While psychiatry has been the subject of many films, video games are not a medium commonly known for examining mental illness.¹ There have been PC games over the years with psychiatric themes, such as Sanitarium (1998), Depression Quest (2013), Fran Bow (2015), and Night in the Woods (2017). Now for perhaps the first time a game has been developed with the practice of psychiatry as its primary focus.

Freud’s Bones is a 2022 game developed by independent Italian game studio Fortuna Imperatore. The result of a successful Kickstarter crowdfunding campaign, Freud’s Bones is advertised as “the first point & click narrative-drive game to pay homage to the birth of psychoanalysis and its founder, addressing the themes of sexuality and neuroses filled with existential doubts.”

In Freud’s Bones, you take control of Sigmund Freud and guide him through his daily tasks. Gameplay is of the simple point-and-click variety, modeled after classic LucasArts-style adventure games of the 1990s such as The Secret of Monkey Island or Day of the Tentacle. Prior to seeing your first patient, the game provides several documents the player can peruse to become familiar with basic concepts of psychoanalysis. Although the game was originally written in Italian (and translation gaffes occasionally arise), generally the English wording is easy to read. However, some players may feel intimidated or bored by the sheer quantity of text the game provides. All in-game text, including books and spoken words, are written and there is no recorded voice acting. Audio consists largely of unintrusive background music and occasional sound effects. The graphical style is simple and cartoonish but pleasant.

Freud’s personal life is a major focus of the game. His real life dog Jofi is a constant presence in Freud’s office. At various times the player will witness Freud’s dreams, act as a voice inside his head, and attempt to interpret mystical Egyptian messages he receives. Players are also tasked with managing Freud’s reputation in the scientific community. This is apparently intended as a reflection of in-game clinical acumen, but it was sometimes difficult to tell what direct influence my actions had on Freud’s reputation.

Freud’s energy may flag at various points during the game, and the player may choose to give him a cigar or a dose of cocaine to stimulate him. These options sound interesting on the surface, but I found the effect of these substances on the game’s actual outcome to be minimal. Some tasks are presented in a less than user-friendly manner. For example, on my initial playthrough I could not figure out how to complete several optional errands such as shopping for more tobacco or selecting a cover for Freud’s books. The player is also given the opportunity to make choices that affect Freud’s personal life, such as whether to pursue an extramarital affair. The game does have a few narrative surprises, including appearances from some of Freud’s well-known contemporaries. One particularly vivid sequence late in the game involves navigating Freud through a hallucination with some bizarre, but very Freudian, imagery.

By far the most interesting and enjoyable part of the game is the psychoanalysis sessions. The player guides Freud through multiple sessions with four different patients. Each of them has a unique story and associated symptoms, and the player can choose a variety of responses. For example, will you take a comforting, paternalistic approach to the patient uncomfortable with her first appointment? Or will you take the more stoic, quiet approach of the analyst and allow the patient to speak without prompting? Part of the player’s quest in guiding Freud through these sessions is to help patients bring their unconscious thoughts to conscious awareness. This is depicted graphically as the thought moves vertically through images representing the id, superego, and ego. Skillful questioning can bring these thoughts to the surface, but poor choices can leave valuable insights buried in the unconscious.

These therapy sessions were unique and engaging, and I wish they constituted a larger portion of the gameplay in Freud’s Bones. More patients, more sessions with each patient, and longer sessions would all have been welcome additions. These analytic sessions eventually culminate in an opportunity to offer a diagnosis, and the player’s accuracy in treatment can result in divergent outcomes for each patient. The game is not lengthy, as it can be played in its entirety in roughly 5-6 hours. Selecting different options for Freud’s personal life and the analysis sessions provides some replay value for subsequent playthroughs.

Overall, Freud’s Bones is a worthy effort for being uniquely designed as interactive entertainment simulating psychoanalysis. It provides an experience of interest to psychiatrists but is also accessible to the general public. While the game has flaws in that it can be overly text-heavy and goals are not always clear, it shines in the moments where it allows the player to participate directly in the process of psychoanalysis. Freud’s Bones is available for purchase on Steam (currently priced at $13.99) and can be played on Windows PCs.

Dr. Weber is a psychiatrist at Intermountain Logan Regional Hospital in Logan, Utah. He disclosed no relevant financial relationships.

References

1. See, for example, Gabbard GO, Gabbard K. Psychiatry and the Cinema, 2nd ed. American Psychiatric Press, Inc.; 1999.

While psychiatry has been the subject of many films, video games are not a medium commonly known for examining mental illness.¹ There have been PC games over the years with psychiatric themes, such as Sanitarium (1998), Depression Quest (2013), Fran Bow (2015), and Night in the Woods (2017). Now for perhaps the first time a game has been developed with the practice of psychiatry as its primary focus.

Freud’s Bones is a 2022 game developed by independent Italian game studio Fortuna Imperatore. The result of a successful Kickstarter crowdfunding campaign, Freud’s Bones is advertised as “the first point & click narrative-drive game to pay homage to the birth of psychoanalysis and its founder, addressing the themes of sexuality and neuroses filled with existential doubts.”

In Freud’s Bones, you take control of Sigmund Freud and guide him through his daily tasks. Gameplay is of the simple point-and-click variety, modeled after classic LucasArts-style adventure games of the 1990s such as The Secret of Monkey Island or Day of the Tentacle. Prior to seeing your first patient, the game provides several documents the player can peruse to become familiar with basic concepts of psychoanalysis. Although the game was originally written in Italian (and translation gaffes occasionally arise), generally the English wording is easy to read. However, some players may feel intimidated or bored by the sheer quantity of text the game provides. All in-game text, including books and spoken words, are written and there is no recorded voice acting. Audio consists largely of unintrusive background music and occasional sound effects. The graphical style is simple and cartoonish but pleasant.

Freud’s personal life is a major focus of the game. His real life dog Jofi is a constant presence in Freud’s office. At various times the player will witness Freud’s dreams, act as a voice inside his head, and attempt to interpret mystical Egyptian messages he receives. Players are also tasked with managing Freud’s reputation in the scientific community. This is apparently intended as a reflection of in-game clinical acumen, but it was sometimes difficult to tell what direct influence my actions had on Freud’s reputation.

Freud’s energy may flag at various points during the game, and the player may choose to give him a cigar or a dose of cocaine to stimulate him. These options sound interesting on the surface, but I found the effect of these substances on the game’s actual outcome to be minimal. Some tasks are presented in a less than user-friendly manner. For example, on my initial playthrough I could not figure out how to complete several optional errands such as shopping for more tobacco or selecting a cover for Freud’s books. The player is also given the opportunity to make choices that affect Freud’s personal life, such as whether to pursue an extramarital affair. The game does have a few narrative surprises, including appearances from some of Freud’s well-known contemporaries. One particularly vivid sequence late in the game involves navigating Freud through a hallucination with some bizarre, but very Freudian, imagery.

By far the most interesting and enjoyable part of the game is the psychoanalysis sessions. The player guides Freud through multiple sessions with four different patients. Each of them has a unique story and associated symptoms, and the player can choose a variety of responses. For example, will you take a comforting, paternalistic approach to the patient uncomfortable with her first appointment? Or will you take the more stoic, quiet approach of the analyst and allow the patient to speak without prompting? Part of the player’s quest in guiding Freud through these sessions is to help patients bring their unconscious thoughts to conscious awareness. This is depicted graphically as the thought moves vertically through images representing the id, superego, and ego. Skillful questioning can bring these thoughts to the surface, but poor choices can leave valuable insights buried in the unconscious.

These therapy sessions were unique and engaging, and I wish they constituted a larger portion of the gameplay in Freud’s Bones. More patients, more sessions with each patient, and longer sessions would all have been welcome additions. These analytic sessions eventually culminate in an opportunity to offer a diagnosis, and the player’s accuracy in treatment can result in divergent outcomes for each patient. The game is not lengthy, as it can be played in its entirety in roughly 5-6 hours. Selecting different options for Freud’s personal life and the analysis sessions provides some replay value for subsequent playthroughs.

Overall, Freud’s Bones is a worthy effort for being uniquely designed as interactive entertainment simulating psychoanalysis. It provides an experience of interest to psychiatrists but is also accessible to the general public. While the game has flaws in that it can be overly text-heavy and goals are not always clear, it shines in the moments where it allows the player to participate directly in the process of psychoanalysis. Freud’s Bones is available for purchase on Steam (currently priced at $13.99) and can be played on Windows PCs.

Dr. Weber is a psychiatrist at Intermountain Logan Regional Hospital in Logan, Utah. He disclosed no relevant financial relationships.

References

1. See, for example, Gabbard GO, Gabbard K. Psychiatry and the Cinema, 2nd ed. American Psychiatric Press, Inc.; 1999.

While psychiatry has been the subject of many films, video games are not a medium commonly known for examining mental illness.¹ There have been PC games over the years with psychiatric themes, such as Sanitarium (1998), Depression Quest (2013), Fran Bow (2015), and Night in the Woods (2017). Now for perhaps the first time a game has been developed with the practice of psychiatry as its primary focus.

Freud’s Bones is a 2022 game developed by independent Italian game studio Fortuna Imperatore. The result of a successful Kickstarter crowdfunding campaign, Freud’s Bones is advertised as “the first point & click narrative-drive game to pay homage to the birth of psychoanalysis and its founder, addressing the themes of sexuality and neuroses filled with existential doubts.”

In Freud’s Bones, you take control of Sigmund Freud and guide him through his daily tasks. Gameplay is of the simple point-and-click variety, modeled after classic LucasArts-style adventure games of the 1990s such as The Secret of Monkey Island or Day of the Tentacle. Prior to seeing your first patient, the game provides several documents the player can peruse to become familiar with basic concepts of psychoanalysis. Although the game was originally written in Italian (and translation gaffes occasionally arise), generally the English wording is easy to read. However, some players may feel intimidated or bored by the sheer quantity of text the game provides. All in-game text, including books and spoken words, are written and there is no recorded voice acting. Audio consists largely of unintrusive background music and occasional sound effects. The graphical style is simple and cartoonish but pleasant.

Freud’s personal life is a major focus of the game. His real life dog Jofi is a constant presence in Freud’s office. At various times the player will witness Freud’s dreams, act as a voice inside his head, and attempt to interpret mystical Egyptian messages he receives. Players are also tasked with managing Freud’s reputation in the scientific community. This is apparently intended as a reflection of in-game clinical acumen, but it was sometimes difficult to tell what direct influence my actions had on Freud’s reputation.

Freud’s energy may flag at various points during the game, and the player may choose to give him a cigar or a dose of cocaine to stimulate him. These options sound interesting on the surface, but I found the effect of these substances on the game’s actual outcome to be minimal. Some tasks are presented in a less than user-friendly manner. For example, on my initial playthrough I could not figure out how to complete several optional errands such as shopping for more tobacco or selecting a cover for Freud’s books. The player is also given the opportunity to make choices that affect Freud’s personal life, such as whether to pursue an extramarital affair. The game does have a few narrative surprises, including appearances from some of Freud’s well-known contemporaries. One particularly vivid sequence late in the game involves navigating Freud through a hallucination with some bizarre, but very Freudian, imagery.

By far the most interesting and enjoyable part of the game is the psychoanalysis sessions. The player guides Freud through multiple sessions with four different patients. Each of them has a unique story and associated symptoms, and the player can choose a variety of responses. For example, will you take a comforting, paternalistic approach to the patient uncomfortable with her first appointment? Or will you take the more stoic, quiet approach of the analyst and allow the patient to speak without prompting? Part of the player’s quest in guiding Freud through these sessions is to help patients bring their unconscious thoughts to conscious awareness. This is depicted graphically as the thought moves vertically through images representing the id, superego, and ego. Skillful questioning can bring these thoughts to the surface, but poor choices can leave valuable insights buried in the unconscious.

These therapy sessions were unique and engaging, and I wish they constituted a larger portion of the gameplay in Freud’s Bones. More patients, more sessions with each patient, and longer sessions would all have been welcome additions. These analytic sessions eventually culminate in an opportunity to offer a diagnosis, and the player’s accuracy in treatment can result in divergent outcomes for each patient. The game is not lengthy, as it can be played in its entirety in roughly 5-6 hours. Selecting different options for Freud’s personal life and the analysis sessions provides some replay value for subsequent playthroughs.

Overall, Freud’s Bones is a worthy effort for being uniquely designed as interactive entertainment simulating psychoanalysis. It provides an experience of interest to psychiatrists but is also accessible to the general public. While the game has flaws in that it can be overly text-heavy and goals are not always clear, it shines in the moments where it allows the player to participate directly in the process of psychoanalysis. Freud’s Bones is available for purchase on Steam (currently priced at $13.99) and can be played on Windows PCs.

Dr. Weber is a psychiatrist at Intermountain Logan Regional Hospital in Logan, Utah. He disclosed no relevant financial relationships.

References

1. See, for example, Gabbard GO, Gabbard K. Psychiatry and the Cinema, 2nd ed. American Psychiatric Press, Inc.; 1999.

Patients with borderline personality disorder and major depressive episodes had a longer time to depression remission than patients with major depressive disorder or bipolar disorder who had major depressive episodes, based on data from 95 individuals.

Major depressive episodes (MDEs) occur in major depressive disorder (MDD) and bipolar disorder (BD), John J. Söderholm, MD, of the University of Helsinki and colleagues wrote. Borderline personality disorder (BPD) includes an increased risk for depression, but data on the relationship between BPD symptoms and depressive illness are limited. In particular, they noted “a lack of studies prospectively comparing the presence of (hypo)manic symptoms over time during the recovery process from MDE between MDD, MDE/BD, and MDE/BPD patients.”

John J. Söderholm

In a cohort study published in the Journal of Affective Disorders, the researchers collected data from 39 adult MDE patients with MDD, 33 with BD, and 23 with BPD. The patients were diagnosed with MDE using the SCID-I/P and SCID-II interviews, mixed symptoms were identified using the Mix-MDE scale, and borderline symptoms were identified using the Borderline Personality Disorder Severity Index.

Over a 6-month follow-up period, the participants completed biweekly online assessments. The primary outcomes were time to first full remission of symptoms and duration and nature of mood episodes.

Overall, the mean number of distinct mood states was 5.75, and the median duration was 60.9 days. When identified by subcohorts, the median number of mood state periods for MDD, BD, and BPD was 4.49, 8.05, and 4.67, respectively. The median durations were 69.2 days, 40.30 days, and 75.6 days, respectively.

The rates of remission for depressive symptoms were similar for MDD, MDE/BD, and MDE/BPD patients. However, MDE/BD patients had a significantly shorter time to first remission (hazard ratio, 2.44). Patients in the BPD group had a significantly longer time to first remission (HR, 0.95).

“When the cohort was divided into quintiles according to BPD feature severity, there was an approximately 1-month difference in time to first period of remission between the first and third and between the third and fifth quintiles, with longer times seen in patients with more severe BPD symptoms,” the researchers wrote.

The study findings were limited by several factors including the small sample size and short follow-up period that prevented investigation of depressive recurrence, the researchers noted. Other limitations included the lack of diagnostic blinding and variation in patients’ treatment schedules.

However, the results were strengthened by the representative samples of subjects with various disorders, the prospective and multimodal assessment of affective states, and the comparison of three patient groups in a single study.

As BPD was associated with a longer time to remission from depressive symptoms, the results suggest that BPD severity may be an indicator of more severe disease in patients with MDD in the context of depression, the researchers concluded.

The study was supported by the Finska Lakaresallskapet, the City of Helsinki, the Hospital District of Helsinki and Uusimaa, and the Finnish Psychiatric Association. The researchers had no financial conflicts to disclose.

Patients with borderline personality disorder and major depressive episodes had a longer time to depression remission than patients with major depressive disorder or bipolar disorder who had major depressive episodes, based on data from 95 individuals.

Major depressive episodes (MDEs) occur in major depressive disorder (MDD) and bipolar disorder (BD), John J. Söderholm, MD, of the University of Helsinki and colleagues wrote. Borderline personality disorder (BPD) includes an increased risk for depression, but data on the relationship between BPD symptoms and depressive illness are limited. In particular, they noted “a lack of studies prospectively comparing the presence of (hypo)manic symptoms over time during the recovery process from MDE between MDD, MDE/BD, and MDE/BPD patients.”

John J. Söderholm

In a cohort study published in the Journal of Affective Disorders, the researchers collected data from 39 adult MDE patients with MDD, 33 with BD, and 23 with BPD. The patients were diagnosed with MDE using the SCID-I/P and SCID-II interviews, mixed symptoms were identified using the Mix-MDE scale, and borderline symptoms were identified using the Borderline Personality Disorder Severity Index.

Over a 6-month follow-up period, the participants completed biweekly online assessments. The primary outcomes were time to first full remission of symptoms and duration and nature of mood episodes.

Overall, the mean number of distinct mood states was 5.75, and the median duration was 60.9 days. When identified by subcohorts, the median number of mood state periods for MDD, BD, and BPD was 4.49, 8.05, and 4.67, respectively. The median durations were 69.2 days, 40.30 days, and 75.6 days, respectively.

The rates of remission for depressive symptoms were similar for MDD, MDE/BD, and MDE/BPD patients. However, MDE/BD patients had a significantly shorter time to first remission (hazard ratio, 2.44). Patients in the BPD group had a significantly longer time to first remission (HR, 0.95).

“When the cohort was divided into quintiles according to BPD feature severity, there was an approximately 1-month difference in time to first period of remission between the first and third and between the third and fifth quintiles, with longer times seen in patients with more severe BPD symptoms,” the researchers wrote.

The study findings were limited by several factors including the small sample size and short follow-up period that prevented investigation of depressive recurrence, the researchers noted. Other limitations included the lack of diagnostic blinding and variation in patients’ treatment schedules.

However, the results were strengthened by the representative samples of subjects with various disorders, the prospective and multimodal assessment of affective states, and the comparison of three patient groups in a single study.

As BPD was associated with a longer time to remission from depressive symptoms, the results suggest that BPD severity may be an indicator of more severe disease in patients with MDD in the context of depression, the researchers concluded.

The study was supported by the Finska Lakaresallskapet, the City of Helsinki, the Hospital District of Helsinki and Uusimaa, and the Finnish Psychiatric Association. The researchers had no financial conflicts to disclose.

Patients with borderline personality disorder and major depressive episodes had a longer time to depression remission than patients with major depressive disorder or bipolar disorder who had major depressive episodes, based on data from 95 individuals.

Major depressive episodes (MDEs) occur in major depressive disorder (MDD) and bipolar disorder (BD), John J. Söderholm, MD, of the University of Helsinki and colleagues wrote. Borderline personality disorder (BPD) includes an increased risk for depression, but data on the relationship between BPD symptoms and depressive illness are limited. In particular, they noted “a lack of studies prospectively comparing the presence of (hypo)manic symptoms over time during the recovery process from MDE between MDD, MDE/BD, and MDE/BPD patients.”

John J. Söderholm

In a cohort study published in the Journal of Affective Disorders, the researchers collected data from 39 adult MDE patients with MDD, 33 with BD, and 23 with BPD. The patients were diagnosed with MDE using the SCID-I/P and SCID-II interviews, mixed symptoms were identified using the Mix-MDE scale, and borderline symptoms were identified using the Borderline Personality Disorder Severity Index.

Over a 6-month follow-up period, the participants completed biweekly online assessments. The primary outcomes were time to first full remission of symptoms and duration and nature of mood episodes.

Overall, the mean number of distinct mood states was 5.75, and the median duration was 60.9 days. When identified by subcohorts, the median number of mood state periods for MDD, BD, and BPD was 4.49, 8.05, and 4.67, respectively. The median durations were 69.2 days, 40.30 days, and 75.6 days, respectively.

The rates of remission for depressive symptoms were similar for MDD, MDE/BD, and MDE/BPD patients. However, MDE/BD patients had a significantly shorter time to first remission (hazard ratio, 2.44). Patients in the BPD group had a significantly longer time to first remission (HR, 0.95).

“When the cohort was divided into quintiles according to BPD feature severity, there was an approximately 1-month difference in time to first period of remission between the first and third and between the third and fifth quintiles, with longer times seen in patients with more severe BPD symptoms,” the researchers wrote.

The study findings were limited by several factors including the small sample size and short follow-up period that prevented investigation of depressive recurrence, the researchers noted. Other limitations included the lack of diagnostic blinding and variation in patients’ treatment schedules.

However, the results were strengthened by the representative samples of subjects with various disorders, the prospective and multimodal assessment of affective states, and the comparison of three patient groups in a single study.

As BPD was associated with a longer time to remission from depressive symptoms, the results suggest that BPD severity may be an indicator of more severe disease in patients with MDD in the context of depression, the researchers concluded.

The study was supported by the Finska Lakaresallskapet, the City of Helsinki, the Hospital District of Helsinki and Uusimaa, and the Finnish Psychiatric Association. The researchers had no financial conflicts to disclose.

The largest combined analysis of birth outcome data for women with systemic lupus erythematosus (SLE) who took belimumab (Benlysta) during pregnancy appears to indicate that the biologic is “unlikely to cause very frequent birth defects,” but the full extent of possible risk remains unknown. The drug’s effect on B cells, immune function, and infections in exposed offspring were not captured in the data, but a separate case report published after the belimumab pregnancy data report indicates that the drug does cross the placenta and builds up in the blood of the newborn, reducing B cells at birth.

Children of women with SLE have increased birth defect risks, and standard SLE therapeutic agents (for example, cyclophosphamide, methotrexate, mycophenolate mofetil) have been implicated in birth defects and pregnancy loss, but birth defect data for biologic drugs such as belimumab are limited. While belimumab animal data revealed no evidence of fetal harm or pregnancy loss rates, there was evidence of immature and mature B-cell count reductions.

Belimumab is approved by the Food and Drug Administration for use in patients aged 5 years and older with active, autoantibody-positive SLE who are taking standard therapy, and also for those with lupus nephritis.

Michelle Petri, MD, of Johns Hopkins University, Baltimore, and coauthors reported in Annals of the Rheumatic Diseases on data they compiled through March 8, 2020, from belimumab clinical trials, the Belimumab Pregnancy Registry (BPR), and postmarketing/spontaneous reports that encompassed 319 pregnancies with known outcomes.

Across 18 clinical trials with 223 live births, birth defects occurred in 4 of 72 (5.6%) belimumab-exposed pregnancies and in 0 of 9 in placebo-exposed pregnancies. Pregnancy loss (excluding elective terminations) occurred in 31.8% (35 of 110) of belimumab-exposed women and 43.8% (7 of 16) of placebo-exposed women in clinical trials. In the BPR retrospective cohort, 4.2% had pregnancy loss. Postmarketing and spontaneous reports had a pregnancy loss rate of 31.4% (43 of 137). Concomitant medications, confounding factors, and/or missing data were noted in all belimumab-exposed women in clinical trials and the BPR cohort. Dr. Petri and colleagues reported no consistent pattern of birth defects across datasets but stated: “Low numbers of exposed pregnancies, presence of confounding factors/other biases, and incomplete information preclude informed recommendations regarding risk of birth defects and pregnancy loss with belimumab use.”

In an interview, coauthor Megan E. B. Clowse, MD, MPH, associate professor of medicine and director of the division of rheumatology and immunology at Duke University, Durham, N.C., said that “the Annals of the Rheumatic Diseases article provides some reassurance that belimumab is unlikely to cause very frequent birth defects. It is clearly not in the risk-range for thalidomide or mycophenolate. However, due to the complexity of collecting these data, this manuscript can’t explore the full extent of possible risks. It also did not provide information about B cells, immune function, or infection risks in exposed offspring.”

A separate case report by Helle Bitter of the department of rheumatology at Sorlandet Hospital Kristiansand (Norway) in Annals of the Rheumatic Diseases is the first to show transplacental passage of belimumab in humans. Other prior reports have shown such transplacental passage for monoclonal IgG antibodies (tumor necrosis factor inhibitors and rituximab). Even though the last infusion was given late in the second trimester, belimumab was present in cord serum at birth, suggesting much higher concentrations before treatment was stopped. While B-cell numbers were reduced at birth, they returned to normal ranges by 4 months post partum when they were undetectable. In the mother, B-cell numbers remained low throughout the study period extending to 7 months after delivery. The authors stated that the child had a normal vaccination response, and except for the reduced B-cell levels at birth, had no adverse effects of prenatal exposure to maternal medication through age 6 years.

“The belimumab transfer in the case report is the level that we would anticipate based on similar studies in infant/mother pairs on other IgG1 antibody biologics like adalimumab – about 60% higher than the maternal level at birth,” Dr. Clowse said. “That the baby has very low B cells at birth is worrisome to me, demonstrating the lasting effect of maternal belimumab on the infant’s immune system, even when the drug was stopped 14 weeks prior to delivery. While this single infant did not have problems with infections, with more widespread use it seems possible that infants would be found to have higher rates of infections after in utero belimumab exposure.”

The field of lupus research greatly needs controlled studies of newer biologics in pregnancy, Dr. Clowse said. “Women with active lupus in pregnancy – particularly with active lupus nephritis – continue to suffer tragic outcomes at an alarming rate. Newer treatments for lupus nephritis provide some hope that we might be able to control lupus nephritis in pregnancy more effectively. The available data suggests the risks of these medications are not so large as to make studies unreasonable. Our current data doesn’t allow us to sufficiently balance the potential risks and benefits in a way that provides clinically useful guidance. Trials of these medications, however, would enable us to identify improved treatment strategies that could result in healthier women, pregnancies, and babies.”

GlaxoSmithKline funded the study. Dr. Clowse reported receiving consulting fees and grants from UCB and GlaxoSmithKline that relate to pregnancy in women with lupus.

The largest combined analysis of birth outcome data for women with systemic lupus erythematosus (SLE) who took belimumab (Benlysta) during pregnancy appears to indicate that the biologic is “unlikely to cause very frequent birth defects,” but the full extent of possible risk remains unknown. The drug’s effect on B cells, immune function, and infections in exposed offspring were not captured in the data, but a separate case report published after the belimumab pregnancy data report indicates that the drug does cross the placenta and builds up in the blood of the newborn, reducing B cells at birth.

Children of women with SLE have increased birth defect risks, and standard SLE therapeutic agents (for example, cyclophosphamide, methotrexate, mycophenolate mofetil) have been implicated in birth defects and pregnancy loss, but birth defect data for biologic drugs such as belimumab are limited. While belimumab animal data revealed no evidence of fetal harm or pregnancy loss rates, there was evidence of immature and mature B-cell count reductions.

Belimumab is approved by the Food and Drug Administration for use in patients aged 5 years and older with active, autoantibody-positive SLE who are taking standard therapy, and also for those with lupus nephritis.

Michelle Petri, MD, of Johns Hopkins University, Baltimore, and coauthors reported in Annals of the Rheumatic Diseases on data they compiled through March 8, 2020, from belimumab clinical trials, the Belimumab Pregnancy Registry (BPR), and postmarketing/spontaneous reports that encompassed 319 pregnancies with known outcomes.

Across 18 clinical trials with 223 live births, birth defects occurred in 4 of 72 (5.6%) belimumab-exposed pregnancies and in 0 of 9 in placebo-exposed pregnancies. Pregnancy loss (excluding elective terminations) occurred in 31.8% (35 of 110) of belimumab-exposed women and 43.8% (7 of 16) of placebo-exposed women in clinical trials. In the BPR retrospective cohort, 4.2% had pregnancy loss. Postmarketing and spontaneous reports had a pregnancy loss rate of 31.4% (43 of 137). Concomitant medications, confounding factors, and/or missing data were noted in all belimumab-exposed women in clinical trials and the BPR cohort. Dr. Petri and colleagues reported no consistent pattern of birth defects across datasets but stated: “Low numbers of exposed pregnancies, presence of confounding factors/other biases, and incomplete information preclude informed recommendations regarding risk of birth defects and pregnancy loss with belimumab use.”

In an interview, coauthor Megan E. B. Clowse, MD, MPH, associate professor of medicine and director of the division of rheumatology and immunology at Duke University, Durham, N.C., said that “the Annals of the Rheumatic Diseases article provides some reassurance that belimumab is unlikely to cause very frequent birth defects. It is clearly not in the risk-range for thalidomide or mycophenolate. However, due to the complexity of collecting these data, this manuscript can’t explore the full extent of possible risks. It also did not provide information about B cells, immune function, or infection risks in exposed offspring.”

A separate case report by Helle Bitter of the department of rheumatology at Sorlandet Hospital Kristiansand (Norway) in Annals of the Rheumatic Diseases is the first to show transplacental passage of belimumab in humans. Other prior reports have shown such transplacental passage for monoclonal IgG antibodies (tumor necrosis factor inhibitors and rituximab). Even though the last infusion was given late in the second trimester, belimumab was present in cord serum at birth, suggesting much higher concentrations before treatment was stopped. While B-cell numbers were reduced at birth, they returned to normal ranges by 4 months post partum when they were undetectable. In the mother, B-cell numbers remained low throughout the study period extending to 7 months after delivery. The authors stated that the child had a normal vaccination response, and except for the reduced B-cell levels at birth, had no adverse effects of prenatal exposure to maternal medication through age 6 years.

“The belimumab transfer in the case report is the level that we would anticipate based on similar studies in infant/mother pairs on other IgG1 antibody biologics like adalimumab – about 60% higher than the maternal level at birth,” Dr. Clowse said. “That the baby has very low B cells at birth is worrisome to me, demonstrating the lasting effect of maternal belimumab on the infant’s immune system, even when the drug was stopped 14 weeks prior to delivery. While this single infant did not have problems with infections, with more widespread use it seems possible that infants would be found to have higher rates of infections after in utero belimumab exposure.”

The field of lupus research greatly needs controlled studies of newer biologics in pregnancy, Dr. Clowse said. “Women with active lupus in pregnancy – particularly with active lupus nephritis – continue to suffer tragic outcomes at an alarming rate. Newer treatments for lupus nephritis provide some hope that we might be able to control lupus nephritis in pregnancy more effectively. The available data suggests the risks of these medications are not so large as to make studies unreasonable. Our current data doesn’t allow us to sufficiently balance the potential risks and benefits in a way that provides clinically useful guidance. Trials of these medications, however, would enable us to identify improved treatment strategies that could result in healthier women, pregnancies, and babies.”

GlaxoSmithKline funded the study. Dr. Clowse reported receiving consulting fees and grants from UCB and GlaxoSmithKline that relate to pregnancy in women with lupus.

The largest combined analysis of birth outcome data for women with systemic lupus erythematosus (SLE) who took belimumab (Benlysta) during pregnancy appears to indicate that the biologic is “unlikely to cause very frequent birth defects,” but the full extent of possible risk remains unknown. The drug’s effect on B cells, immune function, and infections in exposed offspring were not captured in the data, but a separate case report published after the belimumab pregnancy data report indicates that the drug does cross the placenta and builds up in the blood of the newborn, reducing B cells at birth.

Children of women with SLE have increased birth defect risks, and standard SLE therapeutic agents (for example, cyclophosphamide, methotrexate, mycophenolate mofetil) have been implicated in birth defects and pregnancy loss, but birth defect data for biologic drugs such as belimumab are limited. While belimumab animal data revealed no evidence of fetal harm or pregnancy loss rates, there was evidence of immature and mature B-cell count reductions.

Belimumab is approved by the Food and Drug Administration for use in patients aged 5 years and older with active, autoantibody-positive SLE who are taking standard therapy, and also for those with lupus nephritis.

Michelle Petri, MD, of Johns Hopkins University, Baltimore, and coauthors reported in Annals of the Rheumatic Diseases on data they compiled through March 8, 2020, from belimumab clinical trials, the Belimumab Pregnancy Registry (BPR), and postmarketing/spontaneous reports that encompassed 319 pregnancies with known outcomes.

Across 18 clinical trials with 223 live births, birth defects occurred in 4 of 72 (5.6%) belimumab-exposed pregnancies and in 0 of 9 in placebo-exposed pregnancies. Pregnancy loss (excluding elective terminations) occurred in 31.8% (35 of 110) of belimumab-exposed women and 43.8% (7 of 16) of placebo-exposed women in clinical trials. In the BPR retrospective cohort, 4.2% had pregnancy loss. Postmarketing and spontaneous reports had a pregnancy loss rate of 31.4% (43 of 137). Concomitant medications, confounding factors, and/or missing data were noted in all belimumab-exposed women in clinical trials and the BPR cohort. Dr. Petri and colleagues reported no consistent pattern of birth defects across datasets but stated: “Low numbers of exposed pregnancies, presence of confounding factors/other biases, and incomplete information preclude informed recommendations regarding risk of birth defects and pregnancy loss with belimumab use.”

In an interview, coauthor Megan E. B. Clowse, MD, MPH, associate professor of medicine and director of the division of rheumatology and immunology at Duke University, Durham, N.C., said that “the Annals of the Rheumatic Diseases article provides some reassurance that belimumab is unlikely to cause very frequent birth defects. It is clearly not in the risk-range for thalidomide or mycophenolate. However, due to the complexity of collecting these data, this manuscript can’t explore the full extent of possible risks. It also did not provide information about B cells, immune function, or infection risks in exposed offspring.”

A separate case report by Helle Bitter of the department of rheumatology at Sorlandet Hospital Kristiansand (Norway) in Annals of the Rheumatic Diseases is the first to show transplacental passage of belimumab in humans. Other prior reports have shown such transplacental passage for monoclonal IgG antibodies (tumor necrosis factor inhibitors and rituximab). Even though the last infusion was given late in the second trimester, belimumab was present in cord serum at birth, suggesting much higher concentrations before treatment was stopped. While B-cell numbers were reduced at birth, they returned to normal ranges by 4 months post partum when they were undetectable. In the mother, B-cell numbers remained low throughout the study period extending to 7 months after delivery. The authors stated that the child had a normal vaccination response, and except for the reduced B-cell levels at birth, had no adverse effects of prenatal exposure to maternal medication through age 6 years.

“The belimumab transfer in the case report is the level that we would anticipate based on similar studies in infant/mother pairs on other IgG1 antibody biologics like adalimumab – about 60% higher than the maternal level at birth,” Dr. Clowse said. “That the baby has very low B cells at birth is worrisome to me, demonstrating the lasting effect of maternal belimumab on the infant’s immune system, even when the drug was stopped 14 weeks prior to delivery. While this single infant did not have problems with infections, with more widespread use it seems possible that infants would be found to have higher rates of infections after in utero belimumab exposure.”

The field of lupus research greatly needs controlled studies of newer biologics in pregnancy, Dr. Clowse said. “Women with active lupus in pregnancy – particularly with active lupus nephritis – continue to suffer tragic outcomes at an alarming rate. Newer treatments for lupus nephritis provide some hope that we might be able to control lupus nephritis in pregnancy more effectively. The available data suggests the risks of these medications are not so large as to make studies unreasonable. Our current data doesn’t allow us to sufficiently balance the potential risks and benefits in a way that provides clinically useful guidance. Trials of these medications, however, would enable us to identify improved treatment strategies that could result in healthier women, pregnancies, and babies.”

GlaxoSmithKline funded the study. Dr. Clowse reported receiving consulting fees and grants from UCB and GlaxoSmithKline that relate to pregnancy in women with lupus.

Despite Mark Twain’s assertion that “there are three kinds of lies: lies, damned lies, and statistics,” we’re going to dive into 20 years’ worth of data and, hopefully, come up with a few statistics that shed some light on the specialty’s workforce since Cardiology News published its first issue in February 2003.

We start with a major issue over these last 20 years: The participation of women in the specialty.

Back in July of 2002, just a few months before the first issue of Cardiology News was published, W. Bruce Fye, MD, then-president of the American College of Cardiology, wrote, “We need to do more to attract female medical graduates to our specialty because they represent almost one-half of the new doctors trained in this country. Cardiology needs to take full advantage of this large talent pool”

Data from the American Medical Association confirm that assertion: Of the nearly 20,000 postgraduate cardiologists in practice that year, only 7.8% were women. And that was at a time when more than 42% of medical school graduates were women, Dr. Fye noted, while also pointing out that “only 10% of cardiology trainees are female, and just 6% of ACC fellows are women.”

The gap between men and women has closed somewhat in the last 20 years, but the specialty continues to lag behind the profession as a whole. Women represented 16.7% of cardiologists in 2022, versus 37% of physicians overall, AMA data show. In 2019, for the first time, the majority of U.S. medical school students (50.5%) were women, according to the Association of American Medical Colleges.

A look at residency numbers from the Accreditation Council for Graduate Medical Education shows that continued slow improvement in the number of women can be expected, as 25.5% of cardiovascular disease residents were women during the 2021-2022 academic year. Only 2 of the 19 other internal medicine subspecialties were lower, and they happened to be interventional cardiology (20.1%) and clinical cardiac electrophysiology (14.5%).

When men are added to the mix, cardiovascular disease had a total of 3,320 active residents training in 268 programs in 2021-2022, making it the largest of the IM subspecialties in both respects. The resident total is up 57% since 2003, when it came in at 2,117, while programs have increased 55% from the 173 that were operating 2 decades ago. During the year in the middle (2011-2012), there were 2,521 residents in 187 programs, so a larger share of the growth has occurred in the last 10 years, the ACGME data indicate.

Despite Mark Twain’s assertion that “there are three kinds of lies: lies, damned lies, and statistics,” we’re going to dive into 20 years’ worth of data and, hopefully, come up with a few statistics that shed some light on the specialty’s workforce since Cardiology News published its first issue in February 2003.

We start with a major issue over these last 20 years: The participation of women in the specialty.

Back in July of 2002, just a few months before the first issue of Cardiology News was published, W. Bruce Fye, MD, then-president of the American College of Cardiology, wrote, “We need to do more to attract female medical graduates to our specialty because they represent almost one-half of the new doctors trained in this country. Cardiology needs to take full advantage of this large talent pool”

Data from the American Medical Association confirm that assertion: Of the nearly 20,000 postgraduate cardiologists in practice that year, only 7.8% were women. And that was at a time when more than 42% of medical school graduates were women, Dr. Fye noted, while also pointing out that “only 10% of cardiology trainees are female, and just 6% of ACC fellows are women.”

The gap between men and women has closed somewhat in the last 20 years, but the specialty continues to lag behind the profession as a whole. Women represented 16.7% of cardiologists in 2022, versus 37% of physicians overall, AMA data show. In 2019, for the first time, the majority of U.S. medical school students (50.5%) were women, according to the Association of American Medical Colleges.

A look at residency numbers from the Accreditation Council for Graduate Medical Education shows that continued slow improvement in the number of women can be expected, as 25.5% of cardiovascular disease residents were women during the 2021-2022 academic year. Only 2 of the 19 other internal medicine subspecialties were lower, and they happened to be interventional cardiology (20.1%) and clinical cardiac electrophysiology (14.5%).

When men are added to the mix, cardiovascular disease had a total of 3,320 active residents training in 268 programs in 2021-2022, making it the largest of the IM subspecialties in both respects. The resident total is up 57% since 2003, when it came in at 2,117, while programs have increased 55% from the 173 that were operating 2 decades ago. During the year in the middle (2011-2012), there were 2,521 residents in 187 programs, so a larger share of the growth has occurred in the last 10 years, the ACGME data indicate.

Despite Mark Twain’s assertion that “there are three kinds of lies: lies, damned lies, and statistics,” we’re going to dive into 20 years’ worth of data and, hopefully, come up with a few statistics that shed some light on the specialty’s workforce since Cardiology News published its first issue in February 2003.

We start with a major issue over these last 20 years: The participation of women in the specialty.

Back in July of 2002, just a few months before the first issue of Cardiology News was published, W. Bruce Fye, MD, then-president of the American College of Cardiology, wrote, “We need to do more to attract female medical graduates to our specialty because they represent almost one-half of the new doctors trained in this country. Cardiology needs to take full advantage of this large talent pool”

Data from the American Medical Association confirm that assertion: Of the nearly 20,000 postgraduate cardiologists in practice that year, only 7.8% were women. And that was at a time when more than 42% of medical school graduates were women, Dr. Fye noted, while also pointing out that “only 10% of cardiology trainees are female, and just 6% of ACC fellows are women.”

The gap between men and women has closed somewhat in the last 20 years, but the specialty continues to lag behind the profession as a whole. Women represented 16.7% of cardiologists in 2022, versus 37% of physicians overall, AMA data show. In 2019, for the first time, the majority of U.S. medical school students (50.5%) were women, according to the Association of American Medical Colleges.

A look at residency numbers from the Accreditation Council for Graduate Medical Education shows that continued slow improvement in the number of women can be expected, as 25.5% of cardiovascular disease residents were women during the 2021-2022 academic year. Only 2 of the 19 other internal medicine subspecialties were lower, and they happened to be interventional cardiology (20.1%) and clinical cardiac electrophysiology (14.5%).

When men are added to the mix, cardiovascular disease had a total of 3,320 active residents training in 268 programs in 2021-2022, making it the largest of the IM subspecialties in both respects. The resident total is up 57% since 2003, when it came in at 2,117, while programs have increased 55% from the 173 that were operating 2 decades ago. During the year in the middle (2011-2012), there were 2,521 residents in 187 programs, so a larger share of the growth has occurred in the last 10 years, the ACGME data indicate.

What were the most exciting mantle cell lymphoma (MCL) updates from the recent meeting of the American Society of Hematology (ASH)?

Dr. Martin: The 2022 ASH meeting reported mostly about MCL research, which is great for the MCL community, because clearly, there is a lot of room for improvement. One of the big trials presented at a plenary session—one which we have been eager to see the results from, but maybe did not expect to see quite so soon—was the European MCL Network TRIANGLE trial. This is a 3-arm trial in which 870 patients were randomized. They had treatment-naive MCL and were younger than 66 years, so they were eligible for more intensive chemotherapy.

Arm A was the standard-of-care arm, defined by the prior European MCL Network TRIANGLE Trial. This was 6 alternating cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride [doxorubicin hydrochloride], vincristine, and prednisone) and R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) – 3 of each followed by autologous stem cell transplant. Arm B was the same regimen with the addition of the first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib to induction followed by 2 years of ibrutinib maintenance. Arm C was the same induction regimen (6 alternating cycles of R-CHOP and R-DHAP plus ibrutinib during induction and maintenance) with no autologous stem cell transplant. Roughly half the patients in the trial, all equally distributed across all arms, received 3 years of maintenance rituximab.

The primary outcome was failure-free survival (FFS). After only 31 months of median follow-up, the trial reported a significant difference in FFS between patients receiving ibrutinib (Arms B and C) and patients who underwent autologous stem cell transplant and did not receive ibrutinib (Arm A).

This clearly shows that 2 years of ibrutinib maintenance significantly improves FFS. FFS was 88% versus 72% (Arm B vs Arm A) at 3 years with a hazard ratio of 0.5. That is a striking hazard ratio, highly statistically significant. Importantly, patients in Arms B and C fared similarly, suggesting that transplant was unnecessary in patients receiving ibrutinib.

What these findings suggest is that in the patient population treated with intensive induction, we are moving beyond autologous stem cell transplant. These results were similar across all subgroups. In fact, outcomes were most striking for patients with higher risk features like high Ki-67 and overexpression of p53.

The patients who need ibrutinib most were those who were most likely to benefit, and that is really encouraging for all of us. There is a clear trend toward an improvement in overall survival with ibrutinib maintenance and there clearly is less toxicity and less treatment-related mortality from avoiding transplant.

It will be important to see this trial published in a peer-reviewed journal with more granular data. But to me, these trial results are groundbreaking. It is a practice-changing trial for sure.

Is there anything else from an investigational approach on the horizon for MCL?

Dr. Martin: Yes. I would like to highlight 2 trials that stand out to me.

First, my colleague Dr. Ruan from Cornell presented on a phase 2 trial of a triplet of acalabrutinib plus lenalidomide plus rituximab with real-time monitoring of minimal residual disease (MRD) in patients with treatment-naive MCL.

This was a small trial with just 24 patients. It was fairly evenly split between low-, medium-, and high-risk MCL international prognostic index (MIPI) scores. All of these patients received the triplet for 1 year of induction followed by an additional year of maintenance with a slightly lower dose of lenalidomide. At the end of 2 years, patients who were in a durable MRD-negative state could stop the oral therapy and just continue with rituximab maintenance.

In a prior trial published in The New England Journal of Medicine, we showed that the lenalidomide plus rituximab regimen has a complete response rate of about 60%. In this new ongoing trial regimen of acalabrutinib plus lenalidomide plus rituximab, we found that at the end of just 1 year of induction treatment, the complete response rate was 83%. With all of the caveats and comparing across trials, this new regimen was clearly active and potentially more active than the prior regimen. It also appeared to be well tolerated without any real significant issues.

I think what this trial plus the TRIANGLE showed us is that BTK inhibitors belong in the front-line setting. That is what patients want. That is what physicians want.

The other trial that I wanted to highlight is an update of something that we saw last year at ASH, specifically a phase 1/2 trial of glofitamab in people with previously treated MCL. The overall response rate was 83% and the complete response rate was 73%. The complete response rate at the first assessment was already almost 50%. These are among patients who have had prior treatment for MCL, including BTK inhibitors.

We are not accustomed to seeing treatments that are so active in the relapsed/refractory MCL patient population, particularly, if they have had a prior BTK inhibitor. So, these results are exciting and promising.

This compares to the ZUMA-2 trial with CAR T-cells. CAR T-cells are also strikingly active in this patient population, but they do have some drawbacks. They have to be administered in a specialized facility and they are associated with fairly high rates of cytokine release syndrome and neurotoxicity.

The rates of grade 3 to 4 cytokine release syndrome and neurotoxicity with glofitamab were low, but not negligible. All cytokine release syndrome events were manageable, and no patients discontinued treatment because of adverse events. This is, potentially, attractive, because it offers an active therapy to a broader subset of patients with MCL who may not be able to access CAR T-cell therapy as easily. A phase 3 trial is in the planning stages, and it is likely that if that trial has positive results, we will see glofitamab approved in the not-too-distant future for people with MCL, and having more options is always great.

Based on these developments, do you see any shifts in your day-to-day practice in the future?

Dr. Martin: I think what has been interesting to me about MCL over the past decade is this idea that not everybody is the same. That should not come as a surprise statement, but MCL does behave differently in different people.

As a physician who treats a lot of patients with MCL, I have seen all of the different ways in which MCL can behave; combine that with the heterogeneity of humanity as a whole. Having guidelines from the NCCN (National Comprehensive Care Network) are helpful, but those guidelines are broad.

Learning how to take all that heterogeneity and variety into account and match the appropriate treatment to each patient is important. What these front-line trials are telling us is that it is OK to do research that does not involve chemotherapy.

In the past, it might have been considered unethical to give a younger patient a treatment without autologous stem cell transplant. But that is clearly not the case now. I think that in real-life practice in the near future, guidelines may actually start to get a little bit easier to follow as we come up with options that are less intensive.

It may be that patients can access treatments that are a little bit easier, that do not involve a transplant. That would be good for people with MCL from all across the country.

What were the most exciting mantle cell lymphoma (MCL) updates from the recent meeting of the American Society of Hematology (ASH)?

Dr. Martin: The 2022 ASH meeting reported mostly about MCL research, which is great for the MCL community, because clearly, there is a lot of room for improvement. One of the big trials presented at a plenary session—one which we have been eager to see the results from, but maybe did not expect to see quite so soon—was the European MCL Network TRIANGLE trial. This is a 3-arm trial in which 870 patients were randomized. They had treatment-naive MCL and were younger than 66 years, so they were eligible for more intensive chemotherapy.

Arm A was the standard-of-care arm, defined by the prior European MCL Network TRIANGLE Trial. This was 6 alternating cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride [doxorubicin hydrochloride], vincristine, and prednisone) and R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) – 3 of each followed by autologous stem cell transplant. Arm B was the same regimen with the addition of the first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib to induction followed by 2 years of ibrutinib maintenance. Arm C was the same induction regimen (6 alternating cycles of R-CHOP and R-DHAP plus ibrutinib during induction and maintenance) with no autologous stem cell transplant. Roughly half the patients in the trial, all equally distributed across all arms, received 3 years of maintenance rituximab.

The primary outcome was failure-free survival (FFS). After only 31 months of median follow-up, the trial reported a significant difference in FFS between patients receiving ibrutinib (Arms B and C) and patients who underwent autologous stem cell transplant and did not receive ibrutinib (Arm A).

This clearly shows that 2 years of ibrutinib maintenance significantly improves FFS. FFS was 88% versus 72% (Arm B vs Arm A) at 3 years with a hazard ratio of 0.5. That is a striking hazard ratio, highly statistically significant. Importantly, patients in Arms B and C fared similarly, suggesting that transplant was unnecessary in patients receiving ibrutinib.

What these findings suggest is that in the patient population treated with intensive induction, we are moving beyond autologous stem cell transplant. These results were similar across all subgroups. In fact, outcomes were most striking for patients with higher risk features like high Ki-67 and overexpression of p53.

The patients who need ibrutinib most were those who were most likely to benefit, and that is really encouraging for all of us. There is a clear trend toward an improvement in overall survival with ibrutinib maintenance and there clearly is less toxicity and less treatment-related mortality from avoiding transplant.

It will be important to see this trial published in a peer-reviewed journal with more granular data. But to me, these trial results are groundbreaking. It is a practice-changing trial for sure.

Is there anything else from an investigational approach on the horizon for MCL?

Dr. Martin: Yes. I would like to highlight 2 trials that stand out to me.

First, my colleague Dr. Ruan from Cornell presented on a phase 2 trial of a triplet of acalabrutinib plus lenalidomide plus rituximab with real-time monitoring of minimal residual disease (MRD) in patients with treatment-naive MCL.

This was a small trial with just 24 patients. It was fairly evenly split between low-, medium-, and high-risk MCL international prognostic index (MIPI) scores. All of these patients received the triplet for 1 year of induction followed by an additional year of maintenance with a slightly lower dose of lenalidomide. At the end of 2 years, patients who were in a durable MRD-negative state could stop the oral therapy and just continue with rituximab maintenance.

In a prior trial published in The New England Journal of Medicine, we showed that the lenalidomide plus rituximab regimen has a complete response rate of about 60%. In this new ongoing trial regimen of acalabrutinib plus lenalidomide plus rituximab, we found that at the end of just 1 year of induction treatment, the complete response rate was 83%. With all of the caveats and comparing across trials, this new regimen was clearly active and potentially more active than the prior regimen. It also appeared to be well tolerated without any real significant issues.

I think what this trial plus the TRIANGLE showed us is that BTK inhibitors belong in the front-line setting. That is what patients want. That is what physicians want.

The other trial that I wanted to highlight is an update of something that we saw last year at ASH, specifically a phase 1/2 trial of glofitamab in people with previously treated MCL. The overall response rate was 83% and the complete response rate was 73%. The complete response rate at the first assessment was already almost 50%. These are among patients who have had prior treatment for MCL, including BTK inhibitors.

We are not accustomed to seeing treatments that are so active in the relapsed/refractory MCL patient population, particularly, if they have had a prior BTK inhibitor. So, these results are exciting and promising.

This compares to the ZUMA-2 trial with CAR T-cells. CAR T-cells are also strikingly active in this patient population, but they do have some drawbacks. They have to be administered in a specialized facility and they are associated with fairly high rates of cytokine release syndrome and neurotoxicity.

The rates of grade 3 to 4 cytokine release syndrome and neurotoxicity with glofitamab were low, but not negligible. All cytokine release syndrome events were manageable, and no patients discontinued treatment because of adverse events. This is, potentially, attractive, because it offers an active therapy to a broader subset of patients with MCL who may not be able to access CAR T-cell therapy as easily. A phase 3 trial is in the planning stages, and it is likely that if that trial has positive results, we will see glofitamab approved in the not-too-distant future for people with MCL, and having more options is always great.

Based on these developments, do you see any shifts in your day-to-day practice in the future?

Dr. Martin: I think what has been interesting to me about MCL over the past decade is this idea that not everybody is the same. That should not come as a surprise statement, but MCL does behave differently in different people.

As a physician who treats a lot of patients with MCL, I have seen all of the different ways in which MCL can behave; combine that with the heterogeneity of humanity as a whole. Having guidelines from the NCCN (National Comprehensive Care Network) are helpful, but those guidelines are broad.

Learning how to take all that heterogeneity and variety into account and match the appropriate treatment to each patient is important. What these front-line trials are telling us is that it is OK to do research that does not involve chemotherapy.

In the past, it might have been considered unethical to give a younger patient a treatment without autologous stem cell transplant. But that is clearly not the case now. I think that in real-life practice in the near future, guidelines may actually start to get a little bit easier to follow as we come up with options that are less intensive.

It may be that patients can access treatments that are a little bit easier, that do not involve a transplant. That would be good for people with MCL from all across the country.

What were the most exciting mantle cell lymphoma (MCL) updates from the recent meeting of the American Society of Hematology (ASH)?

Dr. Martin: The 2022 ASH meeting reported mostly about MCL research, which is great for the MCL community, because clearly, there is a lot of room for improvement. One of the big trials presented at a plenary session—one which we have been eager to see the results from, but maybe did not expect to see quite so soon—was the European MCL Network TRIANGLE trial. This is a 3-arm trial in which 870 patients were randomized. They had treatment-naive MCL and were younger than 66 years, so they were eligible for more intensive chemotherapy.

Arm A was the standard-of-care arm, defined by the prior European MCL Network TRIANGLE Trial. This was 6 alternating cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride [doxorubicin hydrochloride], vincristine, and prednisone) and R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) – 3 of each followed by autologous stem cell transplant. Arm B was the same regimen with the addition of the first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib to induction followed by 2 years of ibrutinib maintenance. Arm C was the same induction regimen (6 alternating cycles of R-CHOP and R-DHAP plus ibrutinib during induction and maintenance) with no autologous stem cell transplant. Roughly half the patients in the trial, all equally distributed across all arms, received 3 years of maintenance rituximab.

The primary outcome was failure-free survival (FFS). After only 31 months of median follow-up, the trial reported a significant difference in FFS between patients receiving ibrutinib (Arms B and C) and patients who underwent autologous stem cell transplant and did not receive ibrutinib (Arm A).

This clearly shows that 2 years of ibrutinib maintenance significantly improves FFS. FFS was 88% versus 72% (Arm B vs Arm A) at 3 years with a hazard ratio of 0.5. That is a striking hazard ratio, highly statistically significant. Importantly, patients in Arms B and C fared similarly, suggesting that transplant was unnecessary in patients receiving ibrutinib.

What these findings suggest is that in the patient population treated with intensive induction, we are moving beyond autologous stem cell transplant. These results were similar across all subgroups. In fact, outcomes were most striking for patients with higher risk features like high Ki-67 and overexpression of p53.

The patients who need ibrutinib most were those who were most likely to benefit, and that is really encouraging for all of us. There is a clear trend toward an improvement in overall survival with ibrutinib maintenance and there clearly is less toxicity and less treatment-related mortality from avoiding transplant.

It will be important to see this trial published in a peer-reviewed journal with more granular data. But to me, these trial results are groundbreaking. It is a practice-changing trial for sure.

Is there anything else from an investigational approach on the horizon for MCL?

Dr. Martin: Yes. I would like to highlight 2 trials that stand out to me.

First, my colleague Dr. Ruan from Cornell presented on a phase 2 trial of a triplet of acalabrutinib plus lenalidomide plus rituximab with real-time monitoring of minimal residual disease (MRD) in patients with treatment-naive MCL.

This was a small trial with just 24 patients. It was fairly evenly split between low-, medium-, and high-risk MCL international prognostic index (MIPI) scores. All of these patients received the triplet for 1 year of induction followed by an additional year of maintenance with a slightly lower dose of lenalidomide. At the end of 2 years, patients who were in a durable MRD-negative state could stop the oral therapy and just continue with rituximab maintenance.

In a prior trial published in The New England Journal of Medicine, we showed that the lenalidomide plus rituximab regimen has a complete response rate of about 60%. In this new ongoing trial regimen of acalabrutinib plus lenalidomide plus rituximab, we found that at the end of just 1 year of induction treatment, the complete response rate was 83%. With all of the caveats and comparing across trials, this new regimen was clearly active and potentially more active than the prior regimen. It also appeared to be well tolerated without any real significant issues.

I think what this trial plus the TRIANGLE showed us is that BTK inhibitors belong in the front-line setting. That is what patients want. That is what physicians want.

The other trial that I wanted to highlight is an update of something that we saw last year at ASH, specifically a phase 1/2 trial of glofitamab in people with previously treated MCL. The overall response rate was 83% and the complete response rate was 73%. The complete response rate at the first assessment was already almost 50%. These are among patients who have had prior treatment for MCL, including BTK inhibitors.

We are not accustomed to seeing treatments that are so active in the relapsed/refractory MCL patient population, particularly, if they have had a prior BTK inhibitor. So, these results are exciting and promising.

This compares to the ZUMA-2 trial with CAR T-cells. CAR T-cells are also strikingly active in this patient population, but they do have some drawbacks. They have to be administered in a specialized facility and they are associated with fairly high rates of cytokine release syndrome and neurotoxicity.

The rates of grade 3 to 4 cytokine release syndrome and neurotoxicity with glofitamab were low, but not negligible. All cytokine release syndrome events were manageable, and no patients discontinued treatment because of adverse events. This is, potentially, attractive, because it offers an active therapy to a broader subset of patients with MCL who may not be able to access CAR T-cell therapy as easily. A phase 3 trial is in the planning stages, and it is likely that if that trial has positive results, we will see glofitamab approved in the not-too-distant future for people with MCL, and having more options is always great.

Based on these developments, do you see any shifts in your day-to-day practice in the future?

Dr. Martin: I think what has been interesting to me about MCL over the past decade is this idea that not everybody is the same. That should not come as a surprise statement, but MCL does behave differently in different people.

As a physician who treats a lot of patients with MCL, I have seen all of the different ways in which MCL can behave; combine that with the heterogeneity of humanity as a whole. Having guidelines from the NCCN (National Comprehensive Care Network) are helpful, but those guidelines are broad.

Learning how to take all that heterogeneity and variety into account and match the appropriate treatment to each patient is important. What these front-line trials are telling us is that it is OK to do research that does not involve chemotherapy.

In the past, it might have been considered unethical to give a younger patient a treatment without autologous stem cell transplant. But that is clearly not the case now. I think that in real-life practice in the near future, guidelines may actually start to get a little bit easier to follow as we come up with options that are less intensive.

It may be that patients can access treatments that are a little bit easier, that do not involve a transplant. That would be good for people with MCL from all across the country.

CASE Pregnant patient with concerning symptoms of infection

A 28-year-old primigravid woman at 26 weeks’ gestation requests evaluation because of a 3-day history of low-grade fever (38.3 °C), chills, malaise, myalgias, pain in her upper back, nausea, diarrhea, and intermittent uterine contractions. Her symptoms began 2 days after she and her husband dined at a local Mexican restaurant. She specifically recalls eating unpasteurized cheese (queso fresco). Her husband also is experiencing similar symptoms.

• What is the most likely diagnosis?
• What tests should be performed to confirm the diagnosis?
• Does this infection pose a risk to the fetus?
• How should this patient be treated?

Listeriosis, a potentially serious foodborne illness, is an unusual infection in pregnancy. It can cause a number of adverse effects in both the pregnant woman and her fetus, including fetal death in utero. In this article, we review the microbiology and epidemiology of Listeria infection, consider the important steps in diagnosis, and discuss treatment options and prevention measures.

The causative organism in listeriosis

Listeriosis is caused by Listeria monocytogenes, a gram-positive, non–spore-forming bacillus. The organism is catalase positive and oxidase negative, and it exhibits tumbling motility when grown in culture. It can grow at temperatures less than 4 °C, which facilitates foodborne transmission of the bacterium despite adequate refrigeration. Of the 13 serotypes of L monocytogenes, the 1/2a, 1/2b, and 4b are most likely to be associated with human infection. The major virulence factors of L monocytogenes are the internalin surface proteins and the pore-forming listeriolysin O (LLO) cytotoxin. These factors enable the organism to effectively invade host cells.¹

The pathogen uses several mechanisms to evade gastrointestinal defenses prior to entry into the bloodstream. It avoids destruction in the stomach by using proton pump inhibitors to elevate the pH of gastric acid. In the duodenum, it survives the antibacterial properties of bile by secreting bile salt hydrolases, which catabolize bile salts. In addition, the cytotoxin listeriolysin S (LLS) disrupts the protective barrier created by the normal gut flora. Once the organism penetrates the gastrointestinal barriers, it disseminates through the blood and lymphatics and then infects other tissues, such as the brain and placenta.^1,2

Pathogenesis of infection

The primary reservoir of Listeria is soil and decaying vegetable matter. The organism also has been isolated from animal feed, water, sewage, and many animal species. With rare exceptions, most infections in adults result from inadvertent ingestion of the organism in contaminated food. In certain high-risk occupations, such as veterinary medicine, farming, and laboratory work, infection of the skin or eye can result from direct contact with an infected animal.³

Of note, foodborne illness caused by Listeria has the third highest mortality rate of any foodborne infection, 16% compared with 35% for Vibrio vulnificus and 17% for Clostridium botulinum.^2,3 The principal foods that have been linked to listeriosis include:

• soft cheeses, particularly those made from unpasteurized milk
• melon
• hot dogs
• lunch meat, such as bologna
• deli meat, especially chicken
• canned foods, such as smoked seafood, and pâté or meat spreads that are labeled “keep refrigerated”
• unpasteurized milk
• sprouts
• hummus.

In healthy adults, listeriosis is usually a short-lived illness. However, in older adults, immunocompromised patients, and pregnant women, the infection can be devastating. Infection in the pregnant woman also poses major danger to the developing fetus because the organism has a special predilection for placental and fetal tissue.^1,3,4

Immunity to Listeria infection depends primarily on T-cell lymphokine activation of macrophages. These latter cells are responsible for clearing the bacterium from the blood. As noted above, the principal virulence factor of L monocytogenes is listeriolysin O, a cholesterol-dependent cytolysin. This substance induces T-cell receptor unresponsiveness, thus interfering with the host immune response to the invading pathogen.^1,3-5

Continue to: Clinical manifestations of listeriosis...

Listeria infections may present with various manifestations, depending on the degree of exposure and the underlying immunocompetence of the host (FIGURE). In its most common and simplest form, listeriosis presents as a mild to moderate gastroenteritis following exposure to contaminated food. Symptoms typically develop within 24 hours of exposure and include fever, myalgias, abdominal or back pain, nausea, vomiting, and diarrhea.⁵

Conversely, in immunocompromised patients, including pregnant women, listeriosis can present as life-threatening sepsis and/or central nervous system (CNS) infection (invasive infection). In this clinical setting, the mean incubation period is 11 days. The manifestations of CNS infection include meningoencephalitis, cerebritis, rhombencephalitis (infection and inflammation of the brain stem), brain abscess, and spinal cord abscess.⁵

In addition to these 2 clinical presentations, listeriosis can cause unusual focal infections as illustrated in the FIGURE. Some of these infections have unique clinical associations. For example, skin or eye infections may occur as a result of direct inoculation in veterinarians, farmers, and laboratory workers. Listeria peritonitis may occur in patients who are receiving peritoneal dialysis and in those who have cirrhosis. Prosthetic joint and graft infections, of course, may occur in patients who have had invasive procedures for implantation of grafts or prosthetic devices.⁵

Listeriosis is especially dangerous in pregnancy because it not only can cause serious injury to the mother and even death but it also may pose a major risk to fetal well-being. Possible perinatal complications include fetal death; preterm labor and delivery; and neonatal sepsis, meningitis, and death.^5-8

Making the diagnosis

Diagnosis begins with a thorough and focused history to assess for characteristic symptoms and possible Listeria exposure. Exposure should be presumed for patients who report consuming high-risk foods, especially foods recently recalled by the US Food and Drug Administration.

In the asymptomatic pregnant patient, diagnostic testing can be deferred, and the patient should be instructed to return for evaluation if symptoms develop within 2 months of exposure. However, symptomatic, febrile patients require testing. The most valuable testing modality is Gram stain and culture of blood. Gram stain typically will show gram-positive pleomorphic rods with rounded ends. Amniocentesis may be indicated if blood cultures are not definitive. Meconium staining of the amniotic fluid and a positive Gram stain are highly indicative of fetal infection. Cultures of the cerebrospinal fluid are indicated in any individual with focal neurologic findings. Stool cultures are rarely indicated.

When obtaining any of the cultures noted above, the clinician should alert the microbiologist of the concern for listeriosis because L monocytogenes can be confused with common contaminants, such as diphtheroids.^5-9

Treatment and follow-up

The treatment of listeriosis in pregnancy depends on the severity of the infection and the immune status of the mother. The TABLE offers several different clinical scenarios and the appropriate treatment for each. As noted, several scenarios may require cultures of the blood, cerebrospinal fluid, and amniotic fluid.^7,9,10

Following treatment of the mother, serial ultrasound examinations should be performed to monitor fetal growth, CNS anatomy, placental morphology, amniotic fluid volume, and umbilical artery Doppler velocimetry. In the presence of fetal growth restriction, oligohydramnios, or abnormal Doppler velocimetry, biophysical profile testing should be performed. After delivery, the placenta should be examined carefully for histologic evidence of Listeria infection, such as miliary abscesses, and cultured for the bacterium.^7-9

Prevention measures

Conservative measures for prevention of Listeria infection in pregnant women include the following^7,10-12:

• Refrigerate milk and milk products at 40 °F (4.4 °C).
• Thoroughly cook raw food from animal sources.
• Wash raw vegetables carefully before eating.
• Keep uncooked meats separate from cooked meats and vegetables.
• Do not consume any beverages or foods made from unpasteurized milk.
• After handling uncooked foods, carefully wash all utensils and hands.
• Avoid all soft cheeses, such as Mexican-style feta, Brie, Camembert, and blue cheese, even if they are supposedly made from pasteurized milk.
• Reheat until steaming hot all leftover foods or ready-to-eat foods, such as hot dogs.
• Do not let juice from hot dogs or lunch meat packages drip onto other foods, utensils, or food preparation surfaces.
• Do not store opened hot dog packages in the refrigerator for more than 1 week. Do not store unopened packages for longer than 2 weeks.
• Do not store unopened lunch and deli meat packages in the refrigerator for longer than 2 weeks. Do not store opened packages for longer than 3 to 5 days.
• If other immunosuppressive conditions are present in combination with pregnancy, thoroughly heat cold cuts before eating.
• Do not eat raw or even lightly cooked sprouts of any kind. Cook sprouts thoroughly. Rinsing sprouts will not remove Listeria organisms.
• Do not eat refrigerated pâté or meat spreads from a deli counter or the refrigerated section of a grocery store.
• Canned or shelf-stable pâté and meat spreads are safe to eat, but be sure to refrigerate them after opening the packages.
• Do not eat refrigerated smoked seafood. Canned or shelf-stable seafood, particularly when incorporated into a casserole, is safe to eat.
• Eat cut melon immediately. Refrigerate uneaten melon quickly if not eaten. Discard cut melon that is left at room temperature for more than 4 hours.

CASE Diagnosis made and prompt treatment initiated

The most likely diagnosis in this patient is listeriosis. Because the patient is moderately ill and experiencing uterine contractions, she should be hospitalized and monitored for progressive cervical dilation. Blood cultures should be obtained to identify L monocytogenes. In addition, an amniocentesis should be performed, and the amniotic fluid should be cultured for this microorganism. Stool culture and culture of the cerebrospinal fluid are not indicated. The patient should be treated with intravenous ampicillin, 2 g every 4 hours for 14 days. If she is allergic to penicillin, the alternative drug is trimethoprim-sulfamethoxazole, 8 to 10 mg/kg per day in 2 divided doses, for 14 days. Prompt and effective treatment of the mother should prevent infection in the fetus and newborn. ●

CASE Pregnant patient with concerning symptoms of infection

A 28-year-old primigravid woman at 26 weeks’ gestation requests evaluation because of a 3-day history of low-grade fever (38.3 °C), chills, malaise, myalgias, pain in her upper back, nausea, diarrhea, and intermittent uterine contractions. Her symptoms began 2 days after she and her husband dined at a local Mexican restaurant. She specifically recalls eating unpasteurized cheese (queso fresco). Her husband also is experiencing similar symptoms.

• What is the most likely diagnosis?
• What tests should be performed to confirm the diagnosis?
• Does this infection pose a risk to the fetus?
• How should this patient be treated?

Listeriosis, a potentially serious foodborne illness, is an unusual infection in pregnancy. It can cause a number of adverse effects in both the pregnant woman and her fetus, including fetal death in utero. In this article, we review the microbiology and epidemiology of Listeria infection, consider the important steps in diagnosis, and discuss treatment options and prevention measures.

The causative organism in listeriosis

Listeriosis is caused by Listeria monocytogenes, a gram-positive, non–spore-forming bacillus. The organism is catalase positive and oxidase negative, and it exhibits tumbling motility when grown in culture. It can grow at temperatures less than 4 °C, which facilitates foodborne transmission of the bacterium despite adequate refrigeration. Of the 13 serotypes of L monocytogenes, the 1/2a, 1/2b, and 4b are most likely to be associated with human infection. The major virulence factors of L monocytogenes are the internalin surface proteins and the pore-forming listeriolysin O (LLO) cytotoxin. These factors enable the organism to effectively invade host cells.¹

The pathogen uses several mechanisms to evade gastrointestinal defenses prior to entry into the bloodstream. It avoids destruction in the stomach by using proton pump inhibitors to elevate the pH of gastric acid. In the duodenum, it survives the antibacterial properties of bile by secreting bile salt hydrolases, which catabolize bile salts. In addition, the cytotoxin listeriolysin S (LLS) disrupts the protective barrier created by the normal gut flora. Once the organism penetrates the gastrointestinal barriers, it disseminates through the blood and lymphatics and then infects other tissues, such as the brain and placenta.^1,2

Pathogenesis of infection

The primary reservoir of Listeria is soil and decaying vegetable matter. The organism also has been isolated from animal feed, water, sewage, and many animal species. With rare exceptions, most infections in adults result from inadvertent ingestion of the organism in contaminated food. In certain high-risk occupations, such as veterinary medicine, farming, and laboratory work, infection of the skin or eye can result from direct contact with an infected animal.³

Of note, foodborne illness caused by Listeria has the third highest mortality rate of any foodborne infection, 16% compared with 35% for Vibrio vulnificus and 17% for Clostridium botulinum.^2,3 The principal foods that have been linked to listeriosis include:

• soft cheeses, particularly those made from unpasteurized milk
• melon
• hot dogs
• lunch meat, such as bologna
• deli meat, especially chicken
• canned foods, such as smoked seafood, and pâté or meat spreads that are labeled “keep refrigerated”
• unpasteurized milk
• sprouts
• hummus.

In healthy adults, listeriosis is usually a short-lived illness. However, in older adults, immunocompromised patients, and pregnant women, the infection can be devastating. Infection in the pregnant woman also poses major danger to the developing fetus because the organism has a special predilection for placental and fetal tissue.^1,3,4

Immunity to Listeria infection depends primarily on T-cell lymphokine activation of macrophages. These latter cells are responsible for clearing the bacterium from the blood. As noted above, the principal virulence factor of L monocytogenes is listeriolysin O, a cholesterol-dependent cytolysin. This substance induces T-cell receptor unresponsiveness, thus interfering with the host immune response to the invading pathogen.^1,3-5

Continue to: Clinical manifestations of listeriosis...

Listeria infections may present with various manifestations, depending on the degree of exposure and the underlying immunocompetence of the host (FIGURE). In its most common and simplest form, listeriosis presents as a mild to moderate gastroenteritis following exposure to contaminated food. Symptoms typically develop within 24 hours of exposure and include fever, myalgias, abdominal or back pain, nausea, vomiting, and diarrhea.⁵

Conversely, in immunocompromised patients, including pregnant women, listeriosis can present as life-threatening sepsis and/or central nervous system (CNS) infection (invasive infection). In this clinical setting, the mean incubation period is 11 days. The manifestations of CNS infection include meningoencephalitis, cerebritis, rhombencephalitis (infection and inflammation of the brain stem), brain abscess, and spinal cord abscess.⁵

In addition to these 2 clinical presentations, listeriosis can cause unusual focal infections as illustrated in the FIGURE. Some of these infections have unique clinical associations. For example, skin or eye infections may occur as a result of direct inoculation in veterinarians, farmers, and laboratory workers. Listeria peritonitis may occur in patients who are receiving peritoneal dialysis and in those who have cirrhosis. Prosthetic joint and graft infections, of course, may occur in patients who have had invasive procedures for implantation of grafts or prosthetic devices.⁵

Listeriosis is especially dangerous in pregnancy because it not only can cause serious injury to the mother and even death but it also may pose a major risk to fetal well-being. Possible perinatal complications include fetal death; preterm labor and delivery; and neonatal sepsis, meningitis, and death.^5-8

Making the diagnosis

Diagnosis begins with a thorough and focused history to assess for characteristic symptoms and possible Listeria exposure. Exposure should be presumed for patients who report consuming high-risk foods, especially foods recently recalled by the US Food and Drug Administration.

In the asymptomatic pregnant patient, diagnostic testing can be deferred, and the patient should be instructed to return for evaluation if symptoms develop within 2 months of exposure. However, symptomatic, febrile patients require testing. The most valuable testing modality is Gram stain and culture of blood. Gram stain typically will show gram-positive pleomorphic rods with rounded ends. Amniocentesis may be indicated if blood cultures are not definitive. Meconium staining of the amniotic fluid and a positive Gram stain are highly indicative of fetal infection. Cultures of the cerebrospinal fluid are indicated in any individual with focal neurologic findings. Stool cultures are rarely indicated.

When obtaining any of the cultures noted above, the clinician should alert the microbiologist of the concern for listeriosis because L monocytogenes can be confused with common contaminants, such as diphtheroids.^5-9

Treatment and follow-up

The treatment of listeriosis in pregnancy depends on the severity of the infection and the immune status of the mother. The TABLE offers several different clinical scenarios and the appropriate treatment for each. As noted, several scenarios may require cultures of the blood, cerebrospinal fluid, and amniotic fluid.^7,9,10

Following treatment of the mother, serial ultrasound examinations should be performed to monitor fetal growth, CNS anatomy, placental morphology, amniotic fluid volume, and umbilical artery Doppler velocimetry. In the presence of fetal growth restriction, oligohydramnios, or abnormal Doppler velocimetry, biophysical profile testing should be performed. After delivery, the placenta should be examined carefully for histologic evidence of Listeria infection, such as miliary abscesses, and cultured for the bacterium.^7-9

Prevention measures

Conservative measures for prevention of Listeria infection in pregnant women include the following^7,10-12:

• Refrigerate milk and milk products at 40 °F (4.4 °C).
• Thoroughly cook raw food from animal sources.
• Wash raw vegetables carefully before eating.
• Keep uncooked meats separate from cooked meats and vegetables.
• Do not consume any beverages or foods made from unpasteurized milk.
• After handling uncooked foods, carefully wash all utensils and hands.
• Avoid all soft cheeses, such as Mexican-style feta, Brie, Camembert, and blue cheese, even if they are supposedly made from pasteurized milk.
• Reheat until steaming hot all leftover foods or ready-to-eat foods, such as hot dogs.
• Do not let juice from hot dogs or lunch meat packages drip onto other foods, utensils, or food preparation surfaces.
• Do not store opened hot dog packages in the refrigerator for more than 1 week. Do not store unopened packages for longer than 2 weeks.
• Do not store unopened lunch and deli meat packages in the refrigerator for longer than 2 weeks. Do not store opened packages for longer than 3 to 5 days.
• If other immunosuppressive conditions are present in combination with pregnancy, thoroughly heat cold cuts before eating.
• Do not eat raw or even lightly cooked sprouts of any kind. Cook sprouts thoroughly. Rinsing sprouts will not remove Listeria organisms.
• Do not eat refrigerated pâté or meat spreads from a deli counter or the refrigerated section of a grocery store.
• Canned or shelf-stable pâté and meat spreads are safe to eat, but be sure to refrigerate them after opening the packages.
• Do not eat refrigerated smoked seafood. Canned or shelf-stable seafood, particularly when incorporated into a casserole, is safe to eat.
• Eat cut melon immediately. Refrigerate uneaten melon quickly if not eaten. Discard cut melon that is left at room temperature for more than 4 hours.

CASE Diagnosis made and prompt treatment initiated

The most likely diagnosis in this patient is listeriosis. Because the patient is moderately ill and experiencing uterine contractions, she should be hospitalized and monitored for progressive cervical dilation. Blood cultures should be obtained to identify L monocytogenes. In addition, an amniocentesis should be performed, and the amniotic fluid should be cultured for this microorganism. Stool culture and culture of the cerebrospinal fluid are not indicated. The patient should be treated with intravenous ampicillin, 2 g every 4 hours for 14 days. If she is allergic to penicillin, the alternative drug is trimethoprim-sulfamethoxazole, 8 to 10 mg/kg per day in 2 divided doses, for 14 days. Prompt and effective treatment of the mother should prevent infection in the fetus and newborn. ●

CASE Pregnant patient with concerning symptoms of infection

A 28-year-old primigravid woman at 26 weeks’ gestation requests evaluation because of a 3-day history of low-grade fever (38.3 °C), chills, malaise, myalgias, pain in her upper back, nausea, diarrhea, and intermittent uterine contractions. Her symptoms began 2 days after she and her husband dined at a local Mexican restaurant. She specifically recalls eating unpasteurized cheese (queso fresco). Her husband also is experiencing similar symptoms.

• What is the most likely diagnosis?
• What tests should be performed to confirm the diagnosis?
• Does this infection pose a risk to the fetus?
• How should this patient be treated?

Listeriosis, a potentially serious foodborne illness, is an unusual infection in pregnancy. It can cause a number of adverse effects in both the pregnant woman and her fetus, including fetal death in utero. In this article, we review the microbiology and epidemiology of Listeria infection, consider the important steps in diagnosis, and discuss treatment options and prevention measures.

The causative organism in listeriosis

Listeriosis is caused by Listeria monocytogenes, a gram-positive, non–spore-forming bacillus. The organism is catalase positive and oxidase negative, and it exhibits tumbling motility when grown in culture. It can grow at temperatures less than 4 °C, which facilitates foodborne transmission of the bacterium despite adequate refrigeration. Of the 13 serotypes of L monocytogenes, the 1/2a, 1/2b, and 4b are most likely to be associated with human infection. The major virulence factors of L monocytogenes are the internalin surface proteins and the pore-forming listeriolysin O (LLO) cytotoxin. These factors enable the organism to effectively invade host cells.¹

The pathogen uses several mechanisms to evade gastrointestinal defenses prior to entry into the bloodstream. It avoids destruction in the stomach by using proton pump inhibitors to elevate the pH of gastric acid. In the duodenum, it survives the antibacterial properties of bile by secreting bile salt hydrolases, which catabolize bile salts. In addition, the cytotoxin listeriolysin S (LLS) disrupts the protective barrier created by the normal gut flora. Once the organism penetrates the gastrointestinal barriers, it disseminates through the blood and lymphatics and then infects other tissues, such as the brain and placenta.^1,2

Pathogenesis of infection

The primary reservoir of Listeria is soil and decaying vegetable matter. The organism also has been isolated from animal feed, water, sewage, and many animal species. With rare exceptions, most infections in adults result from inadvertent ingestion of the organism in contaminated food. In certain high-risk occupations, such as veterinary medicine, farming, and laboratory work, infection of the skin or eye can result from direct contact with an infected animal.³

Of note, foodborne illness caused by Listeria has the third highest mortality rate of any foodborne infection, 16% compared with 35% for Vibrio vulnificus and 17% for Clostridium botulinum.^2,3 The principal foods that have been linked to listeriosis include:

• soft cheeses, particularly those made from unpasteurized milk
• melon
• hot dogs
• lunch meat, such as bologna
• deli meat, especially chicken
• canned foods, such as smoked seafood, and pâté or meat spreads that are labeled “keep refrigerated”
• unpasteurized milk
• sprouts
• hummus.

In healthy adults, listeriosis is usually a short-lived illness. However, in older adults, immunocompromised patients, and pregnant women, the infection can be devastating. Infection in the pregnant woman also poses major danger to the developing fetus because the organism has a special predilection for placental and fetal tissue.^1,3,4

Immunity to Listeria infection depends primarily on T-cell lymphokine activation of macrophages. These latter cells are responsible for clearing the bacterium from the blood. As noted above, the principal virulence factor of L monocytogenes is listeriolysin O, a cholesterol-dependent cytolysin. This substance induces T-cell receptor unresponsiveness, thus interfering with the host immune response to the invading pathogen.^1,3-5

Continue to: Clinical manifestations of listeriosis...

Listeria infections may present with various manifestations, depending on the degree of exposure and the underlying immunocompetence of the host (FIGURE). In its most common and simplest form, listeriosis presents as a mild to moderate gastroenteritis following exposure to contaminated food. Symptoms typically develop within 24 hours of exposure and include fever, myalgias, abdominal or back pain, nausea, vomiting, and diarrhea.⁵

Conversely, in immunocompromised patients, including pregnant women, listeriosis can present as life-threatening sepsis and/or central nervous system (CNS) infection (invasive infection). In this clinical setting, the mean incubation period is 11 days. The manifestations of CNS infection include meningoencephalitis, cerebritis, rhombencephalitis (infection and inflammation of the brain stem), brain abscess, and spinal cord abscess.⁵

In addition to these 2 clinical presentations, listeriosis can cause unusual focal infections as illustrated in the FIGURE. Some of these infections have unique clinical associations. For example, skin or eye infections may occur as a result of direct inoculation in veterinarians, farmers, and laboratory workers. Listeria peritonitis may occur in patients who are receiving peritoneal dialysis and in those who have cirrhosis. Prosthetic joint and graft infections, of course, may occur in patients who have had invasive procedures for implantation of grafts or prosthetic devices.⁵

Listeriosis is especially dangerous in pregnancy because it not only can cause serious injury to the mother and even death but it also may pose a major risk to fetal well-being. Possible perinatal complications include fetal death; preterm labor and delivery; and neonatal sepsis, meningitis, and death.^5-8

Making the diagnosis

Diagnosis begins with a thorough and focused history to assess for characteristic symptoms and possible Listeria exposure. Exposure should be presumed for patients who report consuming high-risk foods, especially foods recently recalled by the US Food and Drug Administration.

In the asymptomatic pregnant patient, diagnostic testing can be deferred, and the patient should be instructed to return for evaluation if symptoms develop within 2 months of exposure. However, symptomatic, febrile patients require testing. The most valuable testing modality is Gram stain and culture of blood. Gram stain typically will show gram-positive pleomorphic rods with rounded ends. Amniocentesis may be indicated if blood cultures are not definitive. Meconium staining of the amniotic fluid and a positive Gram stain are highly indicative of fetal infection. Cultures of the cerebrospinal fluid are indicated in any individual with focal neurologic findings. Stool cultures are rarely indicated.

When obtaining any of the cultures noted above, the clinician should alert the microbiologist of the concern for listeriosis because L monocytogenes can be confused with common contaminants, such as diphtheroids.^5-9

Treatment and follow-up

The treatment of listeriosis in pregnancy depends on the severity of the infection and the immune status of the mother. The TABLE offers several different clinical scenarios and the appropriate treatment for each. As noted, several scenarios may require cultures of the blood, cerebrospinal fluid, and amniotic fluid.^7,9,10

Following treatment of the mother, serial ultrasound examinations should be performed to monitor fetal growth, CNS anatomy, placental morphology, amniotic fluid volume, and umbilical artery Doppler velocimetry. In the presence of fetal growth restriction, oligohydramnios, or abnormal Doppler velocimetry, biophysical profile testing should be performed. After delivery, the placenta should be examined carefully for histologic evidence of Listeria infection, such as miliary abscesses, and cultured for the bacterium.^7-9

Prevention measures

Conservative measures for prevention of Listeria infection in pregnant women include the following^7,10-12:

• Refrigerate milk and milk products at 40 °F (4.4 °C).
• Thoroughly cook raw food from animal sources.
• Wash raw vegetables carefully before eating.
• Keep uncooked meats separate from cooked meats and vegetables.
• Do not consume any beverages or foods made from unpasteurized milk.
• After handling uncooked foods, carefully wash all utensils and hands.
• Avoid all soft cheeses, such as Mexican-style feta, Brie, Camembert, and blue cheese, even if they are supposedly made from pasteurized milk.
• Reheat until steaming hot all leftover foods or ready-to-eat foods, such as hot dogs.
• Do not let juice from hot dogs or lunch meat packages drip onto other foods, utensils, or food preparation surfaces.
• Do not store opened hot dog packages in the refrigerator for more than 1 week. Do not store unopened packages for longer than 2 weeks.
• Do not store unopened lunch and deli meat packages in the refrigerator for longer than 2 weeks. Do not store opened packages for longer than 3 to 5 days.
• If other immunosuppressive conditions are present in combination with pregnancy, thoroughly heat cold cuts before eating.
• Do not eat raw or even lightly cooked sprouts of any kind. Cook sprouts thoroughly. Rinsing sprouts will not remove Listeria organisms.
• Do not eat refrigerated pâté or meat spreads from a deli counter or the refrigerated section of a grocery store.
• Canned or shelf-stable pâté and meat spreads are safe to eat, but be sure to refrigerate them after opening the packages.
• Do not eat refrigerated smoked seafood. Canned or shelf-stable seafood, particularly when incorporated into a casserole, is safe to eat.
• Eat cut melon immediately. Refrigerate uneaten melon quickly if not eaten. Discard cut melon that is left at room temperature for more than 4 hours.

CASE Diagnosis made and prompt treatment initiated

The most likely diagnosis in this patient is listeriosis. Because the patient is moderately ill and experiencing uterine contractions, she should be hospitalized and monitored for progressive cervical dilation. Blood cultures should be obtained to identify L monocytogenes. In addition, an amniocentesis should be performed, and the amniotic fluid should be cultured for this microorganism. Stool culture and culture of the cerebrospinal fluid are not indicated. The patient should be treated with intravenous ampicillin, 2 g every 4 hours for 14 days. If she is allergic to penicillin, the alternative drug is trimethoprim-sulfamethoxazole, 8 to 10 mg/kg per day in 2 divided doses, for 14 days. Prompt and effective treatment of the mother should prevent infection in the fetus and newborn. ●

Asthma affects more than 300 million people worldwide.¹ While many of these cases can achieve control with standard therapy, 5% to 10% of these cases are classified as severe asthma, remaining poorly controlled despite treatment with inhaled corticosteroids (ICS) and long-acting β agonists (LABA).² These patients also account for the majority of morbidity and mortality associated with the disease, with increased hospitalizations, intensive care unit (ICU) stays, detrimental adverse effects of oral corticosteroids (OCS), and lower quality of life.^3-6 Additionally, the financial repercussions of severe asthma are notable; in the United States, the estimated cost of asthma management is $82 billion annually, with $3 billion accounting for asthma-related work/school absences.⁷

In the past several years, the use of anti-immunoglobulin E (IgE), anti-interleukin-4 (IL-4), and anti-IL-5 biologic agents for severe asthma has been shown to decrease asthma exacerbations, improve lung function, reduce corticosteroid use, and decrease hospitalizations, especially for type 2 helper T cell (TH2-high) asthma.^8-10 However, clinicians have observed significant barriers to the implementation and widespread use of biologics, including insurance coverage, long wait times, follow-up, and limited access for lower income groups.^11,12

This article describes a unique model for a severe asthma clinic located at the Washington DC Veterans Affairs Medical Center (WDCVAMC) that is dually staffed by an allergist and pulmonologist. This clinic uses biologic agents for patients with difficult-to-treat asthma, many of whom require repeated or prolonged steroid use, in addition to prolonged and recurrent hospitalizations for exacerbations. The objective of this clinic is to provide a standardized approach to the management of severe asthma with the perspective of both an allergist and pulmonologist, thereby reducing the need to schedule appointments with multiple specialties and reducing delays in initiating biologics. This article presents the preliminary findings of 30 months of severe asthma management with various biologic agents, examining the impact of these therapies on hospitalizations, asthma exacerbations, ICU stays, and OCS use. The findings of this study support the benefits of biologics and suggest that the use of these agents within a dually staffed clinic may be a particularly effective model through which to manage severe asthma.

Background

Asthma affects approximately 20 million adults in the United States.¹³ Veterans are a population particularly impacted by asthma. Between 2015 and 2018, 10.9% of all veterans reported being diagnosed with asthma and 5.1% stated that they currently have asthma, compared with 13.4% and 8.0% of nonveterans, respectively.¹⁴ Veterans are susceptible to many of the factors that can trigger exacerbations while engaging in military service, such as chemical and environmental exposures both abroad and domestically.^15,16 Additionally, medication adherence is often challenging among the veteran population, particularly with more involved therapy, such as inhaler use.¹⁷ Such factors contribute to asthma exacerbations, with 2.9% of veterans reporting at least 1 asthma exacerbation in the past 12 months.¹⁴

Over the past several years, the development and use of biologic agents have transformed the management of severe asthma.⁸ Before the development of biologic agents for severe asthma, treatment options for patients were limited. While OCS are frequently used for asthma exacerbations, they are associated with a multiplicity of undesirable adverse effects, including weight gain, mood lability, gastrointestinal upset, hyperglycemia, risk of bone fractures, and hypertension.^18-20 The regular use of OCS are particularly problematic among other medical comorbidities commonly affecting the veteran population, such as diabetes and hypertension.^21-22

The WDCVAMC severe allergy clinic used 3 biologic agents: omalizumab (anti-IgE), benralizumab (anti-IL-5), and agent dupilumab (anti-IL-4). These medications have shown significant improvements in quality of life, reduction in asthma exacerbations and hospitalizations, and decreased use of OCS.^8,9 While research has firmly established the medical benefits of the use of biologic agents in severe asthma, several barriers exist in implementing widespread use.^11,12

In Gelhorn and colleagues’ study examining both physician and patient challenges in the use of biologics for severe asthma, scheduling, administrative time, and insurance costs were found to be major barriers to the use of these medications.¹² Patients expressed a preference for the administration of these medications in a specialist’s office but cited long wait times and scheduling difficulties as barriers. One of the most notable challenges from the physician perspective was the difficulty in obtaining reimbursement from insurance companies, requiring them to devote significant portions of time to prior authorizations and documentation.¹²

This article examines a dual specialty clinic that focuses on the treatment of severe asthma with biologic agents. This model is unique for several reasons. First, given the US Department of Veterans Affairs (VA) health care model, the health care practitioners (HCPs) in this clinic can avoid much of the administrative burden of obtaining reimbursement or working with insurance companies. Additionally, by dedicating specific days to the severe asthma clinic, patients do not experience long wait times to see both an allergist and pulmonologist. By seeing both clinicians, concurrent allergic and pulmonary issues can be addressed in the same visit, rather than delaying treatment by waiting on 2 specialist appointments.

Severe Asthma Clinic

The severe asthma clinic was started in September 2017 by a pulmonologist and an allergist at WDCVAMC. After experiencing substantial delays with the initiation of biologics for their patients and multiple referrals between their clinics, these physicians wanted to start a dually staffed asthma clinic to specifically focus on evaluating and treating severe asthma. A dedicated severe asthma clinic allowed the allergist and pulmonologist to streamline resources and collaborate to advocate for patients with the pharmacy section. Additionally, patients can benefit from the perspective of both specialists, as both the pulmonologist and allergist evaluate each patient and discuss the next steps of management.

This clinic is composed of 4 registered nurses, an allergist, and a pulmonologist. Clinic is held twice monthly through both telemedicine and in-office visits. The VA has strict guidelines for the use of certain biologics, including blood eosinophil count > 150 cells/µL, failure of traditional therapy, and frequent use of OCS. Additionally, to ensure these biologic agents are prescribed to patients that will benefit from them, the patients enrolled in this clinic are already on maximum therapy for their asthma, meaning all other therapeutic options (inhalers and oral medications) are being used. The clinic services all patients with severe asthma, not just patients who are on biologic therapy. Often, patients are referred to the severe allergy clinic late in their disease course given a lack of familiarity with biologic agents from prescribers and both institutional and insurance barriers.

Before the COVID-19 pandemic, spirometry and fractional exhaled nitric oxide (FENO) tests were recorded at each visit. Initially during the pandemic, the clinic transitioned to primarily telemedicine visits due to patients’ hesitance to seek in-person care. More recently, the clinic has transitioned back to primarily office visits; patients are seen in clinic on average every 3 months. At each visit, the patient is seen by both the pulmonologist and allergist. Additionally, the nursing staff reviews inhaler adherence with patients, spacer use, documents, Asthma Control Test (ACT) scores, and schedules follow-up visits.

Every 4 to 8 weeks, patients receive biologics agent at the WDCVAMC infusion center depending on the agent. The infusion center also instructs patients how to handle self-administered medications, like benralizumab, if the patient expresses a preference for taking it at home. Omalizumab has a boxed warning for anaphylaxis, although the other biologics in this study have a low risk of anaphylaxis. All patients receiving omalizumab, benralizumab, and dupilumab were provided with epinephrine injection devices in case of an allergic reaction and were taught how to use them in the clinic.^23,24

If patients continued to experience asthma exacerbations after the initiation of a biologic, a change in agent was considered after 4 to 6 months. Additionally, a complete blood count, respiratory allergy panel, and pulmonary function tests (PFTs) were completed.

Clinic Patients

Preliminary data were obtained from a retrospective chart review of 15 patients enrolled in the severe asthma clinic over 30 months. The inclusion criteria for chart review consisted of patients aged > 18 years receiving a biologic agent for > 3 months for the treatment of severe asthma. The outcomes examined included steroid use, emergency department (ED) visits, hospitalizations, FEV₁, and ICU stays.

Seven patients used benralizumab, 6 used dupilumab, and 2 used omalizumab (Table).

There was a notable clinical improvement in these patients. Before starting a biologic agent, all the patients in this study were prescribed steroids at least once a year for an asthma exacerbation, with a mean of 4.2 steroid tapers per year.

Discussion

The 15 patients in this initial data were referred to the severe asthma clinic by pulmonology, ear, nose, and throat (ENT), primary care, and a hospitalist during an in-patient stay. As the enrollment in our clinic grows, an increasing number of patients are referred from the allergy clinic as well. Patients in the severe asthma clinic also are referred by regional centers as news of the clinic is spread by word of mouth to surrounding VA facilities. As our clinic gains the capacity to serve more patients, we hope to contact WDCVAMC primary care, pulmonology, allergy, and ENT departments to raise awareness of the clinic.

Benralizumab and dupilumab were the most used agents in this preliminary data. This finding was largely due to the ability of patients to self-administer benralizumab, which was particularly beneficial during the COVID-19 pandemic. Of note, 5 patients in this study switched from another biologic agent to benralizumab due to the ability to self-administer. Three of 5 patients that required steroids after initiating benralizumab used fewer steroids than they had previously. This finding suggests benralizumab may be the preferred agent when travel time to health care is a challenge, reducing the need for frequent clinic visits and transportation.

This preliminary data supports previous studies that have demonstrated that biologic agents improve clinical outcomes by reducing asthma exacerbations, OCS use, hospitalizations, and ICU stays for patients on all 4 biologic agents. In addition to improving patient health through avoiding complications of prolonged OCS use and hospital stays, the decrease in ED visits and hospitalizations provides a substantial cost reduction to the health care system.  

These findings highlight the strength of a unique model of a combined allergy/pulmonary clinic. Before this combined clinic model, both pulmonology and allergy clinics noted delays in the initiation of biologics for patients who were potential candidates. Impediments include referrals between each specialty for evaluation of concurrent pulmonary conditions or allergy testing, overlap in asthma management, and a delay in coordination with the pharmacy department to start biologic agents. A dedicated severe asthma clinic staffed by both an allergist and pulmonologist provides a convenient option for patients to be seen by both specialists, reducing the need for separate appointments with each specialty, transportation to those appointments, and clinical time. This is particularly beneficial in a clinic such as this model, as this clinic serves patients from 4 states and Washington, DC. An additional benefit of this model is trained staff who directly communicate with the pharmacy in the initiation of these agents, allocate time to educating patients in biologic use, and coordinate follow-up.

Limitations

There were several limitations to this report. First, the number of patients examined in this preliminary data set is small. Due to the COVID-19 pandemic, there was a limited ability to see patients in person, and patients were seen exclusively over telemedicine for several months. For this reason, collecting data such as patient surveys and laboratory work following the initiation of a biologic was a challenge. Additionally, during the height of COVID-19, WDCVAMC did not perform aerosolizing procedures, such as PFTs and FENOs; thus, peak flows were obtained instead. Examining metrics, such as FENOs and IgE levels, and expanding PFT data would provide additional insight into the impact of biologic agents on clinical outcomes. Patient survey data in the form of ACTs or satisfaction surveys would also yield important data examining the impact of this clinic design and biologic use on patient experience. As of December 2022, 114 patients are enrolled in the clinic. We are working to collect the above laboratory results and spirometry for these patients so that these results can be published with a more robust data set. Another limitation of the information presented is that it is a retrospective data analysis; the data collected was contingent upon documentation and the assumption that these patients were exclusively receiving care through the VA. For example, steroid use before and after initiation of biologic was taken from asthma clinic notes and the patient’s medication list. Therefore, there is a possibility that not all instances were accounted for if that patient sought care outside the VA or whether it was not documented in a follow-up note.

Conclusions

The model of a combined allergy/pulmonology clinic can be particularly efficacious in the treatment of severe asthma, as it reduces the need for multiple appointments with different specialties, reduces wait time before starting a biologic agent, and offers the perspective of 2 specialists. This kind of model could be an example to many clinics in the VA. With a rapid increase in telemedicine due to the COVID-19 pandemic, multiple physicians consulting simultaneously is becoming a more feasible possibility across multiple specialties. As the use of biologics becomes more widespread, a combined clinic design is an efficient and promising method to improve severe asthma management.

This preliminary data continue to support previous research that shows biologic agents have led to better clinical outcomes through the reduction of asthma exacerbations, hospitalizations, and improved PFTs. While this initial data set highlights the results for 15 patients, there are 86 patients currently enrolled in this clinic. We are collecting additional data to publish more comprehensive results.

Asthma affects more than 300 million people worldwide.¹ While many of these cases can achieve control with standard therapy, 5% to 10% of these cases are classified as severe asthma, remaining poorly controlled despite treatment with inhaled corticosteroids (ICS) and long-acting β agonists (LABA).² These patients also account for the majority of morbidity and mortality associated with the disease, with increased hospitalizations, intensive care unit (ICU) stays, detrimental adverse effects of oral corticosteroids (OCS), and lower quality of life.^3-6 Additionally, the financial repercussions of severe asthma are notable; in the United States, the estimated cost of asthma management is $82 billion annually, with $3 billion accounting for asthma-related work/school absences.⁷

In the past several years, the use of anti-immunoglobulin E (IgE), anti-interleukin-4 (IL-4), and anti-IL-5 biologic agents for severe asthma has been shown to decrease asthma exacerbations, improve lung function, reduce corticosteroid use, and decrease hospitalizations, especially for type 2 helper T cell (TH2-high) asthma.^8-10 However, clinicians have observed significant barriers to the implementation and widespread use of biologics, including insurance coverage, long wait times, follow-up, and limited access for lower income groups.^11,12

This article describes a unique model for a severe asthma clinic located at the Washington DC Veterans Affairs Medical Center (WDCVAMC) that is dually staffed by an allergist and pulmonologist. This clinic uses biologic agents for patients with difficult-to-treat asthma, many of whom require repeated or prolonged steroid use, in addition to prolonged and recurrent hospitalizations for exacerbations. The objective of this clinic is to provide a standardized approach to the management of severe asthma with the perspective of both an allergist and pulmonologist, thereby reducing the need to schedule appointments with multiple specialties and reducing delays in initiating biologics. This article presents the preliminary findings of 30 months of severe asthma management with various biologic agents, examining the impact of these therapies on hospitalizations, asthma exacerbations, ICU stays, and OCS use. The findings of this study support the benefits of biologics and suggest that the use of these agents within a dually staffed clinic may be a particularly effective model through which to manage severe asthma.

Background

Asthma affects approximately 20 million adults in the United States.¹³ Veterans are a population particularly impacted by asthma. Between 2015 and 2018, 10.9% of all veterans reported being diagnosed with asthma and 5.1% stated that they currently have asthma, compared with 13.4% and 8.0% of nonveterans, respectively.¹⁴ Veterans are susceptible to many of the factors that can trigger exacerbations while engaging in military service, such as chemical and environmental exposures both abroad and domestically.^15,16 Additionally, medication adherence is often challenging among the veteran population, particularly with more involved therapy, such as inhaler use.¹⁷ Such factors contribute to asthma exacerbations, with 2.9% of veterans reporting at least 1 asthma exacerbation in the past 12 months.¹⁴

Over the past several years, the development and use of biologic agents have transformed the management of severe asthma.⁸ Before the development of biologic agents for severe asthma, treatment options for patients were limited. While OCS are frequently used for asthma exacerbations, they are associated with a multiplicity of undesirable adverse effects, including weight gain, mood lability, gastrointestinal upset, hyperglycemia, risk of bone fractures, and hypertension.^18-20 The regular use of OCS are particularly problematic among other medical comorbidities commonly affecting the veteran population, such as diabetes and hypertension.^21-22

The WDCVAMC severe allergy clinic used 3 biologic agents: omalizumab (anti-IgE), benralizumab (anti-IL-5), and agent dupilumab (anti-IL-4). These medications have shown significant improvements in quality of life, reduction in asthma exacerbations and hospitalizations, and decreased use of OCS.^8,9 While research has firmly established the medical benefits of the use of biologic agents in severe asthma, several barriers exist in implementing widespread use.^11,12

In Gelhorn and colleagues’ study examining both physician and patient challenges in the use of biologics for severe asthma, scheduling, administrative time, and insurance costs were found to be major barriers to the use of these medications.¹² Patients expressed a preference for the administration of these medications in a specialist’s office but cited long wait times and scheduling difficulties as barriers. One of the most notable challenges from the physician perspective was the difficulty in obtaining reimbursement from insurance companies, requiring them to devote significant portions of time to prior authorizations and documentation.¹²

This article examines a dual specialty clinic that focuses on the treatment of severe asthma with biologic agents. This model is unique for several reasons. First, given the US Department of Veterans Affairs (VA) health care model, the health care practitioners (HCPs) in this clinic can avoid much of the administrative burden of obtaining reimbursement or working with insurance companies. Additionally, by dedicating specific days to the severe asthma clinic, patients do not experience long wait times to see both an allergist and pulmonologist. By seeing both clinicians, concurrent allergic and pulmonary issues can be addressed in the same visit, rather than delaying treatment by waiting on 2 specialist appointments.

Severe Asthma Clinic

The severe asthma clinic was started in September 2017 by a pulmonologist and an allergist at WDCVAMC. After experiencing substantial delays with the initiation of biologics for their patients and multiple referrals between their clinics, these physicians wanted to start a dually staffed asthma clinic to specifically focus on evaluating and treating severe asthma. A dedicated severe asthma clinic allowed the allergist and pulmonologist to streamline resources and collaborate to advocate for patients with the pharmacy section. Additionally, patients can benefit from the perspective of both specialists, as both the pulmonologist and allergist evaluate each patient and discuss the next steps of management.

This clinic is composed of 4 registered nurses, an allergist, and a pulmonologist. Clinic is held twice monthly through both telemedicine and in-office visits. The VA has strict guidelines for the use of certain biologics, including blood eosinophil count > 150 cells/µL, failure of traditional therapy, and frequent use of OCS. Additionally, to ensure these biologic agents are prescribed to patients that will benefit from them, the patients enrolled in this clinic are already on maximum therapy for their asthma, meaning all other therapeutic options (inhalers and oral medications) are being used. The clinic services all patients with severe asthma, not just patients who are on biologic therapy. Often, patients are referred to the severe allergy clinic late in their disease course given a lack of familiarity with biologic agents from prescribers and both institutional and insurance barriers.

Before the COVID-19 pandemic, spirometry and fractional exhaled nitric oxide (FENO) tests were recorded at each visit. Initially during the pandemic, the clinic transitioned to primarily telemedicine visits due to patients’ hesitance to seek in-person care. More recently, the clinic has transitioned back to primarily office visits; patients are seen in clinic on average every 3 months. At each visit, the patient is seen by both the pulmonologist and allergist. Additionally, the nursing staff reviews inhaler adherence with patients, spacer use, documents, Asthma Control Test (ACT) scores, and schedules follow-up visits.

Every 4 to 8 weeks, patients receive biologics agent at the WDCVAMC infusion center depending on the agent. The infusion center also instructs patients how to handle self-administered medications, like benralizumab, if the patient expresses a preference for taking it at home. Omalizumab has a boxed warning for anaphylaxis, although the other biologics in this study have a low risk of anaphylaxis. All patients receiving omalizumab, benralizumab, and dupilumab were provided with epinephrine injection devices in case of an allergic reaction and were taught how to use them in the clinic.^23,24

If patients continued to experience asthma exacerbations after the initiation of a biologic, a change in agent was considered after 4 to 6 months. Additionally, a complete blood count, respiratory allergy panel, and pulmonary function tests (PFTs) were completed.

Clinic Patients

Preliminary data were obtained from a retrospective chart review of 15 patients enrolled in the severe asthma clinic over 30 months. The inclusion criteria for chart review consisted of patients aged > 18 years receiving a biologic agent for > 3 months for the treatment of severe asthma. The outcomes examined included steroid use, emergency department (ED) visits, hospitalizations, FEV₁, and ICU stays.

Seven patients used benralizumab, 6 used dupilumab, and 2 used omalizumab (Table).

There was a notable clinical improvement in these patients. Before starting a biologic agent, all the patients in this study were prescribed steroids at least once a year for an asthma exacerbation, with a mean of 4.2 steroid tapers per year.

Discussion

The 15 patients in this initial data were referred to the severe asthma clinic by pulmonology, ear, nose, and throat (ENT), primary care, and a hospitalist during an in-patient stay. As the enrollment in our clinic grows, an increasing number of patients are referred from the allergy clinic as well. Patients in the severe asthma clinic also are referred by regional centers as news of the clinic is spread by word of mouth to surrounding VA facilities. As our clinic gains the capacity to serve more patients, we hope to contact WDCVAMC primary care, pulmonology, allergy, and ENT departments to raise awareness of the clinic.

Benralizumab and dupilumab were the most used agents in this preliminary data. This finding was largely due to the ability of patients to self-administer benralizumab, which was particularly beneficial during the COVID-19 pandemic. Of note, 5 patients in this study switched from another biologic agent to benralizumab due to the ability to self-administer. Three of 5 patients that required steroids after initiating benralizumab used fewer steroids than they had previously. This finding suggests benralizumab may be the preferred agent when travel time to health care is a challenge, reducing the need for frequent clinic visits and transportation.

This preliminary data supports previous studies that have demonstrated that biologic agents improve clinical outcomes by reducing asthma exacerbations, OCS use, hospitalizations, and ICU stays for patients on all 4 biologic agents. In addition to improving patient health through avoiding complications of prolonged OCS use and hospital stays, the decrease in ED visits and hospitalizations provides a substantial cost reduction to the health care system.  

These findings highlight the strength of a unique model of a combined allergy/pulmonary clinic. Before this combined clinic model, both pulmonology and allergy clinics noted delays in the initiation of biologics for patients who were potential candidates. Impediments include referrals between each specialty for evaluation of concurrent pulmonary conditions or allergy testing, overlap in asthma management, and a delay in coordination with the pharmacy department to start biologic agents. A dedicated severe asthma clinic staffed by both an allergist and pulmonologist provides a convenient option for patients to be seen by both specialists, reducing the need for separate appointments with each specialty, transportation to those appointments, and clinical time. This is particularly beneficial in a clinic such as this model, as this clinic serves patients from 4 states and Washington, DC. An additional benefit of this model is trained staff who directly communicate with the pharmacy in the initiation of these agents, allocate time to educating patients in biologic use, and coordinate follow-up.

Limitations

There were several limitations to this report. First, the number of patients examined in this preliminary data set is small. Due to the COVID-19 pandemic, there was a limited ability to see patients in person, and patients were seen exclusively over telemedicine for several months. For this reason, collecting data such as patient surveys and laboratory work following the initiation of a biologic was a challenge. Additionally, during the height of COVID-19, WDCVAMC did not perform aerosolizing procedures, such as PFTs and FENOs; thus, peak flows were obtained instead. Examining metrics, such as FENOs and IgE levels, and expanding PFT data would provide additional insight into the impact of biologic agents on clinical outcomes. Patient survey data in the form of ACTs or satisfaction surveys would also yield important data examining the impact of this clinic design and biologic use on patient experience. As of December 2022, 114 patients are enrolled in the clinic. We are working to collect the above laboratory results and spirometry for these patients so that these results can be published with a more robust data set. Another limitation of the information presented is that it is a retrospective data analysis; the data collected was contingent upon documentation and the assumption that these patients were exclusively receiving care through the VA. For example, steroid use before and after initiation of biologic was taken from asthma clinic notes and the patient’s medication list. Therefore, there is a possibility that not all instances were accounted for if that patient sought care outside the VA or whether it was not documented in a follow-up note.

Conclusions

The model of a combined allergy/pulmonology clinic can be particularly efficacious in the treatment of severe asthma, as it reduces the need for multiple appointments with different specialties, reduces wait time before starting a biologic agent, and offers the perspective of 2 specialists. This kind of model could be an example to many clinics in the VA. With a rapid increase in telemedicine due to the COVID-19 pandemic, multiple physicians consulting simultaneously is becoming a more feasible possibility across multiple specialties. As the use of biologics becomes more widespread, a combined clinic design is an efficient and promising method to improve severe asthma management.

This preliminary data continue to support previous research that shows biologic agents have led to better clinical outcomes through the reduction of asthma exacerbations, hospitalizations, and improved PFTs. While this initial data set highlights the results for 15 patients, there are 86 patients currently enrolled in this clinic. We are collecting additional data to publish more comprehensive results.

Asthma affects more than 300 million people worldwide.¹ While many of these cases can achieve control with standard therapy, 5% to 10% of these cases are classified as severe asthma, remaining poorly controlled despite treatment with inhaled corticosteroids (ICS) and long-acting β agonists (LABA).² These patients also account for the majority of morbidity and mortality associated with the disease, with increased hospitalizations, intensive care unit (ICU) stays, detrimental adverse effects of oral corticosteroids (OCS), and lower quality of life.^3-6 Additionally, the financial repercussions of severe asthma are notable; in the United States, the estimated cost of asthma management is $82 billion annually, with $3 billion accounting for asthma-related work/school absences.⁷

In the past several years, the use of anti-immunoglobulin E (IgE), anti-interleukin-4 (IL-4), and anti-IL-5 biologic agents for severe asthma has been shown to decrease asthma exacerbations, improve lung function, reduce corticosteroid use, and decrease hospitalizations, especially for type 2 helper T cell (TH2-high) asthma.^8-10 However, clinicians have observed significant barriers to the implementation and widespread use of biologics, including insurance coverage, long wait times, follow-up, and limited access for lower income groups.^11,12

This article describes a unique model for a severe asthma clinic located at the Washington DC Veterans Affairs Medical Center (WDCVAMC) that is dually staffed by an allergist and pulmonologist. This clinic uses biologic agents for patients with difficult-to-treat asthma, many of whom require repeated or prolonged steroid use, in addition to prolonged and recurrent hospitalizations for exacerbations. The objective of this clinic is to provide a standardized approach to the management of severe asthma with the perspective of both an allergist and pulmonologist, thereby reducing the need to schedule appointments with multiple specialties and reducing delays in initiating biologics. This article presents the preliminary findings of 30 months of severe asthma management with various biologic agents, examining the impact of these therapies on hospitalizations, asthma exacerbations, ICU stays, and OCS use. The findings of this study support the benefits of biologics and suggest that the use of these agents within a dually staffed clinic may be a particularly effective model through which to manage severe asthma.

Background

Asthma affects approximately 20 million adults in the United States.¹³ Veterans are a population particularly impacted by asthma. Between 2015 and 2018, 10.9% of all veterans reported being diagnosed with asthma and 5.1% stated that they currently have asthma, compared with 13.4% and 8.0% of nonveterans, respectively.¹⁴ Veterans are susceptible to many of the factors that can trigger exacerbations while engaging in military service, such as chemical and environmental exposures both abroad and domestically.^15,16 Additionally, medication adherence is often challenging among the veteran population, particularly with more involved therapy, such as inhaler use.¹⁷ Such factors contribute to asthma exacerbations, with 2.9% of veterans reporting at least 1 asthma exacerbation in the past 12 months.¹⁴

Over the past several years, the development and use of biologic agents have transformed the management of severe asthma.⁸ Before the development of biologic agents for severe asthma, treatment options for patients were limited. While OCS are frequently used for asthma exacerbations, they are associated with a multiplicity of undesirable adverse effects, including weight gain, mood lability, gastrointestinal upset, hyperglycemia, risk of bone fractures, and hypertension.^18-20 The regular use of OCS are particularly problematic among other medical comorbidities commonly affecting the veteran population, such as diabetes and hypertension.^21-22

The WDCVAMC severe allergy clinic used 3 biologic agents: omalizumab (anti-IgE), benralizumab (anti-IL-5), and agent dupilumab (anti-IL-4). These medications have shown significant improvements in quality of life, reduction in asthma exacerbations and hospitalizations, and decreased use of OCS.^8,9 While research has firmly established the medical benefits of the use of biologic agents in severe asthma, several barriers exist in implementing widespread use.^11,12

In Gelhorn and colleagues’ study examining both physician and patient challenges in the use of biologics for severe asthma, scheduling, administrative time, and insurance costs were found to be major barriers to the use of these medications.¹² Patients expressed a preference for the administration of these medications in a specialist’s office but cited long wait times and scheduling difficulties as barriers. One of the most notable challenges from the physician perspective was the difficulty in obtaining reimbursement from insurance companies, requiring them to devote significant portions of time to prior authorizations and documentation.¹²

This article examines a dual specialty clinic that focuses on the treatment of severe asthma with biologic agents. This model is unique for several reasons. First, given the US Department of Veterans Affairs (VA) health care model, the health care practitioners (HCPs) in this clinic can avoid much of the administrative burden of obtaining reimbursement or working with insurance companies. Additionally, by dedicating specific days to the severe asthma clinic, patients do not experience long wait times to see both an allergist and pulmonologist. By seeing both clinicians, concurrent allergic and pulmonary issues can be addressed in the same visit, rather than delaying treatment by waiting on 2 specialist appointments.

Severe Asthma Clinic

The severe asthma clinic was started in September 2017 by a pulmonologist and an allergist at WDCVAMC. After experiencing substantial delays with the initiation of biologics for their patients and multiple referrals between their clinics, these physicians wanted to start a dually staffed asthma clinic to specifically focus on evaluating and treating severe asthma. A dedicated severe asthma clinic allowed the allergist and pulmonologist to streamline resources and collaborate to advocate for patients with the pharmacy section. Additionally, patients can benefit from the perspective of both specialists, as both the pulmonologist and allergist evaluate each patient and discuss the next steps of management.

This clinic is composed of 4 registered nurses, an allergist, and a pulmonologist. Clinic is held twice monthly through both telemedicine and in-office visits. The VA has strict guidelines for the use of certain biologics, including blood eosinophil count > 150 cells/µL, failure of traditional therapy, and frequent use of OCS. Additionally, to ensure these biologic agents are prescribed to patients that will benefit from them, the patients enrolled in this clinic are already on maximum therapy for their asthma, meaning all other therapeutic options (inhalers and oral medications) are being used. The clinic services all patients with severe asthma, not just patients who are on biologic therapy. Often, patients are referred to the severe allergy clinic late in their disease course given a lack of familiarity with biologic agents from prescribers and both institutional and insurance barriers.

Before the COVID-19 pandemic, spirometry and fractional exhaled nitric oxide (FENO) tests were recorded at each visit. Initially during the pandemic, the clinic transitioned to primarily telemedicine visits due to patients’ hesitance to seek in-person care. More recently, the clinic has transitioned back to primarily office visits; patients are seen in clinic on average every 3 months. At each visit, the patient is seen by both the pulmonologist and allergist. Additionally, the nursing staff reviews inhaler adherence with patients, spacer use, documents, Asthma Control Test (ACT) scores, and schedules follow-up visits.

Every 4 to 8 weeks, patients receive biologics agent at the WDCVAMC infusion center depending on the agent. The infusion center also instructs patients how to handle self-administered medications, like benralizumab, if the patient expresses a preference for taking it at home. Omalizumab has a boxed warning for anaphylaxis, although the other biologics in this study have a low risk of anaphylaxis. All patients receiving omalizumab, benralizumab, and dupilumab were provided with epinephrine injection devices in case of an allergic reaction and were taught how to use them in the clinic.^23,24

If patients continued to experience asthma exacerbations after the initiation of a biologic, a change in agent was considered after 4 to 6 months. Additionally, a complete blood count, respiratory allergy panel, and pulmonary function tests (PFTs) were completed.

Clinic Patients

Preliminary data were obtained from a retrospective chart review of 15 patients enrolled in the severe asthma clinic over 30 months. The inclusion criteria for chart review consisted of patients aged > 18 years receiving a biologic agent for > 3 months for the treatment of severe asthma. The outcomes examined included steroid use, emergency department (ED) visits, hospitalizations, FEV₁, and ICU stays.

Seven patients used benralizumab, 6 used dupilumab, and 2 used omalizumab (Table).

There was a notable clinical improvement in these patients. Before starting a biologic agent, all the patients in this study were prescribed steroids at least once a year for an asthma exacerbation, with a mean of 4.2 steroid tapers per year.

Discussion

The 15 patients in this initial data were referred to the severe asthma clinic by pulmonology, ear, nose, and throat (ENT), primary care, and a hospitalist during an in-patient stay. As the enrollment in our clinic grows, an increasing number of patients are referred from the allergy clinic as well. Patients in the severe asthma clinic also are referred by regional centers as news of the clinic is spread by word of mouth to surrounding VA facilities. As our clinic gains the capacity to serve more patients, we hope to contact WDCVAMC primary care, pulmonology, allergy, and ENT departments to raise awareness of the clinic.

Benralizumab and dupilumab were the most used agents in this preliminary data. This finding was largely due to the ability of patients to self-administer benralizumab, which was particularly beneficial during the COVID-19 pandemic. Of note, 5 patients in this study switched from another biologic agent to benralizumab due to the ability to self-administer. Three of 5 patients that required steroids after initiating benralizumab used fewer steroids than they had previously. This finding suggests benralizumab may be the preferred agent when travel time to health care is a challenge, reducing the need for frequent clinic visits and transportation.

This preliminary data supports previous studies that have demonstrated that biologic agents improve clinical outcomes by reducing asthma exacerbations, OCS use, hospitalizations, and ICU stays for patients on all 4 biologic agents. In addition to improving patient health through avoiding complications of prolonged OCS use and hospital stays, the decrease in ED visits and hospitalizations provides a substantial cost reduction to the health care system.  

These findings highlight the strength of a unique model of a combined allergy/pulmonary clinic. Before this combined clinic model, both pulmonology and allergy clinics noted delays in the initiation of biologics for patients who were potential candidates. Impediments include referrals between each specialty for evaluation of concurrent pulmonary conditions or allergy testing, overlap in asthma management, and a delay in coordination with the pharmacy department to start biologic agents. A dedicated severe asthma clinic staffed by both an allergist and pulmonologist provides a convenient option for patients to be seen by both specialists, reducing the need for separate appointments with each specialty, transportation to those appointments, and clinical time. This is particularly beneficial in a clinic such as this model, as this clinic serves patients from 4 states and Washington, DC. An additional benefit of this model is trained staff who directly communicate with the pharmacy in the initiation of these agents, allocate time to educating patients in biologic use, and coordinate follow-up.

Limitations

There were several limitations to this report. First, the number of patients examined in this preliminary data set is small. Due to the COVID-19 pandemic, there was a limited ability to see patients in person, and patients were seen exclusively over telemedicine for several months. For this reason, collecting data such as patient surveys and laboratory work following the initiation of a biologic was a challenge. Additionally, during the height of COVID-19, WDCVAMC did not perform aerosolizing procedures, such as PFTs and FENOs; thus, peak flows were obtained instead. Examining metrics, such as FENOs and IgE levels, and expanding PFT data would provide additional insight into the impact of biologic agents on clinical outcomes. Patient survey data in the form of ACTs or satisfaction surveys would also yield important data examining the impact of this clinic design and biologic use on patient experience. As of December 2022, 114 patients are enrolled in the clinic. We are working to collect the above laboratory results and spirometry for these patients so that these results can be published with a more robust data set. Another limitation of the information presented is that it is a retrospective data analysis; the data collected was contingent upon documentation and the assumption that these patients were exclusively receiving care through the VA. For example, steroid use before and after initiation of biologic was taken from asthma clinic notes and the patient’s medication list. Therefore, there is a possibility that not all instances were accounted for if that patient sought care outside the VA or whether it was not documented in a follow-up note.

Conclusions

The model of a combined allergy/pulmonology clinic can be particularly efficacious in the treatment of severe asthma, as it reduces the need for multiple appointments with different specialties, reduces wait time before starting a biologic agent, and offers the perspective of 2 specialists. This kind of model could be an example to many clinics in the VA. With a rapid increase in telemedicine due to the COVID-19 pandemic, multiple physicians consulting simultaneously is becoming a more feasible possibility across multiple specialties. As the use of biologics becomes more widespread, a combined clinic design is an efficient and promising method to improve severe asthma management.

This preliminary data continue to support previous research that shows biologic agents have led to better clinical outcomes through the reduction of asthma exacerbations, hospitalizations, and improved PFTs. While this initial data set highlights the results for 15 patients, there are 86 patients currently enrolled in this clinic. We are collecting additional data to publish more comprehensive results.

Kikuchi-Fujimoto disease (KFD) is a rare, usually self-limited cause of cervical lymphadenitis that is more prevalent among patients of Asian descent.¹ The pathogenesis of KFD remains unknown. Clinically, KFD may mimic malignant lymphoproliferative disorders, autoimmune diseases such as systemic lupus erythematosus (SLE) lymphadenitis, and infectious conditions such as HIV and tuberculous lymphadenitis. The most common presentation of KFD involves fever and rapidly evolving cervical lymphadenopathy.^2,3 Due to its rarity, KFD is not always considered in the differential diagnosis for fever with tender lymphadenopathy, and up to one-third of cases are initially misdiagnosed.²

Definitive diagnosis requires lymph node biopsy. It is critical to achieving a timely diagnosis of KFD to exclude more serious conditions, initiate appropriate treatment, and minimize undue stress for patients. We describe a case of KFD in a patient who was met with delays in obtaining a definitive diagnosis for his symptoms.

Case Presentation

A 27-year-old previously healthy White man presented to the emergency department with subacute, progressive right-sided neck pain and swelling. In the week leading up to presentation, he also noted intermittent fevers, night sweats, and abdominal pain. His symptoms were unrelieved with acetaminophen and aspirin. He reported no sick contacts, recent travel, or animal exposures. He had no known history of autoimmune disease, malignancy, or immunocompromising conditions. Vital signs at the time of presentation were notable for a temperature of 39.0 °C. On examination, he had several firm, mobile, and exquisitely tender lymph nodes in the right upper anterior cervical chain. Abdominal examination was notable for left upper quadrant tenderness with palpable splenomegaly. Due to initial concern that his symptoms represented bacterial lymphadenitis, he was started on broad-spectrum antibiotics and admitted to the hospital for an expedited infectious workup.

Initial laboratory studies were notable for a white blood cell count of 3.7 × 10⁹/L with 57.5% neutrophils and 27.0% lymphocytes on differential.

Discussion

KFD is a rare cause of cervical lymphadenitis that was first described in 1972. Although cases have been reported worldwide, it is seen with higher prevalence in Asian countries. KFD was previously thought to have a female predominance, but recent reviews suggest a female to male ratio close to 1:1.¹ The pathogenesis of KFD remains unknown, though some studies have suggested Epstein-Barr virus infection as a potential trigger.^4,5 Human herpesvirus (HHV) 6, HHV 7, HHV 8, HSV, HIV, and parvovirus B19 also have been implicated as potential triggers, though no causative relationship has been established.^2,5,6 Autoimmunity may also play a role in the pathogenesis of KFD given its histopathologic overlap with SLE lymphadenitis.^1,7

The most common presenting symptoms of KFD include fever and tender cervical lymphadenopathy. Many patients also experience constitutional symptoms such as weight loss, night sweats, and fatigue.² KFD is characterized by enlarged cervical lymph nodes, typically > 2 cm in diameter.³ Cutaneous manifestations of KFD are common and may manifest as nonspecific papules, plaques, nodules, or facial malar erythema.^1,2 Case reports also have described KFD manifesting with ataxia, arthritis, parotitis, or ocular pathologies such as conjunctivitis and uveitis.^1,2,8,9 Hepatosplenomegaly is a relatively rare manifestation of KFD seen in approximately 3% of cases.¹⁰ When present, hepatosplenomegaly may make the diagnosis of KFD especially difficult to distinguish from lymphoproliferative disorders such as lymphoma. Laboratory findings in KFD are nonspecific and include elevated levels of lactate dehydrogenase, erythrocyte sedimentation rate, C-reactive protein, and liver enzymes.³ Both lymphocytosis and lymphopenia have been described.³Definitive diagnosis of KFD is achieved through lymph node biopsy and histologic examination. Histopathologic findings of KFD include areas of coagulative necrosis and histiocytic proliferation within the cortical and paracortical regions of the lymph node. Scattered nuclear debris also may be seen, though this histologic finding also is seen with lymphoma. The absence of neutrophils is characteristic of KFD.² In our patient, a core needle biopsy was initially pursued but returned nondiagnostic. A PET-CT also was obtained, though KFD may mimic lymphoma on PET as was seen in this patient’s case as well as in prior case reports.¹¹ An excisional lymph node biopsy was ultimately performed and secured the diagnosis of KFD.

Although ultrasound-guided core needle biopsy was unable to yield the diagnosis for our patient, its diagnostic accuracy is still superior to that of fine needle aspiration and is therefore suggested as the primary diagnostic modality when KFD is suspected.¹² Core needle biopsy also is less invasive, less time consuming, and perhaps more cost-effective than an open excisional biopsy, which often requires the use of an operating room and monitored anesthesia care.¹² Understandably, our patient experienced significant stress while awaiting a final diagnosis. Whenever possible, lymph node biopsy should be prioritized over other diagnostic modalities to achieve a timely and definitive diagnosis.

KFD has no established treatment guidelines. Supportive care with antipyretics and analgesics is the most common initial approach, as KFD is typically a self-limited disease that resolves in 1 to 4 months.² Patients with severe, persistent symptoms have been successfully treated with corticosteroids and hydroxychloroquine, with monotherapy typically trialed before concomitant use.^2,13 After 2 courses of prednisone, our patient was prescribed single-agent hydroxychloroquine due to his recurrent symptoms and debilitating AEs from the steroids. Other case reports have described hydroxychloroquine as a treatment option when steroids fail to provide symptom relief or when there are recurrences of KFD.^14-19 Retinopathy can occur as a result of long-term hydroxychloroquine use. As such, patients anticipated to require long-term hydroxychloroquine therapy should receive a baseline eye examination within months of drug initiation and repeat examination after 5 years of therapy.²⁰

After symptom resolution, continued follow-up with a health care professional is recommended due to the potential for KFD recurrence or the development of a new autoimmune disease. The rate of KFD recurrence was previously described as 3%, but a more recent review found the rate of recurrence to be approximately 15% at > 6 months follow-up.^1,3 Recurrence is often described during or shortly after the tapering of steroids.^13,16,21,22 Recurrent KFD can be diagnosed with repeat lymph node biopsy, which also serves to exclude other disease processes.^13,16 However, recurrence also has been diagnosed clinically based on the patient’s symptoms and laboratory investigations.^21,22Continued surveillance of patients with KFD is also necessary to monitor for the development of new autoimmune diseases, especially SLE. SLE lymphadenitis shares many histopathologic characteristics with KFD. Case reports have described the development of SLE in patients with a history of KFD.^2,7 Other autoimmune conditions described in patients with prior KFD include Sjögren syndrome, Hashimoto thyroiditis, Graves disease, mixed connective tissue disease, and antiphospholipid syndrome.^3,23 Among patients with KFD, female sex, painful adenopathy, and cytopenias are significantly associated with the later development of autoimmune disease.²³

Patient Perspective

This began for me in September 2020 out of the blue. I woke up one day with a random lymph node in my neck but otherwise felt completely healthy, and within 2 to 3 weeks I had never been more sick in my entire life. It came with bouts of fevers, neck pain from the swelling, stomach pain (I later learned an enlarged spleen was the source), terrible night sweats, violent chills where the shaking was uncontrollable for hours at a time, loss of appetite, and countless other symptoms that have come and gone over the past year.

It did take a little while to get a diagnosis, but I understand the autoimmune field is tricky. For about 4 to 5 weeks, I was told to prepare for a lymphoma diagnosis. I ended up doing 2 rounds of prednisone, one for 3 weeks at the end of 2020 and one for 2 months from March to May. The initial round helped quite a bit, but the second round did not have any effect on the lingering symptoms. In my opinion, prednisone is miserable to be on long term and I do not recommend it. The daily AEs that came with it included mood swings, insomnia, weight gain, and more. I have been on hydroxychloroquine now for almost 2 months and although it has some AEs of its own, it is nowhere near as rough as the prednisone and has helped manage my remaining symptoms quite a bit.

This certainly has not been a fun experience, but I was under great care during my time in the hospital and continue to be under good care through the rheumatology clinic. The one thing that could have made a huge difference would have been the issues involved in getting my surgery scheduled while I was still inpatient, which took quite a while. The pain during that time was so intense and unlike anything I have ever experienced before, and it was only the surgery that finally brought me some relief. To paint you a picture, I have broken bones, split my leg open, and have roughly 40 to 50 hours of tattoo work on me, and I have never experienced the level of pain like I felt in my neck and stomach. I remember feeling like someone had wound up and hit me with a baseball bat. The surgery brought me immense relief and if it had occurred when it was originally supposed to, I would have been spared 3 or so days of this type of pain.

It has been almost 10 months since my surgery and diagnosis, and life has mostly returned to normal for me. I am still on long-term medication as I mentioned, and I still deal with fatigue, spleen pain, and several other symptoms, but it is much more under control these days. I feel very fortunate to have been under and continue to be under such great care.

Conclusions

This case report highlights the importance of recognizing KFD as a rare but possible cause of fever and necrotizing cervical lymphadenopathy. KFD often mimics malignant lymphoproliferative disorders, autoimmune diseases such as SLE lymphadenitis, and infectious conditions such as HIV and tuberculous lymphadenitis. While KFD is seen with higher prevalence in Asian countries and was previously thought to be more predominant in females, the diagnosis should still be considered irrespective of geographic location or patient sex. Lymph node biopsy is the preferred diagnostic approach for patients with suspected KFD. Treatment is typically supportive but may consist of glucocorticoids in severe cases. Hydroxychloroquine may be used in refractory cases or as a steroid-sparing regimen when steroid AEs are poorly tolerated. Long-term follow-up is critical for patients with KFD to monitor for both disease recurrence and the development of autoimmune disease, especially SLE.

Acknowledgments

The authors thank Dr. Jacob Pilley for his detailed review of the patient’s pathology results. The authors also extend their gratitude to the patient, who deepened our understanding of this condition and what it is like to live with it.

Kikuchi-Fujimoto disease (KFD) is a rare, usually self-limited cause of cervical lymphadenitis that is more prevalent among patients of Asian descent.¹ The pathogenesis of KFD remains unknown. Clinically, KFD may mimic malignant lymphoproliferative disorders, autoimmune diseases such as systemic lupus erythematosus (SLE) lymphadenitis, and infectious conditions such as HIV and tuberculous lymphadenitis. The most common presentation of KFD involves fever and rapidly evolving cervical lymphadenopathy.^2,3 Due to its rarity, KFD is not always considered in the differential diagnosis for fever with tender lymphadenopathy, and up to one-third of cases are initially misdiagnosed.²

Definitive diagnosis requires lymph node biopsy. It is critical to achieving a timely diagnosis of KFD to exclude more serious conditions, initiate appropriate treatment, and minimize undue stress for patients. We describe a case of KFD in a patient who was met with delays in obtaining a definitive diagnosis for his symptoms.

Case Presentation

A 27-year-old previously healthy White man presented to the emergency department with subacute, progressive right-sided neck pain and swelling. In the week leading up to presentation, he also noted intermittent fevers, night sweats, and abdominal pain. His symptoms were unrelieved with acetaminophen and aspirin. He reported no sick contacts, recent travel, or animal exposures. He had no known history of autoimmune disease, malignancy, or immunocompromising conditions. Vital signs at the time of presentation were notable for a temperature of 39.0 °C. On examination, he had several firm, mobile, and exquisitely tender lymph nodes in the right upper anterior cervical chain. Abdominal examination was notable for left upper quadrant tenderness with palpable splenomegaly. Due to initial concern that his symptoms represented bacterial lymphadenitis, he was started on broad-spectrum antibiotics and admitted to the hospital for an expedited infectious workup.

Initial laboratory studies were notable for a white blood cell count of 3.7 × 10⁹/L with 57.5% neutrophils and 27.0% lymphocytes on differential.

Discussion

KFD is a rare cause of cervical lymphadenitis that was first described in 1972. Although cases have been reported worldwide, it is seen with higher prevalence in Asian countries. KFD was previously thought to have a female predominance, but recent reviews suggest a female to male ratio close to 1:1.¹ The pathogenesis of KFD remains unknown, though some studies have suggested Epstein-Barr virus infection as a potential trigger.^4,5 Human herpesvirus (HHV) 6, HHV 7, HHV 8, HSV, HIV, and parvovirus B19 also have been implicated as potential triggers, though no causative relationship has been established.^2,5,6 Autoimmunity may also play a role in the pathogenesis of KFD given its histopathologic overlap with SLE lymphadenitis.^1,7

The most common presenting symptoms of KFD include fever and tender cervical lymphadenopathy. Many patients also experience constitutional symptoms such as weight loss, night sweats, and fatigue.² KFD is characterized by enlarged cervical lymph nodes, typically > 2 cm in diameter.³ Cutaneous manifestations of KFD are common and may manifest as nonspecific papules, plaques, nodules, or facial malar erythema.^1,2 Case reports also have described KFD manifesting with ataxia, arthritis, parotitis, or ocular pathologies such as conjunctivitis and uveitis.^1,2,8,9 Hepatosplenomegaly is a relatively rare manifestation of KFD seen in approximately 3% of cases.¹⁰ When present, hepatosplenomegaly may make the diagnosis of KFD especially difficult to distinguish from lymphoproliferative disorders such as lymphoma. Laboratory findings in KFD are nonspecific and include elevated levels of lactate dehydrogenase, erythrocyte sedimentation rate, C-reactive protein, and liver enzymes.³ Both lymphocytosis and lymphopenia have been described.³Definitive diagnosis of KFD is achieved through lymph node biopsy and histologic examination. Histopathologic findings of KFD include areas of coagulative necrosis and histiocytic proliferation within the cortical and paracortical regions of the lymph node. Scattered nuclear debris also may be seen, though this histologic finding also is seen with lymphoma. The absence of neutrophils is characteristic of KFD.² In our patient, a core needle biopsy was initially pursued but returned nondiagnostic. A PET-CT also was obtained, though KFD may mimic lymphoma on PET as was seen in this patient’s case as well as in prior case reports.¹¹ An excisional lymph node biopsy was ultimately performed and secured the diagnosis of KFD.

Although ultrasound-guided core needle biopsy was unable to yield the diagnosis for our patient, its diagnostic accuracy is still superior to that of fine needle aspiration and is therefore suggested as the primary diagnostic modality when KFD is suspected.¹² Core needle biopsy also is less invasive, less time consuming, and perhaps more cost-effective than an open excisional biopsy, which often requires the use of an operating room and monitored anesthesia care.¹² Understandably, our patient experienced significant stress while awaiting a final diagnosis. Whenever possible, lymph node biopsy should be prioritized over other diagnostic modalities to achieve a timely and definitive diagnosis.

KFD has no established treatment guidelines. Supportive care with antipyretics and analgesics is the most common initial approach, as KFD is typically a self-limited disease that resolves in 1 to 4 months.² Patients with severe, persistent symptoms have been successfully treated with corticosteroids and hydroxychloroquine, with monotherapy typically trialed before concomitant use.^2,13 After 2 courses of prednisone, our patient was prescribed single-agent hydroxychloroquine due to his recurrent symptoms and debilitating AEs from the steroids. Other case reports have described hydroxychloroquine as a treatment option when steroids fail to provide symptom relief or when there are recurrences of KFD.^14-19 Retinopathy can occur as a result of long-term hydroxychloroquine use. As such, patients anticipated to require long-term hydroxychloroquine therapy should receive a baseline eye examination within months of drug initiation and repeat examination after 5 years of therapy.²⁰

After symptom resolution, continued follow-up with a health care professional is recommended due to the potential for KFD recurrence or the development of a new autoimmune disease. The rate of KFD recurrence was previously described as 3%, but a more recent review found the rate of recurrence to be approximately 15% at > 6 months follow-up.^1,3 Recurrence is often described during or shortly after the tapering of steroids.^13,16,21,22 Recurrent KFD can be diagnosed with repeat lymph node biopsy, which also serves to exclude other disease processes.^13,16 However, recurrence also has been diagnosed clinically based on the patient’s symptoms and laboratory investigations.^21,22Continued surveillance of patients with KFD is also necessary to monitor for the development of new autoimmune diseases, especially SLE. SLE lymphadenitis shares many histopathologic characteristics with KFD. Case reports have described the development of SLE in patients with a history of KFD.^2,7 Other autoimmune conditions described in patients with prior KFD include Sjögren syndrome, Hashimoto thyroiditis, Graves disease, mixed connective tissue disease, and antiphospholipid syndrome.^3,23 Among patients with KFD, female sex, painful adenopathy, and cytopenias are significantly associated with the later development of autoimmune disease.²³

Patient Perspective

This began for me in September 2020 out of the blue. I woke up one day with a random lymph node in my neck but otherwise felt completely healthy, and within 2 to 3 weeks I had never been more sick in my entire life. It came with bouts of fevers, neck pain from the swelling, stomach pain (I later learned an enlarged spleen was the source), terrible night sweats, violent chills where the shaking was uncontrollable for hours at a time, loss of appetite, and countless other symptoms that have come and gone over the past year.

It did take a little while to get a diagnosis, but I understand the autoimmune field is tricky. For about 4 to 5 weeks, I was told to prepare for a lymphoma diagnosis. I ended up doing 2 rounds of prednisone, one for 3 weeks at the end of 2020 and one for 2 months from March to May. The initial round helped quite a bit, but the second round did not have any effect on the lingering symptoms. In my opinion, prednisone is miserable to be on long term and I do not recommend it. The daily AEs that came with it included mood swings, insomnia, weight gain, and more. I have been on hydroxychloroquine now for almost 2 months and although it has some AEs of its own, it is nowhere near as rough as the prednisone and has helped manage my remaining symptoms quite a bit.

This certainly has not been a fun experience, but I was under great care during my time in the hospital and continue to be under good care through the rheumatology clinic. The one thing that could have made a huge difference would have been the issues involved in getting my surgery scheduled while I was still inpatient, which took quite a while. The pain during that time was so intense and unlike anything I have ever experienced before, and it was only the surgery that finally brought me some relief. To paint you a picture, I have broken bones, split my leg open, and have roughly 40 to 50 hours of tattoo work on me, and I have never experienced the level of pain like I felt in my neck and stomach. I remember feeling like someone had wound up and hit me with a baseball bat. The surgery brought me immense relief and if it had occurred when it was originally supposed to, I would have been spared 3 or so days of this type of pain.

It has been almost 10 months since my surgery and diagnosis, and life has mostly returned to normal for me. I am still on long-term medication as I mentioned, and I still deal with fatigue, spleen pain, and several other symptoms, but it is much more under control these days. I feel very fortunate to have been under and continue to be under such great care.

Conclusions

This case report highlights the importance of recognizing KFD as a rare but possible cause of fever and necrotizing cervical lymphadenopathy. KFD often mimics malignant lymphoproliferative disorders, autoimmune diseases such as SLE lymphadenitis, and infectious conditions such as HIV and tuberculous lymphadenitis. While KFD is seen with higher prevalence in Asian countries and was previously thought to be more predominant in females, the diagnosis should still be considered irrespective of geographic location or patient sex. Lymph node biopsy is the preferred diagnostic approach for patients with suspected KFD. Treatment is typically supportive but may consist of glucocorticoids in severe cases. Hydroxychloroquine may be used in refractory cases or as a steroid-sparing regimen when steroid AEs are poorly tolerated. Long-term follow-up is critical for patients with KFD to monitor for both disease recurrence and the development of autoimmune disease, especially SLE.

Acknowledgments

The authors thank Dr. Jacob Pilley for his detailed review of the patient’s pathology results. The authors also extend their gratitude to the patient, who deepened our understanding of this condition and what it is like to live with it.

Kikuchi-Fujimoto disease (KFD) is a rare, usually self-limited cause of cervical lymphadenitis that is more prevalent among patients of Asian descent.¹ The pathogenesis of KFD remains unknown. Clinically, KFD may mimic malignant lymphoproliferative disorders, autoimmune diseases such as systemic lupus erythematosus (SLE) lymphadenitis, and infectious conditions such as HIV and tuberculous lymphadenitis. The most common presentation of KFD involves fever and rapidly evolving cervical lymphadenopathy.^2,3 Due to its rarity, KFD is not always considered in the differential diagnosis for fever with tender lymphadenopathy, and up to one-third of cases are initially misdiagnosed.²

Definitive diagnosis requires lymph node biopsy. It is critical to achieving a timely diagnosis of KFD to exclude more serious conditions, initiate appropriate treatment, and minimize undue stress for patients. We describe a case of KFD in a patient who was met with delays in obtaining a definitive diagnosis for his symptoms.

Case Presentation

A 27-year-old previously healthy White man presented to the emergency department with subacute, progressive right-sided neck pain and swelling. In the week leading up to presentation, he also noted intermittent fevers, night sweats, and abdominal pain. His symptoms were unrelieved with acetaminophen and aspirin. He reported no sick contacts, recent travel, or animal exposures. He had no known history of autoimmune disease, malignancy, or immunocompromising conditions. Vital signs at the time of presentation were notable for a temperature of 39.0 °C. On examination, he had several firm, mobile, and exquisitely tender lymph nodes in the right upper anterior cervical chain. Abdominal examination was notable for left upper quadrant tenderness with palpable splenomegaly. Due to initial concern that his symptoms represented bacterial lymphadenitis, he was started on broad-spectrum antibiotics and admitted to the hospital for an expedited infectious workup.

Initial laboratory studies were notable for a white blood cell count of 3.7 × 10⁹/L with 57.5% neutrophils and 27.0% lymphocytes on differential.

Discussion

KFD is a rare cause of cervical lymphadenitis that was first described in 1972. Although cases have been reported worldwide, it is seen with higher prevalence in Asian countries. KFD was previously thought to have a female predominance, but recent reviews suggest a female to male ratio close to 1:1.¹ The pathogenesis of KFD remains unknown, though some studies have suggested Epstein-Barr virus infection as a potential trigger.^4,5 Human herpesvirus (HHV) 6, HHV 7, HHV 8, HSV, HIV, and parvovirus B19 also have been implicated as potential triggers, though no causative relationship has been established.^2,5,6 Autoimmunity may also play a role in the pathogenesis of KFD given its histopathologic overlap with SLE lymphadenitis.^1,7

The most common presenting symptoms of KFD include fever and tender cervical lymphadenopathy. Many patients also experience constitutional symptoms such as weight loss, night sweats, and fatigue.² KFD is characterized by enlarged cervical lymph nodes, typically > 2 cm in diameter.³ Cutaneous manifestations of KFD are common and may manifest as nonspecific papules, plaques, nodules, or facial malar erythema.^1,2 Case reports also have described KFD manifesting with ataxia, arthritis, parotitis, or ocular pathologies such as conjunctivitis and uveitis.^1,2,8,9 Hepatosplenomegaly is a relatively rare manifestation of KFD seen in approximately 3% of cases.¹⁰ When present, hepatosplenomegaly may make the diagnosis of KFD especially difficult to distinguish from lymphoproliferative disorders such as lymphoma. Laboratory findings in KFD are nonspecific and include elevated levels of lactate dehydrogenase, erythrocyte sedimentation rate, C-reactive protein, and liver enzymes.³ Both lymphocytosis and lymphopenia have been described.³Definitive diagnosis of KFD is achieved through lymph node biopsy and histologic examination. Histopathologic findings of KFD include areas of coagulative necrosis and histiocytic proliferation within the cortical and paracortical regions of the lymph node. Scattered nuclear debris also may be seen, though this histologic finding also is seen with lymphoma. The absence of neutrophils is characteristic of KFD.² In our patient, a core needle biopsy was initially pursued but returned nondiagnostic. A PET-CT also was obtained, though KFD may mimic lymphoma on PET as was seen in this patient’s case as well as in prior case reports.¹¹ An excisional lymph node biopsy was ultimately performed and secured the diagnosis of KFD.

Although ultrasound-guided core needle biopsy was unable to yield the diagnosis for our patient, its diagnostic accuracy is still superior to that of fine needle aspiration and is therefore suggested as the primary diagnostic modality when KFD is suspected.¹² Core needle biopsy also is less invasive, less time consuming, and perhaps more cost-effective than an open excisional biopsy, which often requires the use of an operating room and monitored anesthesia care.¹² Understandably, our patient experienced significant stress while awaiting a final diagnosis. Whenever possible, lymph node biopsy should be prioritized over other diagnostic modalities to achieve a timely and definitive diagnosis.

KFD has no established treatment guidelines. Supportive care with antipyretics and analgesics is the most common initial approach, as KFD is typically a self-limited disease that resolves in 1 to 4 months.² Patients with severe, persistent symptoms have been successfully treated with corticosteroids and hydroxychloroquine, with monotherapy typically trialed before concomitant use.^2,13 After 2 courses of prednisone, our patient was prescribed single-agent hydroxychloroquine due to his recurrent symptoms and debilitating AEs from the steroids. Other case reports have described hydroxychloroquine as a treatment option when steroids fail to provide symptom relief or when there are recurrences of KFD.^14-19 Retinopathy can occur as a result of long-term hydroxychloroquine use. As such, patients anticipated to require long-term hydroxychloroquine therapy should receive a baseline eye examination within months of drug initiation and repeat examination after 5 years of therapy.²⁰

After symptom resolution, continued follow-up with a health care professional is recommended due to the potential for KFD recurrence or the development of a new autoimmune disease. The rate of KFD recurrence was previously described as 3%, but a more recent review found the rate of recurrence to be approximately 15% at > 6 months follow-up.^1,3 Recurrence is often described during or shortly after the tapering of steroids.^13,16,21,22 Recurrent KFD can be diagnosed with repeat lymph node biopsy, which also serves to exclude other disease processes.^13,16 However, recurrence also has been diagnosed clinically based on the patient’s symptoms and laboratory investigations.^21,22Continued surveillance of patients with KFD is also necessary to monitor for the development of new autoimmune diseases, especially SLE. SLE lymphadenitis shares many histopathologic characteristics with KFD. Case reports have described the development of SLE in patients with a history of KFD.^2,7 Other autoimmune conditions described in patients with prior KFD include Sjögren syndrome, Hashimoto thyroiditis, Graves disease, mixed connective tissue disease, and antiphospholipid syndrome.^3,23 Among patients with KFD, female sex, painful adenopathy, and cytopenias are significantly associated with the later development of autoimmune disease.²³

Patient Perspective

This began for me in September 2020 out of the blue. I woke up one day with a random lymph node in my neck but otherwise felt completely healthy, and within 2 to 3 weeks I had never been more sick in my entire life. It came with bouts of fevers, neck pain from the swelling, stomach pain (I later learned an enlarged spleen was the source), terrible night sweats, violent chills where the shaking was uncontrollable for hours at a time, loss of appetite, and countless other symptoms that have come and gone over the past year.

It did take a little while to get a diagnosis, but I understand the autoimmune field is tricky. For about 4 to 5 weeks, I was told to prepare for a lymphoma diagnosis. I ended up doing 2 rounds of prednisone, one for 3 weeks at the end of 2020 and one for 2 months from March to May. The initial round helped quite a bit, but the second round did not have any effect on the lingering symptoms. In my opinion, prednisone is miserable to be on long term and I do not recommend it. The daily AEs that came with it included mood swings, insomnia, weight gain, and more. I have been on hydroxychloroquine now for almost 2 months and although it has some AEs of its own, it is nowhere near as rough as the prednisone and has helped manage my remaining symptoms quite a bit.

This certainly has not been a fun experience, but I was under great care during my time in the hospital and continue to be under good care through the rheumatology clinic. The one thing that could have made a huge difference would have been the issues involved in getting my surgery scheduled while I was still inpatient, which took quite a while. The pain during that time was so intense and unlike anything I have ever experienced before, and it was only the surgery that finally brought me some relief. To paint you a picture, I have broken bones, split my leg open, and have roughly 40 to 50 hours of tattoo work on me, and I have never experienced the level of pain like I felt in my neck and stomach. I remember feeling like someone had wound up and hit me with a baseball bat. The surgery brought me immense relief and if it had occurred when it was originally supposed to, I would have been spared 3 or so days of this type of pain.

It has been almost 10 months since my surgery and diagnosis, and life has mostly returned to normal for me. I am still on long-term medication as I mentioned, and I still deal with fatigue, spleen pain, and several other symptoms, but it is much more under control these days. I feel very fortunate to have been under and continue to be under such great care.

Conclusions

This case report highlights the importance of recognizing KFD as a rare but possible cause of fever and necrotizing cervical lymphadenopathy. KFD often mimics malignant lymphoproliferative disorders, autoimmune diseases such as SLE lymphadenitis, and infectious conditions such as HIV and tuberculous lymphadenitis. While KFD is seen with higher prevalence in Asian countries and was previously thought to be more predominant in females, the diagnosis should still be considered irrespective of geographic location or patient sex. Lymph node biopsy is the preferred diagnostic approach for patients with suspected KFD. Treatment is typically supportive but may consist of glucocorticoids in severe cases. Hydroxychloroquine may be used in refractory cases or as a steroid-sparing regimen when steroid AEs are poorly tolerated. Long-term follow-up is critical for patients with KFD to monitor for both disease recurrence and the development of autoimmune disease, especially SLE.

Acknowledgments

The authors thank Dr. Jacob Pilley for his detailed review of the patient’s pathology results. The authors also extend their gratitude to the patient, who deepened our understanding of this condition and what it is like to live with it.

Highlights in follicular lymphoma from the 2022 American Society of Hematology (ASH) Annual Meeting are discussed by Dr Thomas Rodgers of the Durham VA Medical Center. 

Dr Rodgers begins with a prognostic model designed to evaluate the risk for disease progression in high-risk patients within 24 months of starting first-line treatment with the intention of better individualizing management in this group. 

Next, he presents long-term phase 3 data comparing first-line rituximab with a watch-and-wait approach. After 12 years of follow-up, results showed no significant difference in overall survival between watch and wait, rituximab induction, and rituximab induction plus maintenance, suggesting to Dr Rodgers that individualized upfront management can lead to similarly excellent outcomes in patients with low tumor burden. 

Turning to relapsed/refractory disease, Dr Rodgers cites a study comparing rituximab plus lenalidomide with rituximab plus placebo. The combination yielded superior results and more durable efficacy than did the control group.  

He also discusses studies on the use of novel agent tazemetostat in combination with lenalidomide, and the bispecific monoclonal antibody mosunetuzumab as monotherapy. The US Food and Drug Administration approved mosunetuzumab in December, expanding the armamentarium for patients with follicular lymphoma who have undergone multiple lines of therapy.  

--

Thomas Rodgers, MD, Assistant Professor, Department of Hematologic Malignancies and Cellular Therapy, Duke University; Staff Physician, Department of Hematology/Oncology, Durham VA Medical Center, Durham, North Carolina 

Thomas Rodgers, MD, has disclosed no relevant financial relationships. 

Highlights in follicular lymphoma from the 2022 American Society of Hematology (ASH) Annual Meeting are discussed by Dr Thomas Rodgers of the Durham VA Medical Center. 

Dr Rodgers begins with a prognostic model designed to evaluate the risk for disease progression in high-risk patients within 24 months of starting first-line treatment with the intention of better individualizing management in this group. 

Next, he presents long-term phase 3 data comparing first-line rituximab with a watch-and-wait approach. After 12 years of follow-up, results showed no significant difference in overall survival between watch and wait, rituximab induction, and rituximab induction plus maintenance, suggesting to Dr Rodgers that individualized upfront management can lead to similarly excellent outcomes in patients with low tumor burden. 

Turning to relapsed/refractory disease, Dr Rodgers cites a study comparing rituximab plus lenalidomide with rituximab plus placebo. The combination yielded superior results and more durable efficacy than did the control group.  

He also discusses studies on the use of novel agent tazemetostat in combination with lenalidomide, and the bispecific monoclonal antibody mosunetuzumab as monotherapy. The US Food and Drug Administration approved mosunetuzumab in December, expanding the armamentarium for patients with follicular lymphoma who have undergone multiple lines of therapy.  

--

Thomas Rodgers, MD, Assistant Professor, Department of Hematologic Malignancies and Cellular Therapy, Duke University; Staff Physician, Department of Hematology/Oncology, Durham VA Medical Center, Durham, North Carolina 

Thomas Rodgers, MD, has disclosed no relevant financial relationships. 

Highlights in follicular lymphoma from the 2022 American Society of Hematology (ASH) Annual Meeting are discussed by Dr Thomas Rodgers of the Durham VA Medical Center. 

Dr Rodgers begins with a prognostic model designed to evaluate the risk for disease progression in high-risk patients within 24 months of starting first-line treatment with the intention of better individualizing management in this group. 

Next, he presents long-term phase 3 data comparing first-line rituximab with a watch-and-wait approach. After 12 years of follow-up, results showed no significant difference in overall survival between watch and wait, rituximab induction, and rituximab induction plus maintenance, suggesting to Dr Rodgers that individualized upfront management can lead to similarly excellent outcomes in patients with low tumor burden. 

Turning to relapsed/refractory disease, Dr Rodgers cites a study comparing rituximab plus lenalidomide with rituximab plus placebo. The combination yielded superior results and more durable efficacy than did the control group.  

He also discusses studies on the use of novel agent tazemetostat in combination with lenalidomide, and the bispecific monoclonal antibody mosunetuzumab as monotherapy. The US Food and Drug Administration approved mosunetuzumab in December, expanding the armamentarium for patients with follicular lymphoma who have undergone multiple lines of therapy.  

--

Thomas Rodgers, MD, Assistant Professor, Department of Hematologic Malignancies and Cellular Therapy, Duke University; Staff Physician, Department of Hematology/Oncology, Durham VA Medical Center, Durham, North Carolina 

Thomas Rodgers, MD, has disclosed no relevant financial relationships. 

Screening for amblyopia during primary care visits is more cost-effective than screening in school settings and optometric examinations in kindergarten-aged children in Toronto, data suggest.

Because of the low prevalence of amblyopia among young children, a population-based screening program may not warrant the resources required, despite the added health benefits of a universal program, according to the researchers.

“Amblyopia is a public health problem. For this reason, population-wide approaches to detect and treat amblyopia are critical, and approaches such as school screening and mandated optometry exams have been recommended and introduced in some jurisdictions,” study author Afua Oteng Asare, OD, PhD, a research assistant professor at the University of Utah in Salt Lake City, told this news organization. Dr. Asare conducted the study as a PhD student at the University of Toronto.

“With increasing budgeting constraints and limited resources, policymakers are relying more on economic analyses that measure value-for-money to inform their decisions on programming,” she said. “Evidence comparing the cost-effectiveness of vision-testing approaches to the status quo is, however, limited.”

The study was published in JAMA Network Open.
 

Analyzing costs

Despite recommendations for routine testing, a notable percentage of children in Canada and the United States don’t receive an annual vision exam. The percentage is even higher among children from low-income households, said Dr. Asare. Universal screening in schools and mandatory optometric examinations may improve vision care. But the cost-effectiveness of these measures is unknown for certain conditions, such as amblyopia, the prevalence of which ranges between 3% and 5% in young children.

In Ontario, Canada’s largest province with about 3 million children, universal funding for children’s annual comprehensive eye exams and vision screening during well-child visits is provided through provincial health insurance.

In 2018, the Ontario Ministry of Health introduced guidelines for administering vision screening in kindergartens by public health departments. However, school-based screening has been difficult to introduce because of increasing costs and budgeting constraints, the authors wrote. As an alternative to underfunded programs, optometric associations in Canada have advocated for physicians to recommend early childhood optometric exams.

The investigators analyzed the incremental costs and health benefits, from the perspective of the Ontario government, of public health school screening and optometrist-based vision exams, compared with standard vision screening conducted during well-child visits with primary care physicians. They focused on the aim of detecting amblyopia and amblyopia-related risk factors in children between ages 3 and 5 years in Toronto.

For the analysis, the research team simulated a hypothetical cohort of 25,000 children over 15 years in a probabilistic health state transition model. They incorporated various assumptions, including that children had irreversible vision impairment if not diagnosed by an optometrist. In addition, incremental costs were adjusted to favor the standard screening strategy during well-child visits.

In the school-based and primary care scenarios, children with a positive or inconclusive test result were referred to an optometrist for diagnosis and treatment, which would incur the cost of an optometric evaluation. If positive, children were treated with prescription glasses and additional patching for amblyopia.

The research team measured outcomes as incremental quality-adjusted life-years (QALYs), and health utilities were derived from data on adults, because of the lack of data on children under age 6 years with amblyopia or amblyopia risk factors. The researchers also estimated direct costs to the Ontario government, including visits with primary care doctors, optometrists, public health nurses, and contract screeners, as well as prescription glasses for children with vision impairment who receive social assistance. Costs were expressed in Canadian dollars (CAD).

Overall, compared with the primary care screening strategy, the school screening and optometric examination strategies were generally less costly and had more health benefits. The incremental difference in cost was a savings per child of $84.09 CAD for school screening and $74.47 CAD for optometric examinations. Optometric examinations yielded the largest gain in QALYs, compared with the primary care screening strategy, producing average QALYs of 0.0508 per child.

However, only 20% of school screening iterations and 29% of optometric exam iterations were cost-effective, relative to the primary care screening strategy, at a willingness-to-pay threshold of $50,000 CAD per QALY gained. For instance, when comparing optometric exams with primary care screenings, if the cost of vision screening was $11.50 CAD, the incremental cost-effectiveness ratio would be $77.95 CAD per QALY gained.
 

Results ‘make sense’  

“We were initially surprised that the alternative screening programs were not cost-effective, compared to status quo vision screening in well-child visits,” said Dr. Asare. “However, the results make sense, considering the study’s universal approach (screening all children regardless of their vision status) and the study’s consideration only of amblyopia, and not of refractive errors, which are even more common in kindergarten children.”

Dr. Asare noted the lack of current data on the rate of vision screenings conducted in childhood by primary care practitioners and on referrals to eye care providers for children with abnormal screenings. Data on vision health disparities and barriers to accessing vision care in young children also are scarce.

“My ultimate research goal is to create and evaluate evidence-based, cost-effective interventions to be used at the point of care by pediatric primary care providers to improve the quality of vision care for children, especially those from socioeconomically deprived backgrounds,” she said. “The take-home message is that school vision screening and mandated eye exams are excellent programs, but they may not be suitable for all contexts.”

Additional studies are needed to look at the cost-effectiveness of the different screening strategies for other aspects included in childhood vision tests, including binocular vision problems, refractive disorders, myopia, allergies, and rare eye diseases.
 

Significant underestimation?

Susan Leat, PhD, a researcher and professor emerita at the University of Waterloo (Ont.) School of Optometry and Vision Science, said, “This study only considers amblyopia, and not all eye diseases and disorders, which significantly underestimates the cost-effectiveness of optometric eye exams.”

Dr. Leat, who wasn’t involved with this study, has researched pediatric optometry and visual development. She and colleagues are developing new tools to test visual acuity in young children.

“If all disorders were taken into account, then optometric testing would be by far the most cost-effective,” she said. “Optometrists can detect all disorders, including more subtle disorders, which if uncorrected or untreated, can impact a child’s early learning.”

The study authors reported no funding for the study. Dr. Asare and Dr. Leat reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

Screening for amblyopia during primary care visits is more cost-effective than screening in school settings and optometric examinations in kindergarten-aged children in Toronto, data suggest.

Because of the low prevalence of amblyopia among young children, a population-based screening program may not warrant the resources required, despite the added health benefits of a universal program, according to the researchers.

“Amblyopia is a public health problem. For this reason, population-wide approaches to detect and treat amblyopia are critical, and approaches such as school screening and mandated optometry exams have been recommended and introduced in some jurisdictions,” study author Afua Oteng Asare, OD, PhD, a research assistant professor at the University of Utah in Salt Lake City, told this news organization. Dr. Asare conducted the study as a PhD student at the University of Toronto.

“With increasing budgeting constraints and limited resources, policymakers are relying more on economic analyses that measure value-for-money to inform their decisions on programming,” she said. “Evidence comparing the cost-effectiveness of vision-testing approaches to the status quo is, however, limited.”

The study was published in JAMA Network Open.
 

Analyzing costs

Despite recommendations for routine testing, a notable percentage of children in Canada and the United States don’t receive an annual vision exam. The percentage is even higher among children from low-income households, said Dr. Asare. Universal screening in schools and mandatory optometric examinations may improve vision care. But the cost-effectiveness of these measures is unknown for certain conditions, such as amblyopia, the prevalence of which ranges between 3% and 5% in young children.

In Ontario, Canada’s largest province with about 3 million children, universal funding for children’s annual comprehensive eye exams and vision screening during well-child visits is provided through provincial health insurance.

In 2018, the Ontario Ministry of Health introduced guidelines for administering vision screening in kindergartens by public health departments. However, school-based screening has been difficult to introduce because of increasing costs and budgeting constraints, the authors wrote. As an alternative to underfunded programs, optometric associations in Canada have advocated for physicians to recommend early childhood optometric exams.

The investigators analyzed the incremental costs and health benefits, from the perspective of the Ontario government, of public health school screening and optometrist-based vision exams, compared with standard vision screening conducted during well-child visits with primary care physicians. They focused on the aim of detecting amblyopia and amblyopia-related risk factors in children between ages 3 and 5 years in Toronto.

For the analysis, the research team simulated a hypothetical cohort of 25,000 children over 15 years in a probabilistic health state transition model. They incorporated various assumptions, including that children had irreversible vision impairment if not diagnosed by an optometrist. In addition, incremental costs were adjusted to favor the standard screening strategy during well-child visits.

In the school-based and primary care scenarios, children with a positive or inconclusive test result were referred to an optometrist for diagnosis and treatment, which would incur the cost of an optometric evaluation. If positive, children were treated with prescription glasses and additional patching for amblyopia.

The research team measured outcomes as incremental quality-adjusted life-years (QALYs), and health utilities were derived from data on adults, because of the lack of data on children under age 6 years with amblyopia or amblyopia risk factors. The researchers also estimated direct costs to the Ontario government, including visits with primary care doctors, optometrists, public health nurses, and contract screeners, as well as prescription glasses for children with vision impairment who receive social assistance. Costs were expressed in Canadian dollars (CAD).

Overall, compared with the primary care screening strategy, the school screening and optometric examination strategies were generally less costly and had more health benefits. The incremental difference in cost was a savings per child of $84.09 CAD for school screening and $74.47 CAD for optometric examinations. Optometric examinations yielded the largest gain in QALYs, compared with the primary care screening strategy, producing average QALYs of 0.0508 per child.

However, only 20% of school screening iterations and 29% of optometric exam iterations were cost-effective, relative to the primary care screening strategy, at a willingness-to-pay threshold of $50,000 CAD per QALY gained. For instance, when comparing optometric exams with primary care screenings, if the cost of vision screening was $11.50 CAD, the incremental cost-effectiveness ratio would be $77.95 CAD per QALY gained.
 

Results ‘make sense’  

“We were initially surprised that the alternative screening programs were not cost-effective, compared to status quo vision screening in well-child visits,” said Dr. Asare. “However, the results make sense, considering the study’s universal approach (screening all children regardless of their vision status) and the study’s consideration only of amblyopia, and not of refractive errors, which are even more common in kindergarten children.”

Dr. Asare noted the lack of current data on the rate of vision screenings conducted in childhood by primary care practitioners and on referrals to eye care providers for children with abnormal screenings. Data on vision health disparities and barriers to accessing vision care in young children also are scarce.

“My ultimate research goal is to create and evaluate evidence-based, cost-effective interventions to be used at the point of care by pediatric primary care providers to improve the quality of vision care for children, especially those from socioeconomically deprived backgrounds,” she said. “The take-home message is that school vision screening and mandated eye exams are excellent programs, but they may not be suitable for all contexts.”

Additional studies are needed to look at the cost-effectiveness of the different screening strategies for other aspects included in childhood vision tests, including binocular vision problems, refractive disorders, myopia, allergies, and rare eye diseases.
 

Significant underestimation?

Susan Leat, PhD, a researcher and professor emerita at the University of Waterloo (Ont.) School of Optometry and Vision Science, said, “This study only considers amblyopia, and not all eye diseases and disorders, which significantly underestimates the cost-effectiveness of optometric eye exams.”

Dr. Leat, who wasn’t involved with this study, has researched pediatric optometry and visual development. She and colleagues are developing new tools to test visual acuity in young children.

“If all disorders were taken into account, then optometric testing would be by far the most cost-effective,” she said. “Optometrists can detect all disorders, including more subtle disorders, which if uncorrected or untreated, can impact a child’s early learning.”

The study authors reported no funding for the study. Dr. Asare and Dr. Leat reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

Screening for amblyopia during primary care visits is more cost-effective than screening in school settings and optometric examinations in kindergarten-aged children in Toronto, data suggest.

Because of the low prevalence of amblyopia among young children, a population-based screening program may not warrant the resources required, despite the added health benefits of a universal program, according to the researchers.

“Amblyopia is a public health problem. For this reason, population-wide approaches to detect and treat amblyopia are critical, and approaches such as school screening and mandated optometry exams have been recommended and introduced in some jurisdictions,” study author Afua Oteng Asare, OD, PhD, a research assistant professor at the University of Utah in Salt Lake City, told this news organization. Dr. Asare conducted the study as a PhD student at the University of Toronto.

“With increasing budgeting constraints and limited resources, policymakers are relying more on economic analyses that measure value-for-money to inform their decisions on programming,” she said. “Evidence comparing the cost-effectiveness of vision-testing approaches to the status quo is, however, limited.”

The study was published in JAMA Network Open.
 

Analyzing costs

Despite recommendations for routine testing, a notable percentage of children in Canada and the United States don’t receive an annual vision exam. The percentage is even higher among children from low-income households, said Dr. Asare. Universal screening in schools and mandatory optometric examinations may improve vision care. But the cost-effectiveness of these measures is unknown for certain conditions, such as amblyopia, the prevalence of which ranges between 3% and 5% in young children.

In Ontario, Canada’s largest province with about 3 million children, universal funding for children’s annual comprehensive eye exams and vision screening during well-child visits is provided through provincial health insurance.

In 2018, the Ontario Ministry of Health introduced guidelines for administering vision screening in kindergartens by public health departments. However, school-based screening has been difficult to introduce because of increasing costs and budgeting constraints, the authors wrote. As an alternative to underfunded programs, optometric associations in Canada have advocated for physicians to recommend early childhood optometric exams.

The investigators analyzed the incremental costs and health benefits, from the perspective of the Ontario government, of public health school screening and optometrist-based vision exams, compared with standard vision screening conducted during well-child visits with primary care physicians. They focused on the aim of detecting amblyopia and amblyopia-related risk factors in children between ages 3 and 5 years in Toronto.

For the analysis, the research team simulated a hypothetical cohort of 25,000 children over 15 years in a probabilistic health state transition model. They incorporated various assumptions, including that children had irreversible vision impairment if not diagnosed by an optometrist. In addition, incremental costs were adjusted to favor the standard screening strategy during well-child visits.

In the school-based and primary care scenarios, children with a positive or inconclusive test result were referred to an optometrist for diagnosis and treatment, which would incur the cost of an optometric evaluation. If positive, children were treated with prescription glasses and additional patching for amblyopia.

The research team measured outcomes as incremental quality-adjusted life-years (QALYs), and health utilities were derived from data on adults, because of the lack of data on children under age 6 years with amblyopia or amblyopia risk factors. The researchers also estimated direct costs to the Ontario government, including visits with primary care doctors, optometrists, public health nurses, and contract screeners, as well as prescription glasses for children with vision impairment who receive social assistance. Costs were expressed in Canadian dollars (CAD).

Overall, compared with the primary care screening strategy, the school screening and optometric examination strategies were generally less costly and had more health benefits. The incremental difference in cost was a savings per child of $84.09 CAD for school screening and $74.47 CAD for optometric examinations. Optometric examinations yielded the largest gain in QALYs, compared with the primary care screening strategy, producing average QALYs of 0.0508 per child.

However, only 20% of school screening iterations and 29% of optometric exam iterations were cost-effective, relative to the primary care screening strategy, at a willingness-to-pay threshold of $50,000 CAD per QALY gained. For instance, when comparing optometric exams with primary care screenings, if the cost of vision screening was $11.50 CAD, the incremental cost-effectiveness ratio would be $77.95 CAD per QALY gained.
 

Results ‘make sense’  

“We were initially surprised that the alternative screening programs were not cost-effective, compared to status quo vision screening in well-child visits,” said Dr. Asare. “However, the results make sense, considering the study’s universal approach (screening all children regardless of their vision status) and the study’s consideration only of amblyopia, and not of refractive errors, which are even more common in kindergarten children.”

Dr. Asare noted the lack of current data on the rate of vision screenings conducted in childhood by primary care practitioners and on referrals to eye care providers for children with abnormal screenings. Data on vision health disparities and barriers to accessing vision care in young children also are scarce.

“My ultimate research goal is to create and evaluate evidence-based, cost-effective interventions to be used at the point of care by pediatric primary care providers to improve the quality of vision care for children, especially those from socioeconomically deprived backgrounds,” she said. “The take-home message is that school vision screening and mandated eye exams are excellent programs, but they may not be suitable for all contexts.”

Additional studies are needed to look at the cost-effectiveness of the different screening strategies for other aspects included in childhood vision tests, including binocular vision problems, refractive disorders, myopia, allergies, and rare eye diseases.
 

Significant underestimation?

Susan Leat, PhD, a researcher and professor emerita at the University of Waterloo (Ont.) School of Optometry and Vision Science, said, “This study only considers amblyopia, and not all eye diseases and disorders, which significantly underestimates the cost-effectiveness of optometric eye exams.”

Dr. Leat, who wasn’t involved with this study, has researched pediatric optometry and visual development. She and colleagues are developing new tools to test visual acuity in young children.

“If all disorders were taken into account, then optometric testing would be by far the most cost-effective,” she said. “Optometrists can detect all disorders, including more subtle disorders, which if uncorrected or untreated, can impact a child’s early learning.”

The study authors reported no funding for the study. Dr. Asare and Dr. Leat reported no relevant disclosures.

A version of this article first appeared on Medscape.com.