings on peripheral blood samples:

• Absolute neutrophil count (ANC) < 500 cells/µL
• Platelet count < 20,000 cells/µL
• Reticulocyte count < 1% corrected or < 20,000 cells/µL.³⁵

In addition to peripheral blood findings, bone marrow biopsy is essential for the diagnosis, and should demonstrate a markedly hypocellular marrow (cellularity < 25%), occasionally with an increase in T lymphocytes.^7,39 Because marrow cellularity varies with age and can be challenging to assess, additional biopsies may be needed to confirm the diagnosis.²⁹ A 1- to 2-cm core biopsy is necessary to confirm hypocellularity, as small areas of residual hematopoiesis may be present and obscure the diagnosis.³⁵

Excluding Hypocellular MDS and IMFS

A diagnostic challenge is the exclusion of hypocellular MDS, especially in the older adult presenting with aplastic anemia, as patients with aplastic anemia may have some degree of erythroid dysplasia on bone marrow morphology.³⁶ The presence of a PNH clone on flow cytometry can aid in diagnosing aplastic anemia and excluding MDS,³⁴ although PNH clones can be present in refractory anemia MDS. Patients with aplastic anemia have a lower ratio of CD34+ cells compared to those with hypoplastic MDS, with one study demonstrating a mean CD34+ percentage of < 0.5% in aplastic anemia versus 3.7% in hypoplastic MDS.⁴⁰ Cytogenetic and molecular testing can also aid in making this distinction by identifying mutations commonly implicated in MDS.⁷ The presence of monosomy 7 (-7) in aplastic anemia patients is associated with a poor overall prognosis.^34,41

Peripheral blood screening using chromosome breakage analysis (done using either mitomycin C or diepoxybutane as in vitro DNA-crosslinking agents) and telomere length testing (of peripheral blood leukocytes) is necessary to exclude the main IMFS, Fanconi anemia and telomere biology disorders, respectively. Ruling out these conditions is imperative, as the approach to treatment varies significantly between IMFS and aplastic anemia. Patients with shortened telomeres should undergo genetic screening for mutations in the telomere maintenance genes to evaluate the underlying defect leading to shortened telomeres. Patients with increased peripheral blood breakage should have genetic testing to detect mutations associated with Fanconi anemia.

Classification

Once the diagnosis of aplastic anemia has been made, the patient should be classified according to the severity of their disease. Disease severity is determined based on peripheral blood ANC:³⁴ non-severe aplastic anemia (NSAA), ANC > 500 polymorphonuclear neutrophils (PMNs)/µL; severe aplastic anemia (SAA), 200–500 PMNs/µL; and very severe (VSAA), 0–200 PMNs/µL.^4,34 Disease classification is important, as VSAA is associated with a decreased OS compared to SAA.² Disease classification may affect treatment decisions, as patients with NSAA may be observed for a short period of time, while conversely patients with SAA have a worse prognosis with delays in therapy.^42-44

Summary

Aplastic anemia is a rare but potentially life-threatening disorder characterized by pancytopenia and a marked reduction in the hematopoietic stem cell compartment. It can be acquired or associated with an IMFS, and the treatment and prognosis vary dramatically between these 2 etiologies. Work-up and diagnosis involves investigating IMFSs and ruling out malignant or infectious etiologies for pancytopenia. After aplastic anemia has been diagnosed, the patient should be classified according to the severity of their disease based on peripheral blood ANC.

Aplastic anemia is a clinical and pathological entity of bone marrow failure that causes progressive loss of hematopoietic progenitor stem cells (HPSC), resulting in pancytopenia.¹ Patients may present along a spectrum, ranging from being asymptomatic with incidental findings on peripheral blood testing to having life-threatening neutropenic infections or bleeding. Aplastic anemia results from either inherited or acquired causes, and the pathophysiology and treatment approach vary significantly between these 2 causes. Therefore, recognition of inherited marrow failure diseases, such as Fanconi anemia and telomere biology disorders, is critical to establishing the management plan. This article reviews the epidemiology, pathophysiology, clinical presentation, and diagnosis of aplastic anemia. Treatment of aplastic anemia is reviewed in a separate article.

Epidemiology

Aplastic anemia is a rare disorder, with an incidence of approximately 1.5 to 7 cases per million individuals per year.^2,3 A recent Scandinavian study reported that the incidence of aplastic anemia among the Swedish population is 2.3 cases per million individuals per year, with a median age at diagnosis of 60 years and a slight female predominance (52% versus 48%, respectively).² This data is congruent with prior observations made in Barcelona, where the incidence was 2.34 cases per million individuals per year, albeit with a slightly higher incidence in males compared to females (2.54 versus 2.16, respectively).⁴ The incidence of aplastic anemia varies globally, with a disproportionate increase in incidence seen among Asian populations, with rates as high as 8.8 per million individuals per year.^3-5 This variation in incidence in Asia versus other countries has not been well explained. There appears to be a bimodal distribution, with incidence peaks seen in young adults and in older adults.^2,3,6

Pathophysiology

Acquired Aplastic Anemia

The leading hypothesis as to the cause of most cases of acquired aplastic anemia is that a dysregulated immune system destroys hematopoietic progenitor cells. Inciting etiologies implicated in the development of acquired aplastic anemia include pregnancy, infection, medications, and exposure to certain chemicals, such as benzene.^1,7 The historical understanding of acquired aplastic anemia implicates cytotoxic T-lymphocyte–mediated destruction of CD34+ hematopoietic stem cells.^1,8,9 This hypothesis served as the basis for treatment of acquired aplastic anemia with immunosuppressive therapy, predominantly anti-thymocyte globulin (ATG) combined with cyclosporine A.^1,8 More recent work has focused on cytokine interactions, particularly the suppressive role of interferon (IFN)-γ on hematopoietic stem cells independent of T-lymphocyte–mediated hematopoietic destruction, which has been demonstrated in a murine model.⁸ The interaction of IFN-γ with the hematopoietic stem cells pool is dynamic. IFN-γ levels are elevated during an acute inflammatory response such as a viral infection, providing further basis for the immune-mediated nature of the acquired disease.¹⁰ Specifically, in vitro studies suggest the effects of IFN-γ on HPSC may be secondary to interruption of thrombopoietin and its respective signaling pathways, which play a key role in hematopoietic stem cell renewal.¹¹ Eltrombopag, a thrombopoietin receptor antagonist, has shown promise in the treatment of refractory aplastic anemia, with studies indicating that its effectiveness is independent of IFN-γ levels.^11,12

Inherited Aplastic Anemia

The inherited marrow failure syndromes (IMFSs) are a group of disorders characterized by cellular maintenance and repair defects, leading to cytopenias, increased cancer risk, structural defects, and risk of end organ damage, such as liver cirrhosis and pulmonary fibrosis.^13-15 The most common diseases include Fanconi anemia, dyskeratosis congenita/telomere biology disorders, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, but with the advent of whole exome sequencing new syndromes continue to be discovered. While classically these disorders present in children, adult presentations of these syndromes are now commonplace. Broadly, the pathophysiology of inherited aplastic anemia relates to the defective hematopoietic progenitor cells and an accelerated decline of the hematopoietic stem cell compartment.

The most common IMFS, Fanconi anemia and telomere biology disorders, are associated with numerous mutations in DNA damage repair pathways and telomere maintenance pathways. TERT, DKC, and TERC mutations are most commonly associated with dyskeratosis congenita, but may also be found infrequently in patients with aplastic anemia presenting at an older age in the absence of the classic phenotypical features.^1,16,17 The recognition of an underlying genetic disorder or telomere biology disorder leading to constitutional aplastic anemia is significant, as these conditions are associated not only with marrow failure, but also endocrinopathies, organ fibrosis, and solid organ malignancies.^13-15 In particular, mutations in the TERT and TERC genes have been associated with dyskeratosis congenita as well as pulmonary fibrosis and cirrhosis.^18,19 The implications of early diagnosis of an IMFS lie in the approach to treatment and prognosis.

Clonal Disorders and Secondary Malignancies

Myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML) are 2 clonal disorders that may arise from a background of aplastic anemia.^9,20,21 Hypoplastic MDS can be difficult to differentiate from aplastic anemia at diagnosis based on morphology alone, although recent work has demonstrated that molecular testing for somatic mutations in ASXL1, DNMT3A, and BCOR can aid in differentiating a subset of aplastic anemia patients who are more likely to progress to MDS.²¹ Clonal populations of cells harboring 6p uniparental disomy are seen in more than 10% of patients with aplastic anemia on cytogenetic analysis, which can help differentiate the diseases.⁹ Yoshizato and colleagues found lower rates of ASXL1 and DNMT3A mutations in patients with aplastic anemia as compared with patients with MDS or AML. In this study, patients with aplastic anemia had higher rates of mutations in PIGA (reflecting the increased paroxysmal nocturnal hemoglobinuria [PNH] clonality seen in aplastic anemia) and BCOR.⁹ Mutations were also found in genes commonly mutated in MDS and AML, including TET2, RUNX1, TP53, and JAK2, albeit at lower frequencies.⁹ These mutations as a whole have not predicted response to therapy or prognosis. However, when performing survival analysis in patients with specific mutations, those commonly encountered in MDS/AML (ASXL1, DNMT3A, TP53, RUNX1, CSMD1) are associated with faster progression to overt MDS/AML and decreased overall survival (OS),^20,21 suggesting these mutations may represent early clonality that can lead to clonal evolution and the development of secondary malignancies. Conversely, mutations in BCOR and BCORL appear to identify patients who may have a favorable outcome in response to immunosuppressive therapy and, similar to patients with PIGA mutations, improved OS.⁹

Paroxysmal Nocturnal Hemoglobinuria

In addition to having an increased risk of myelodysplasia and malignancy due to the development of a dominant pre-malignant clone, patients with aplastic anemia often harbor progenitor cell clones associated with PNH.^1,17 PNH clones have been identified in more than 50% of patients with aplastic anemia.^22,23 PNH represents a clonal disorder of hematopoiesis in which cells harbor X-linked somatic mutations in the PIGA gene; this gene encodes a protein responsible for the synthesis of glycosylphosphatidylinositol (GPI) anchors on the cell surface.^22,24 The lack of these cell surface proteins, specifically CD55 (also known as decay accelerating factor) and CD59 (also known as membrane inhibitor of reactive lysis), predisposes red cells to increased complement-mediated lysis.²⁵ The exact mechanism for the development of these clones in patients with aplastic anemia is not fully understood. Current theories hypothesize that these clones are protected from the immune-mediated destruction of normal hematopoietic stem cells due to the absence of the cell surface proteins.^1,20 The role of these clones over time in patients with aplastic anemia is less clear, though recent work demonstrated that despite differences in clonality over the disease course, aplastic anemia patients with small PNH clones are less likely to develop overt hemolysis and larger PNH clones compared to patients harboring larger (≥ 50%) PNH clones at diagnosis.^23,26,27 Additionally, PNH clones in patients with aplastic anemia infrequently become clinically significant.²⁷ It should be noted that these conditions exist along a continuum; that is, patients with aplastic anemia may develop PNH clones, while conversely patients with PNH may develop aplastic anemia.²⁰ Patients with PNH clones should be followed via peripheral blood flow cytometry in addition to complete blood count to track clonal stability and identify clinically significant PNH among aplastic anemia patients.²⁸

Patients with aplastic anemia typically are diagnosed either due to asymptomatic cytopenias found on peripheral blood sampling, symptomatic anemia, bleeding secondary to thrombocytopenia, or wound healing and infectious complications related to neutropenia.²⁹ A thorough history to understand the timing of symptoms, recent infectious symptoms/exposure, habits, and chemical or toxin exposures (including medications, travel, and supplements) helps guide diagnostic testing. Family history is also critical, with attention given to premature graying, pulmonary, renal, and liver disease, and blood disorders.

Patients with an IMFS, (eg, Fanconi anemia or dyskeratosis congenita) may have associated phenotypical findings such as urogenital abnormalities or short stature; in addition, those with dyskeratosis congenita may present with the classic triad of oral leukoplakia, lacy skin pigmentation, and dystrophic nails.⁷ However, in patients with IMFS, classic phenotypical findings may be lacking in up to 30% to 40% of patients.⁷ As described previously, while congenital malformations are common in Fanconi anemia and dyskeratosis congenita, a third of patients may have no or only subtle phenotypical abnormalities, including alterations in skin or hair pigmentation, skeletal and growth abnormalities, and endocrine disorders.³⁰ The International Fanconi Anemia Registry identified central nervous system, genitourinary, skin and musculoskeletal, ophthalmic, and gastrointestinal system malformations among children with Fanconi anemia.^31,32 Patients with dyskeratosis congenita may present with pulmonary fibrosis, hepatic cirrhosis, or premature graying, as highlighted in a recent study by DiNardo and colleagues.³³ Therefore, physicians must have a heightened index of suspicion in patients with subtle phenotypical findings and associated cytopenias.

Diagnosis

Differential Diagnosis

The diagnosis of aplastic anemia should be suspected in any patient presenting with pancytopenia. Aplastic anemia is a diagnosis of exclusion.³⁴ Other conditions associated with peripheral blood pancytopenia should be considered including infections (HIV, hepatitis, parvovirus B19, cytomegalovirus, Epstein-Barr virus, varicella-zoster virus), nutritional deficiencies (vitamin B12, folate, copper, zinc), autoimmune disease (systemic lupus erythematosus, rheumatoid arthritis, hemophagocytic lymphohistiocytosis), hypersplenism, marrow-occupying diseases (eg, leukemia, lymphoma, MDS), solid malignancies, and fibrosis (Table).⁷

Diagnostic Evaluation

The workup for aplastic anemia should include a thorough history and physical exam to search simultaneously for alternative diagnoses and clues pointing to potential etiologic agents.⁷ Diagnostic tests to be performed include a complete blood count with differential, reticulocyte count, immature platelet fraction, flow cytometry (to rule out lymphoproliferative disorders and atypical myeloid cells and to evaluate for PNH), and bone marrow biopsy with subsequent cytogenetic, immunohistochemical, and molecular testing.³⁵ The typical findings in aplastic anemia include peripheral blood pancytopenia without dysplastic features and bone marrow biopsy demonstrating a hypocellular marrow.⁷ A relative lymphocytosis in the peripheral blood is common.⁷ In patients with a significant PNH clone, a macrocytosis along with elevated lactate dehydrogenase and elevated reticulocyte and granulocyte counts may be present.³⁶

The diagnosis (based on the Camitta criteria³⁷ and modified Camitta criteria³⁸ for severe aplastic anemia) requires 2 of the following findings on peripheral blood samples:

• Absolute neutrophil count (ANC) < 500 cells/µL
• Platelet count < 20,000 cells/µL
• Reticulocyte count < 1% corrected or < 20,000 cells/µL.³⁵

In addition to peripheral blood findings, bone marrow biopsy is essential for the diagnosis, and should demonstrate a markedly hypocellular marrow (cellularity < 25%), occasionally with an increase in T lymphocytes.^7,39 Because marrow cellularity varies with age and can be challenging to assess, additional biopsies may be needed to confirm the diagnosis.²⁹ A 1- to 2-cm core biopsy is necessary to confirm hypocellularity, as small areas of residual hematopoiesis may be present and obscure the diagnosis.³⁵

Excluding Hypocellular MDS and IMFS

A diagnostic challenge is the exclusion of hypocellular MDS, especially in the older adult presenting with aplastic anemia, as patients with aplastic anemia may have some degree of erythroid dysplasia on bone marrow morphology.³⁶ The presence of a PNH clone on flow cytometry can aid in diagnosing aplastic anemia and excluding MDS,³⁴ although PNH clones can be present in refractory anemia MDS. Patients with aplastic anemia have a lower ratio of CD34+ cells compared to those with hypoplastic MDS, with one study demonstrating a mean CD34+ percentage of < 0.5% in aplastic anemia versus 3.7% in hypoplastic MDS.⁴⁰ Cytogenetic and molecular testing can also aid in making this distinction by identifying mutations commonly implicated in MDS.⁷ The presence of monosomy 7 (-7) in aplastic anemia patients is associated with a poor overall prognosis.^34,41

Peripheral blood screening using chromosome breakage analysis (done using either mitomycin C or diepoxybutane as in vitro DNA-crosslinking agents) and telomere length testing (of peripheral blood leukocytes) is necessary to exclude the main IMFS, Fanconi anemia and telomere biology disorders, respectively. Ruling out these conditions is imperative, as the approach to treatment varies significantly between IMFS and aplastic anemia. Patients with shortened telomeres should undergo genetic screening for mutations in the telomere maintenance genes to evaluate the underlying defect leading to shortened telomeres. Patients with increased peripheral blood breakage should have genetic testing to detect mutations associated with Fanconi anemia.

Classification

Once the diagnosis of aplastic anemia has been made, the patient should be classified according to the severity of their disease. Disease severity is determined based on peripheral blood ANC:³⁴ non-severe aplastic anemia (NSAA), ANC > 500 polymorphonuclear neutrophils (PMNs)/µL; severe aplastic anemia (SAA), 200–500 PMNs/µL; and very severe (VSAA), 0–200 PMNs/µL.^4,34 Disease classification is important, as VSAA is associated with a decreased OS compared to SAA.² Disease classification may affect treatment decisions, as patients with NSAA may be observed for a short period of time, while conversely patients with SAA have a worse prognosis with delays in therapy.^42-44

Summary

Aplastic anemia is a rare but potentially life-threatening disorder characterized by pancytopenia and a marked reduction in the hematopoietic stem cell compartment. It can be acquired or associated with an IMFS, and the treatment and prognosis vary dramatically between these 2 etiologies. Work-up and diagnosis involves investigating IMFSs and ruling out malignant or infectious etiologies for pancytopenia. After aplastic anemia has been diagnosed, the patient should be classified according to the severity of their disease based on peripheral blood ANC.

Aplastic anemia is a clinical and pathological entity of bone marrow failure that causes progressive loss of hematopoietic progenitor stem cells (HPSC), resulting in pancytopenia.¹ Patients may present along a spectrum, ranging from being asymptomatic with incidental findings on peripheral blood testing to having life-threatening neutropenic infections or bleeding. Aplastic anemia results from either inherited or acquired causes, and the pathophysiology and treatment approach vary significantly between these 2 causes. Therefore, recognition of inherited marrow failure diseases, such as Fanconi anemia and telomere biology disorders, is critical to establishing the management plan. This article reviews the epidemiology, pathophysiology, clinical presentation, and diagnosis of aplastic anemia. Treatment of aplastic anemia is reviewed in a separate article.

Epidemiology

Aplastic anemia is a rare disorder, with an incidence of approximately 1.5 to 7 cases per million individuals per year.^2,3 A recent Scandinavian study reported that the incidence of aplastic anemia among the Swedish population is 2.3 cases per million individuals per year, with a median age at diagnosis of 60 years and a slight female predominance (52% versus 48%, respectively).² This data is congruent with prior observations made in Barcelona, where the incidence was 2.34 cases per million individuals per year, albeit with a slightly higher incidence in males compared to females (2.54 versus 2.16, respectively).⁴ The incidence of aplastic anemia varies globally, with a disproportionate increase in incidence seen among Asian populations, with rates as high as 8.8 per million individuals per year.^3-5 This variation in incidence in Asia versus other countries has not been well explained. There appears to be a bimodal distribution, with incidence peaks seen in young adults and in older adults.^2,3,6

Pathophysiology

Acquired Aplastic Anemia

The leading hypothesis as to the cause of most cases of acquired aplastic anemia is that a dysregulated immune system destroys hematopoietic progenitor cells. Inciting etiologies implicated in the development of acquired aplastic anemia include pregnancy, infection, medications, and exposure to certain chemicals, such as benzene.^1,7 The historical understanding of acquired aplastic anemia implicates cytotoxic T-lymphocyte–mediated destruction of CD34+ hematopoietic stem cells.^1,8,9 This hypothesis served as the basis for treatment of acquired aplastic anemia with immunosuppressive therapy, predominantly anti-thymocyte globulin (ATG) combined with cyclosporine A.^1,8 More recent work has focused on cytokine interactions, particularly the suppressive role of interferon (IFN)-γ on hematopoietic stem cells independent of T-lymphocyte–mediated hematopoietic destruction, which has been demonstrated in a murine model.⁸ The interaction of IFN-γ with the hematopoietic stem cells pool is dynamic. IFN-γ levels are elevated during an acute inflammatory response such as a viral infection, providing further basis for the immune-mediated nature of the acquired disease.¹⁰ Specifically, in vitro studies suggest the effects of IFN-γ on HPSC may be secondary to interruption of thrombopoietin and its respective signaling pathways, which play a key role in hematopoietic stem cell renewal.¹¹ Eltrombopag, a thrombopoietin receptor antagonist, has shown promise in the treatment of refractory aplastic anemia, with studies indicating that its effectiveness is independent of IFN-γ levels.^11,12

Inherited Aplastic Anemia

The inherited marrow failure syndromes (IMFSs) are a group of disorders characterized by cellular maintenance and repair defects, leading to cytopenias, increased cancer risk, structural defects, and risk of end organ damage, such as liver cirrhosis and pulmonary fibrosis.^13-15 The most common diseases include Fanconi anemia, dyskeratosis congenita/telomere biology disorders, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, but with the advent of whole exome sequencing new syndromes continue to be discovered. While classically these disorders present in children, adult presentations of these syndromes are now commonplace. Broadly, the pathophysiology of inherited aplastic anemia relates to the defective hematopoietic progenitor cells and an accelerated decline of the hematopoietic stem cell compartment.

The most common IMFS, Fanconi anemia and telomere biology disorders, are associated with numerous mutations in DNA damage repair pathways and telomere maintenance pathways. TERT, DKC, and TERC mutations are most commonly associated with dyskeratosis congenita, but may also be found infrequently in patients with aplastic anemia presenting at an older age in the absence of the classic phenotypical features.^1,16,17 The recognition of an underlying genetic disorder or telomere biology disorder leading to constitutional aplastic anemia is significant, as these conditions are associated not only with marrow failure, but also endocrinopathies, organ fibrosis, and solid organ malignancies.^13-15 In particular, mutations in the TERT and TERC genes have been associated with dyskeratosis congenita as well as pulmonary fibrosis and cirrhosis.^18,19 The implications of early diagnosis of an IMFS lie in the approach to treatment and prognosis.

Clonal Disorders and Secondary Malignancies

Myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML) are 2 clonal disorders that may arise from a background of aplastic anemia.^9,20,21 Hypoplastic MDS can be difficult to differentiate from aplastic anemia at diagnosis based on morphology alone, although recent work has demonstrated that molecular testing for somatic mutations in ASXL1, DNMT3A, and BCOR can aid in differentiating a subset of aplastic anemia patients who are more likely to progress to MDS.²¹ Clonal populations of cells harboring 6p uniparental disomy are seen in more than 10% of patients with aplastic anemia on cytogenetic analysis, which can help differentiate the diseases.⁹ Yoshizato and colleagues found lower rates of ASXL1 and DNMT3A mutations in patients with aplastic anemia as compared with patients with MDS or AML. In this study, patients with aplastic anemia had higher rates of mutations in PIGA (reflecting the increased paroxysmal nocturnal hemoglobinuria [PNH] clonality seen in aplastic anemia) and BCOR.⁹ Mutations were also found in genes commonly mutated in MDS and AML, including TET2, RUNX1, TP53, and JAK2, albeit at lower frequencies.⁹ These mutations as a whole have not predicted response to therapy or prognosis. However, when performing survival analysis in patients with specific mutations, those commonly encountered in MDS/AML (ASXL1, DNMT3A, TP53, RUNX1, CSMD1) are associated with faster progression to overt MDS/AML and decreased overall survival (OS),^20,21 suggesting these mutations may represent early clonality that can lead to clonal evolution and the development of secondary malignancies. Conversely, mutations in BCOR and BCORL appear to identify patients who may have a favorable outcome in response to immunosuppressive therapy and, similar to patients with PIGA mutations, improved OS.⁹

Paroxysmal Nocturnal Hemoglobinuria

In addition to having an increased risk of myelodysplasia and malignancy due to the development of a dominant pre-malignant clone, patients with aplastic anemia often harbor progenitor cell clones associated with PNH.^1,17 PNH clones have been identified in more than 50% of patients with aplastic anemia.^22,23 PNH represents a clonal disorder of hematopoiesis in which cells harbor X-linked somatic mutations in the PIGA gene; this gene encodes a protein responsible for the synthesis of glycosylphosphatidylinositol (GPI) anchors on the cell surface.^22,24 The lack of these cell surface proteins, specifically CD55 (also known as decay accelerating factor) and CD59 (also known as membrane inhibitor of reactive lysis), predisposes red cells to increased complement-mediated lysis.²⁵ The exact mechanism for the development of these clones in patients with aplastic anemia is not fully understood. Current theories hypothesize that these clones are protected from the immune-mediated destruction of normal hematopoietic stem cells due to the absence of the cell surface proteins.^1,20 The role of these clones over time in patients with aplastic anemia is less clear, though recent work demonstrated that despite differences in clonality over the disease course, aplastic anemia patients with small PNH clones are less likely to develop overt hemolysis and larger PNH clones compared to patients harboring larger (≥ 50%) PNH clones at diagnosis.^23,26,27 Additionally, PNH clones in patients with aplastic anemia infrequently become clinically significant.²⁷ It should be noted that these conditions exist along a continuum; that is, patients with aplastic anemia may develop PNH clones, while conversely patients with PNH may develop aplastic anemia.²⁰ Patients with PNH clones should be followed via peripheral blood flow cytometry in addition to complete blood count to track clonal stability and identify clinically significant PNH among aplastic anemia patients.²⁸

Patients with aplastic anemia typically are diagnosed either due to asymptomatic cytopenias found on peripheral blood sampling, symptomatic anemia, bleeding secondary to thrombocytopenia, or wound healing and infectious complications related to neutropenia.²⁹ A thorough history to understand the timing of symptoms, recent infectious symptoms/exposure, habits, and chemical or toxin exposures (including medications, travel, and supplements) helps guide diagnostic testing. Family history is also critical, with attention given to premature graying, pulmonary, renal, and liver disease, and blood disorders.

Patients with an IMFS, (eg, Fanconi anemia or dyskeratosis congenita) may have associated phenotypical findings such as urogenital abnormalities or short stature; in addition, those with dyskeratosis congenita may present with the classic triad of oral leukoplakia, lacy skin pigmentation, and dystrophic nails.⁷ However, in patients with IMFS, classic phenotypical findings may be lacking in up to 30% to 40% of patients.⁷ As described previously, while congenital malformations are common in Fanconi anemia and dyskeratosis congenita, a third of patients may have no or only subtle phenotypical abnormalities, including alterations in skin or hair pigmentation, skeletal and growth abnormalities, and endocrine disorders.³⁰ The International Fanconi Anemia Registry identified central nervous system, genitourinary, skin and musculoskeletal, ophthalmic, and gastrointestinal system malformations among children with Fanconi anemia.^31,32 Patients with dyskeratosis congenita may present with pulmonary fibrosis, hepatic cirrhosis, or premature graying, as highlighted in a recent study by DiNardo and colleagues.³³ Therefore, physicians must have a heightened index of suspicion in patients with subtle phenotypical findings and associated cytopenias.

Diagnosis

Differential Diagnosis

The diagnosis of aplastic anemia should be suspected in any patient presenting with pancytopenia. Aplastic anemia is a diagnosis of exclusion.³⁴ Other conditions associated with peripheral blood pancytopenia should be considered including infections (HIV, hepatitis, parvovirus B19, cytomegalovirus, Epstein-Barr virus, varicella-zoster virus), nutritional deficiencies (vitamin B12, folate, copper, zinc), autoimmune disease (systemic lupus erythematosus, rheumatoid arthritis, hemophagocytic lymphohistiocytosis), hypersplenism, marrow-occupying diseases (eg, leukemia, lymphoma, MDS), solid malignancies, and fibrosis (Table).⁷

Diagnostic Evaluation

The workup for aplastic anemia should include a thorough history and physical exam to search simultaneously for alternative diagnoses and clues pointing to potential etiologic agents.⁷ Diagnostic tests to be performed include a complete blood count with differential, reticulocyte count, immature platelet fraction, flow cytometry (to rule out lymphoproliferative disorders and atypical myeloid cells and to evaluate for PNH), and bone marrow biopsy with subsequent cytogenetic, immunohistochemical, and molecular testing.³⁵ The typical findings in aplastic anemia include peripheral blood pancytopenia without dysplastic features and bone marrow biopsy demonstrating a hypocellular marrow.⁷ A relative lymphocytosis in the peripheral blood is common.⁷ In patients with a significant PNH clone, a macrocytosis along with elevated lactate dehydrogenase and elevated reticulocyte and granulocyte counts may be present.³⁶

The diagnosis (based on the Camitta criteria³⁷ and modified Camitta criteria³⁸ for severe aplastic anemia) requires 2 of the following findings on peripheral blood samples:

• Absolute neutrophil count (ANC) < 500 cells/µL
• Platelet count < 20,000 cells/µL
• Reticulocyte count < 1% corrected or < 20,000 cells/µL.³⁵

In addition to peripheral blood findings, bone marrow biopsy is essential for the diagnosis, and should demonstrate a markedly hypocellular marrow (cellularity < 25%), occasionally with an increase in T lymphocytes.^7,39 Because marrow cellularity varies with age and can be challenging to assess, additional biopsies may be needed to confirm the diagnosis.²⁹ A 1- to 2-cm core biopsy is necessary to confirm hypocellularity, as small areas of residual hematopoiesis may be present and obscure the diagnosis.³⁵

Excluding Hypocellular MDS and IMFS

A diagnostic challenge is the exclusion of hypocellular MDS, especially in the older adult presenting with aplastic anemia, as patients with aplastic anemia may have some degree of erythroid dysplasia on bone marrow morphology.³⁶ The presence of a PNH clone on flow cytometry can aid in diagnosing aplastic anemia and excluding MDS,³⁴ although PNH clones can be present in refractory anemia MDS. Patients with aplastic anemia have a lower ratio of CD34+ cells compared to those with hypoplastic MDS, with one study demonstrating a mean CD34+ percentage of < 0.5% in aplastic anemia versus 3.7% in hypoplastic MDS.⁴⁰ Cytogenetic and molecular testing can also aid in making this distinction by identifying mutations commonly implicated in MDS.⁷ The presence of monosomy 7 (-7) in aplastic anemia patients is associated with a poor overall prognosis.^34,41

Peripheral blood screening using chromosome breakage analysis (done using either mitomycin C or diepoxybutane as in vitro DNA-crosslinking agents) and telomere length testing (of peripheral blood leukocytes) is necessary to exclude the main IMFS, Fanconi anemia and telomere biology disorders, respectively. Ruling out these conditions is imperative, as the approach to treatment varies significantly between IMFS and aplastic anemia. Patients with shortened telomeres should undergo genetic screening for mutations in the telomere maintenance genes to evaluate the underlying defect leading to shortened telomeres. Patients with increased peripheral blood breakage should have genetic testing to detect mutations associated with Fanconi anemia.

Classification

Once the diagnosis of aplastic anemia has been made, the patient should be classified according to the severity of their disease. Disease severity is determined based on peripheral blood ANC:³⁴ non-severe aplastic anemia (NSAA), ANC > 500 polymorphonuclear neutrophils (PMNs)/µL; severe aplastic anemia (SAA), 200–500 PMNs/µL; and very severe (VSAA), 0–200 PMNs/µL.^4,34 Disease classification is important, as VSAA is associated with a decreased OS compared to SAA.² Disease classification may affect treatment decisions, as patients with NSAA may be observed for a short period of time, while conversely patients with SAA have a worse prognosis with delays in therapy.^42-44

Summary

Aplastic anemia is a rare but potentially life-threatening disorder characterized by pancytopenia and a marked reduction in the hematopoietic stem cell compartment. It can be acquired or associated with an IMFS, and the treatment and prognosis vary dramatically between these 2 etiologies. Work-up and diagnosis involves investigating IMFSs and ruling out malignant or infectious etiologies for pancytopenia. After aplastic anemia has been diagnosed, the patient should be classified according to the severity of their disease based on peripheral blood ANC.

Among people of the same age, the degree of frailty influences the association between Alzheimer’s disease pathology and Alzheimer’s dementia, according to research published online ahead of print Jan. 17 in Lancet Neurology. Data suggest that frailty reduces the threshold for Alzheimer’s disease pathology to cause cognitive decline. Frailty also may contribute to other mechanisms that cause dementia, such as inflammation and immunosenescence, said the investigators.

“While more research is needed, given that frailty is potentially reversible, it is possible that helping people to maintain function and independence in later life could reduce both dementia risk and the severity of debilitating symptoms common in this disease,” said Professor Kenneth Rockwood, MD, of the Nova Scotia Health Authority and Dalhousie University in Halifax, N.S., in a press release.
 

More susceptible to dementia?

The presence of amyloid plaques and neurofibrillary tangles is not a sufficient condition for the clinical expression of dementia. Some patients with a high degree of Alzheimer’s disease pathology have no apparent cognitive decline. Other factors therefore may modify the relationship between pathology and dementia.

Most people who develop Alzheimer’s disease dementia are older than 65 years, and many of these patients are frail. Frailty is understood as a decreased physiologic reserve and an increased risk for adverse health outcomes. Dr. Rockwood and his colleagues hypothesized that frailty moderates the clinical expression of dementia in relation to Alzheimer’s disease pathology.

To test their hypothesis, the investigators performed a cross-sectional analysis of data from the Rush Memory and Aging Project, which collects clinical and pathologic data from adults older than 59 years without dementia at baseline who live in Illinois. Since 1997, participants have undergone annual clinical and neuropsychological evaluations, and the cohort has been followed for 21 years. For their analysis, Dr. Rockwood and his colleagues included participants without dementia or with Alzheimer’s dementia at their last clinical assessment. Eligible participants had died, and complete autopsy data were available for them.

The researchers measured Alzheimer’s disease pathology using a summary measure of neurofibrillary tangles and neuritic and diffuse plaques. Clinical diagnoses of Alzheimer’s dementia were based on clinician consensus. Dr. Rockwood and his colleagues retrospectively created a 41-item frailty index from variables (e.g., symptoms, signs, comorbidities, and function) that were obtained at each clinical evaluation.

Logistic regression and moderation modeling allowed the investigators to evaluate relationships between Alzheimer’s disease pathology, frailty, and Alzheimer’s dementia. Dr. Rockwood and hus colleagues adjusted all analyses for age, sex, and education.

In all, 456 participants were included in the analysis. The sample’s mean age at death was 89.7 years, and 69% of participants were women. At participants’ last clinical assessment, 242 (53%) had possible or probable Alzheimer’s dementia.

The sample’s mean frailty index was 0.42. The median frailty index was 0.41, a value similar to the threshold commonly used to distinguish between moderate and severe frailty. People with high frailty index scores (i.e., 0.41 or greater) were older, had lower Mini-Mental State Examination scores, were more likely to have a diagnosis of dementia, and had a higher Braak stage than those with moderate or low frailty index scores.
 

Significant interaction between frailty and Alzheimer’s disease

After the investigators adjusted for age, sex, and education, frailty (odds ratio, 1.76) and Alzheimer’s disease pathology (OR, 4.81) were independently associated with Alzheimer’s dementia. When the investigators added frailty to the model for the relationship between Alzheimer’s disease pathology and Alzheimer’s dementia, the model fit improved. They found a significant interaction between frailty and Alzheimer’s disease pathology (OR, 0.73). People with a low amount of frailty were better able to tolerate Alzheimer’s disease pathology, and people with higher amounts of frailty were more likely to have more Alzheimer’s disease pathology and clinical dementia.

One of the study’s limitations is that it is a secondary analysis, according to Dr. Rockwood and his colleagues. In addition, frailty was measured close to participants’ time of death, and the measurements may thus reflect terminal decline. Participant deaths resulting from causes other than those related to dementia might have confounded the results. Finally, the sample came entirely from people living in retirement homes in Illinois, which might have introduced bias. Future research should use a population-based sample, said the authors.

Frailty could be a basis for risk stratification and could inform the management and treatment of older adults, said Dr. Rockwood and his colleagues. The study results have “the potential to improve our understanding of disease expression, explain failures in pharmacologic treatment, and aid in the development of more appropriate therapeutic targets, approaches, and measurements of success,” they concluded.

The study had no source of funding. The authors reported receiving fees and grants from DGI Clinical, GlaxoSmithKline, Pfizer, and Sanofi. Authors also received support from governmental bodies such as the National Institutes of Health and the Canadian Institutes of Health Research.

egreb@mdedge.com

SOURCE: Wallace LMK et al. Lancet Neurol. 2019;18:177-84.

Among people of the same age, the degree of frailty influences the association between Alzheimer’s disease pathology and Alzheimer’s dementia, according to research published online ahead of print Jan. 17 in Lancet Neurology. Data suggest that frailty reduces the threshold for Alzheimer’s disease pathology to cause cognitive decline. Frailty also may contribute to other mechanisms that cause dementia, such as inflammation and immunosenescence, said the investigators.

“While more research is needed, given that frailty is potentially reversible, it is possible that helping people to maintain function and independence in later life could reduce both dementia risk and the severity of debilitating symptoms common in this disease,” said Professor Kenneth Rockwood, MD, of the Nova Scotia Health Authority and Dalhousie University in Halifax, N.S., in a press release.
 

More susceptible to dementia?

The presence of amyloid plaques and neurofibrillary tangles is not a sufficient condition for the clinical expression of dementia. Some patients with a high degree of Alzheimer’s disease pathology have no apparent cognitive decline. Other factors therefore may modify the relationship between pathology and dementia.

Most people who develop Alzheimer’s disease dementia are older than 65 years, and many of these patients are frail. Frailty is understood as a decreased physiologic reserve and an increased risk for adverse health outcomes. Dr. Rockwood and his colleagues hypothesized that frailty moderates the clinical expression of dementia in relation to Alzheimer’s disease pathology.

To test their hypothesis, the investigators performed a cross-sectional analysis of data from the Rush Memory and Aging Project, which collects clinical and pathologic data from adults older than 59 years without dementia at baseline who live in Illinois. Since 1997, participants have undergone annual clinical and neuropsychological evaluations, and the cohort has been followed for 21 years. For their analysis, Dr. Rockwood and his colleagues included participants without dementia or with Alzheimer’s dementia at their last clinical assessment. Eligible participants had died, and complete autopsy data were available for them.

The researchers measured Alzheimer’s disease pathology using a summary measure of neurofibrillary tangles and neuritic and diffuse plaques. Clinical diagnoses of Alzheimer’s dementia were based on clinician consensus. Dr. Rockwood and his colleagues retrospectively created a 41-item frailty index from variables (e.g., symptoms, signs, comorbidities, and function) that were obtained at each clinical evaluation.

Logistic regression and moderation modeling allowed the investigators to evaluate relationships between Alzheimer’s disease pathology, frailty, and Alzheimer’s dementia. Dr. Rockwood and hus colleagues adjusted all analyses for age, sex, and education.

In all, 456 participants were included in the analysis. The sample’s mean age at death was 89.7 years, and 69% of participants were women. At participants’ last clinical assessment, 242 (53%) had possible or probable Alzheimer’s dementia.

The sample’s mean frailty index was 0.42. The median frailty index was 0.41, a value similar to the threshold commonly used to distinguish between moderate and severe frailty. People with high frailty index scores (i.e., 0.41 or greater) were older, had lower Mini-Mental State Examination scores, were more likely to have a diagnosis of dementia, and had a higher Braak stage than those with moderate or low frailty index scores.
 

Significant interaction between frailty and Alzheimer’s disease

After the investigators adjusted for age, sex, and education, frailty (odds ratio, 1.76) and Alzheimer’s disease pathology (OR, 4.81) were independently associated with Alzheimer’s dementia. When the investigators added frailty to the model for the relationship between Alzheimer’s disease pathology and Alzheimer’s dementia, the model fit improved. They found a significant interaction between frailty and Alzheimer’s disease pathology (OR, 0.73). People with a low amount of frailty were better able to tolerate Alzheimer’s disease pathology, and people with higher amounts of frailty were more likely to have more Alzheimer’s disease pathology and clinical dementia.

One of the study’s limitations is that it is a secondary analysis, according to Dr. Rockwood and his colleagues. In addition, frailty was measured close to participants’ time of death, and the measurements may thus reflect terminal decline. Participant deaths resulting from causes other than those related to dementia might have confounded the results. Finally, the sample came entirely from people living in retirement homes in Illinois, which might have introduced bias. Future research should use a population-based sample, said the authors.

Frailty could be a basis for risk stratification and could inform the management and treatment of older adults, said Dr. Rockwood and his colleagues. The study results have “the potential to improve our understanding of disease expression, explain failures in pharmacologic treatment, and aid in the development of more appropriate therapeutic targets, approaches, and measurements of success,” they concluded.

The study had no source of funding. The authors reported receiving fees and grants from DGI Clinical, GlaxoSmithKline, Pfizer, and Sanofi. Authors also received support from governmental bodies such as the National Institutes of Health and the Canadian Institutes of Health Research.

egreb@mdedge.com

SOURCE: Wallace LMK et al. Lancet Neurol. 2019;18:177-84.

Among people of the same age, the degree of frailty influences the association between Alzheimer’s disease pathology and Alzheimer’s dementia, according to research published online ahead of print Jan. 17 in Lancet Neurology. Data suggest that frailty reduces the threshold for Alzheimer’s disease pathology to cause cognitive decline. Frailty also may contribute to other mechanisms that cause dementia, such as inflammation and immunosenescence, said the investigators.

“While more research is needed, given that frailty is potentially reversible, it is possible that helping people to maintain function and independence in later life could reduce both dementia risk and the severity of debilitating symptoms common in this disease,” said Professor Kenneth Rockwood, MD, of the Nova Scotia Health Authority and Dalhousie University in Halifax, N.S., in a press release.
 

More susceptible to dementia?

The presence of amyloid plaques and neurofibrillary tangles is not a sufficient condition for the clinical expression of dementia. Some patients with a high degree of Alzheimer’s disease pathology have no apparent cognitive decline. Other factors therefore may modify the relationship between pathology and dementia.

Most people who develop Alzheimer’s disease dementia are older than 65 years, and many of these patients are frail. Frailty is understood as a decreased physiologic reserve and an increased risk for adverse health outcomes. Dr. Rockwood and his colleagues hypothesized that frailty moderates the clinical expression of dementia in relation to Alzheimer’s disease pathology.

To test their hypothesis, the investigators performed a cross-sectional analysis of data from the Rush Memory and Aging Project, which collects clinical and pathologic data from adults older than 59 years without dementia at baseline who live in Illinois. Since 1997, participants have undergone annual clinical and neuropsychological evaluations, and the cohort has been followed for 21 years. For their analysis, Dr. Rockwood and his colleagues included participants without dementia or with Alzheimer’s dementia at their last clinical assessment. Eligible participants had died, and complete autopsy data were available for them.

The researchers measured Alzheimer’s disease pathology using a summary measure of neurofibrillary tangles and neuritic and diffuse plaques. Clinical diagnoses of Alzheimer’s dementia were based on clinician consensus. Dr. Rockwood and his colleagues retrospectively created a 41-item frailty index from variables (e.g., symptoms, signs, comorbidities, and function) that were obtained at each clinical evaluation.

Logistic regression and moderation modeling allowed the investigators to evaluate relationships between Alzheimer’s disease pathology, frailty, and Alzheimer’s dementia. Dr. Rockwood and hus colleagues adjusted all analyses for age, sex, and education.

In all, 456 participants were included in the analysis. The sample’s mean age at death was 89.7 years, and 69% of participants were women. At participants’ last clinical assessment, 242 (53%) had possible or probable Alzheimer’s dementia.

The sample’s mean frailty index was 0.42. The median frailty index was 0.41, a value similar to the threshold commonly used to distinguish between moderate and severe frailty. People with high frailty index scores (i.e., 0.41 or greater) were older, had lower Mini-Mental State Examination scores, were more likely to have a diagnosis of dementia, and had a higher Braak stage than those with moderate or low frailty index scores.
 

Significant interaction between frailty and Alzheimer’s disease

After the investigators adjusted for age, sex, and education, frailty (odds ratio, 1.76) and Alzheimer’s disease pathology (OR, 4.81) were independently associated with Alzheimer’s dementia. When the investigators added frailty to the model for the relationship between Alzheimer’s disease pathology and Alzheimer’s dementia, the model fit improved. They found a significant interaction between frailty and Alzheimer’s disease pathology (OR, 0.73). People with a low amount of frailty were better able to tolerate Alzheimer’s disease pathology, and people with higher amounts of frailty were more likely to have more Alzheimer’s disease pathology and clinical dementia.

One of the study’s limitations is that it is a secondary analysis, according to Dr. Rockwood and his colleagues. In addition, frailty was measured close to participants’ time of death, and the measurements may thus reflect terminal decline. Participant deaths resulting from causes other than those related to dementia might have confounded the results. Finally, the sample came entirely from people living in retirement homes in Illinois, which might have introduced bias. Future research should use a population-based sample, said the authors.

Frailty could be a basis for risk stratification and could inform the management and treatment of older adults, said Dr. Rockwood and his colleagues. The study results have “the potential to improve our understanding of disease expression, explain failures in pharmacologic treatment, and aid in the development of more appropriate therapeutic targets, approaches, and measurements of success,” they concluded.

The study had no source of funding. The authors reported receiving fees and grants from DGI Clinical, GlaxoSmithKline, Pfizer, and Sanofi. Authors also received support from governmental bodies such as the National Institutes of Health and the Canadian Institutes of Health Research.

egreb@mdedge.com

SOURCE: Wallace LMK et al. Lancet Neurol. 2019;18:177-84.